Activity

Filter

Cancel
Date Panel Item Activity
3000 actions
Breast Cancer v0.19 NF1 Chirag Patel Gene: nf1 has been classified as Green List (High Evidence).
Breast Cancer v0.18 PALB2 Chirag Patel Classified gene: PALB2 as Green List (high evidence)
Breast Cancer v0.18 PALB2 Chirag Patel Gene: palb2 has been classified as Green List (High Evidence).
Breast Cancer v0.17 PTEN Chirag Patel Classified gene: PTEN as Green List (high evidence)
Breast Cancer v0.17 PTEN Chirag Patel Gene: pten has been classified as Green List (High Evidence).
Breast Cancer v0.16 RAD51C Chirag Patel Classified gene: RAD51C as Green List (high evidence)
Breast Cancer v0.16 RAD51C Chirag Patel Gene: rad51c has been classified as Green List (High Evidence).
Breast Cancer v0.15 RAD51D Chirag Patel Classified gene: RAD51D as Green List (high evidence)
Breast Cancer v0.15 RAD51D Chirag Patel Gene: rad51d has been classified as Green List (High Evidence).
Breast Cancer v0.14 STK11 Chirag Patel Classified gene: STK11 as Green List (high evidence)
Breast Cancer v0.14 STK11 Chirag Patel Gene: stk11 has been classified as Green List (High Evidence).
Breast Cancer v0.13 TP53 Chirag Patel Classified gene: TP53 as Green List (high evidence)
Breast Cancer v0.13 TP53 Chirag Patel Gene: tp53 has been classified as Green List (High Evidence).
Breast Cancer v0.12 TP53 Chirag Patel gene: TP53 was added
gene: TP53 was added to Breast Cancer. Sources: Expert list,Expert Review
Mode of inheritance for gene: TP53 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: TP53 were set to Breast cancer, MONDO:0007254; Li-Fraumeni syndrome, MONDO:0018875; Li-Fraumeni syndrome, MIM#151623
Review for gene: TP53 was set to GREEN
Added comment: ClinGen definitive. Breast cancers reported in condition.

Consider possibility that an identified variant could represent ACE (aberrant clonal expansion), which can be due to clonal haematopoiesis of indeterminate potential (CHIP) or an occult hematologic malignancy, especially in older patients who have undergone prior chemotherapy (PMID: 36040522).
Sources: Expert list, Expert Review
Breast Cancer v0.11 STK11 Chirag Patel gene: STK11 was added
gene: STK11 was added to Breast Cancer. Sources: Expert list,Expert Review
Mode of inheritance for gene: STK11 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: STK11 were set to Breast cancer, MONDO:0007254; Peutz-Jeghers syndrome, MONDO:0008280; Peutz-Jeghers syndrome, MIM#175200
Review for gene: STK11 was set to GREEN
Added comment: ClinGen definitive. Breast cancers reported in condition.

Single gene testing may be more appropriate if clinical features of JPS.
Sources: Expert list, Expert Review
Breast Cancer v0.10 RAD51D Chirag Patel gene: RAD51D was added
gene: RAD51D was added to Breast Cancer. Sources: Expert list,Expert Review
Mode of inheritance for gene: RAD51D was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: RAD51D were set to Breast cancer, MONDO:0007254; RAD51D-related cancer predisposition, MONDO:0700274; Breast-ovarian cancer, familial, susceptibility to, 4, MONDO:0013669; Breast-ovarian cancer, familial, susceptibility to, 4, MIM#614291
Review for gene: RAD51D was set to GREEN
Added comment: ClinGen definitive. Breast cancers reported in condition.
Sources: Expert list, Expert Review
Breast Cancer v0.9 RAD51C Chirag Patel gene: RAD51C was added
gene: RAD51C was added to Breast Cancer. Sources: Expert list,Expert Review
Mode of inheritance for gene: RAD51C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: RAD51C were set to Breast cancer, MONDO:0007254; RAD51C-related cancer predisposition, MONDO:0700273; Breast-ovarian cancer, familial, susceptibility to, 3, MONDO:0013253; Breast-ovarian cancer, familial, susceptibility to, 3, MIM#613399
Review for gene: RAD51C was set to GREEN
Added comment: ClinGen definitive. Breast cancers reported in condition.
Sources: Expert list, Expert Review
Breast Cancer v0.8 PTEN Chirag Patel gene: PTEN was added
gene: PTEN was added to Breast Cancer. Sources: Expert list,Expert Review
Mode of inheritance for gene: PTEN was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: PTEN were set to Breast cancer, MONDO:0007254; PTEN hamartoma tumor syndrome, MONDO:0017623; PTEN hamartoma tumour syndromes, MIM#158350
Review for gene: PTEN was set to GREEN
Added comment: ClinGen definitive. Breast cancers reported in condition.
Sources: Expert list, Expert Review
Breast Cancer v0.7 PALB2 Chirag Patel gene: PALB2 was added
gene: PALB2 was added to Breast Cancer. Sources: Expert list,Expert Review
Mode of inheritance for gene: PALB2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: PALB2 were set to Breast cancer, MONDO:0007254; PALB2-related cancer predisposition, MONDO:0700272; Breast-ovarian cancer, familial, susceptibility to, 5, MIM#620442; Pancreatic cancer, susceptibility to, 3, MIM#613348
Review for gene: PALB2 was set to GREEN
Added comment: ClinGen definitive. Breast cancers reported in condition.
Sources: Expert list, Expert Review
Breast Cancer v0.6 NF1 Chirag Patel gene: NF1 was added
gene: NF1 was added to Breast Cancer. Sources: Expert list,Expert Review
Mode of inheritance for gene: NF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: NF1 were set to Breast cancer, MONDO:0007254; Neurofibromatosis type 1, MONDO:0018975; Neurofibromatosis, type 1, MIM#162200
Review for gene: NF1 was set to GREEN
Added comment: ClinGen definitive. Breast cancers reported in condition.

Single gene testing may be more appropriate if clinical features of NF1.
Sources: Expert list, Expert Review
Breast Cancer v0.5 CDH1 Chirag Patel gene: CDH1 was added
gene: CDH1 was added to Breast Cancer. Sources: Expert list,Expert Review
Mode of inheritance for gene: CDH1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: CDH1 were set to Breast cancer, MONDO:0007254; CDH1-related diffuse gastric and lobular breast cancer syndrome, MONDO:0100488; Diffuse gastric and lobular breast cancer syndrome with or without cleft lip and/or palate, MIM#137215
Review for gene: CDH1 was set to GREEN
Added comment: ClinGen definitive. Breast cancers reported in condition.
Sources: Expert list, Expert Review
Breast Cancer v0.4 BRCA2 Chirag Patel gene: BRCA2 was added
gene: BRCA2 was added to Breast Cancer. Sources: Expert list,Expert Review
Mode of inheritance for gene: BRCA2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: BRCA2 were set to Breast cancer, MONDO:0007254; BRCA2-related cancer predisposition, MONDO:0700269; Breast-ovarian cancer, familial, 2, MIM#612555
Review for gene: BRCA2 was set to GREEN
Added comment: ClinGen definitive. Breast cancers reported in condition.
Sources: Expert list, Expert Review
Breast Cancer v0.3 BRCA1 Chirag Patel gene: BRCA1 was added
gene: BRCA1 was added to Breast Cancer. Sources: Expert list,Expert Review
Mode of inheritance for gene: BRCA1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: BRCA1 were set to Breast cancer, MONDO:0007254; BRCA1-related cancer predisposition, MONDO:0700268; Breast-ovarian cancer, familial, 1, MIM#604370
Review for gene: BRCA1 was set to GREEN
Added comment: ClinGen definitive. Breast cancers reported in condition.
Sources: Expert list, Expert Review
Breast Cancer v0.2 ATM Chirag Patel gene: ATM was added
gene: ATM was added to Breast Cancer. Sources: Expert list,Expert Review
Mode of inheritance for gene: ATM was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: ATM were set to Breast cancer, MONDO:0007254; ATM-related cancer predisposition, MONDO:0700270; Breast cancer, susceptibility to, MIM#114480
Review for gene: ATM was set to GREEN
Added comment: ClinGen definitive. Breast cancers reported in condition.

Consider possibility that an identified variant could represent ACE (aberrant clonal expansion), which can be due to clonal haematopoiesis of indeterminate potential (CHIP) or an occult hematologic malignancy, especially in older patients who have undergone prior chemotherapy (PMID: 36040522).
Sources: Expert list, Expert Review
Breast Cancer v0.1 CHEK2 Chirag Patel gene: CHEK2 was added
gene: CHEK2 was added to Breast Cancer. Sources: Expert list,Expert Review,Literature
Mode of inheritance for gene: CHEK2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CHEK2 were set to PMID: 33322746, 36529447
Phenotypes for gene: CHEK2 were set to Breast cancer, MONDO:0007254; CHEK2-related cancer predisposition, MONDO:0700271; Breast/prostate cancer, susceptibility to, MIM#609265
Review for gene: CHEK2 was set to GREEN
Added comment: Established gene-disease association. Breast cancers reported in condition.

Consider possibility that an identified variant could represent ACE (aberrant clonal expansion), which can be due to clonal haematopoiesis of indeterminate potential (CHIP) or an occult hematologic malignancy, especially in older patients who have undergone prior chemotherapy (PMID: 36040522).
Sources: Expert list, Expert Review, Literature
Colorectal Cancer and Polyposis v0.39 MLH1 Chirag Patel Classified gene: MLH1 as Green List (high evidence)
Colorectal Cancer and Polyposis v0.39 MLH1 Chirag Patel Gene: mlh1 has been classified as Green List (High Evidence).
Colorectal Cancer and Polyposis v0.38 MSH2 Chirag Patel Classified gene: MSH2 as Green List (high evidence)
Colorectal Cancer and Polyposis v0.38 MSH2 Chirag Patel Gene: msh2 has been classified as Green List (High Evidence).
Colorectal Cancer and Polyposis v0.37 MSH6 Chirag Patel Classified gene: MSH6 as Green List (high evidence)
Colorectal Cancer and Polyposis v0.37 MSH6 Chirag Patel Gene: msh6 has been classified as Green List (High Evidence).
Colorectal Cancer and Polyposis v0.36 PMS2 Chirag Patel Classified gene: PMS2 as Green List (high evidence)
Colorectal Cancer and Polyposis v0.36 PMS2 Chirag Patel Gene: pms2 has been classified as Green List (High Evidence).
Colorectal Cancer and Polyposis v0.35 MUTYH Chirag Patel Classified gene: MUTYH as Green List (high evidence)
Colorectal Cancer and Polyposis v0.35 MUTYH Chirag Patel Gene: mutyh has been classified as Green List (High Evidence).
Colorectal Cancer and Polyposis v0.34 NTHL1 Chirag Patel Classified gene: NTHL1 as Green List (high evidence)
Colorectal Cancer and Polyposis v0.34 NTHL1 Chirag Patel Gene: nthl1 has been classified as Green List (High Evidence).
Colorectal Cancer and Polyposis v0.33 MSH3 Chirag Patel Classified gene: MSH3 as Green List (high evidence)
Colorectal Cancer and Polyposis v0.33 MSH3 Chirag Patel Gene: msh3 has been classified as Green List (High Evidence).
Colorectal Cancer and Polyposis v0.32 GREM1 Chirag Patel Classified gene: GREM1 as Green List (high evidence)
Colorectal Cancer and Polyposis v0.32 GREM1 Chirag Patel Gene: grem1 has been classified as Green List (High Evidence).
Colorectal Cancer and Polyposis v0.31 RNF43 Chirag Patel Classified gene: RNF43 as Green List (high evidence)
Colorectal Cancer and Polyposis v0.31 RNF43 Chirag Patel Gene: rnf43 has been classified as Green List (High Evidence).
Colorectal Cancer and Polyposis v0.30 RNF43 Chirag Patel gene: RNF43 was added
gene: RNF43 was added to Colorectal Cancer and Polyposis. Sources: Expert list,Expert Review,Literature
Mode of inheritance for gene: RNF43 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RNF43 were set to PMID: 24512911, 34541672, 27329244, 27081527, 29330307
Phenotypes for gene: RNF43 were set to Colorectal cancer, MONDO:0005575; Polyposis, MONDO:0000147; Sessile serrated polyposis cancer syndrome, MONDO:0014919; Sessile serrated polyposis cancer syndrome, MIM#617108
Review for gene: RNF43 was set to GREEN
Added comment: ClinGen definitive. Colorectal cancers and/or polyposis reported in condition.
Sources: Expert list, Expert Review, Literature
Colorectal Cancer and Polyposis v0.29 GREM1 Chirag Patel edited their review of gene: GREM1: Changed phenotypes: Colorectal cancer, MONDO:0005575, Polyposis, MONDO:0000147, Hereditary mixed polyposis syndrome, MONDO:0011023, GREM1-associated polyposis, no MIM#
Colorectal Cancer and Polyposis v0.29 GREM1 Chirag Patel gene: GREM1 was added
gene: GREM1 was added to Colorectal Cancer and Polyposis. Sources: Expert list,Expert Review,Literature
Mode of inheritance for gene: GREM1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GREM1 were set to PMID: 22561515, 25419707
Mode of pathogenicity for gene: GREM1 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: GREM1 was set to GREEN
Added comment: ClinGen definitive. Colorectal cancers and/or polyposis reported in condition. GOF variants.

Four variants leading to partial or complete duplication of GREM1 regulatory regions or coding sequences have been reported, resulting in increased allele-specific GREM1 expression. Most are carriers of the Ashkenazi founder variant, a 40kb duplication upstream of GREM1 (SCG5-GREM1 dup).
Sources: Expert list, Expert Review, Literature
Colorectal Cancer and Polyposis v0.28 MSH3 Chirag Patel gene: MSH3 was added
gene: MSH3 was added to Colorectal Cancer and Polyposis. Sources: Expert list,Expert Review
Mode of inheritance for gene: MSH3 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: MSH3 were set to Colorectal cancer, MONDO:0005575; Polyposis, MONDO:0000147; Familial adenomatous polyposis 4, MONDO:0044300; Familial adenomatous polyposis 4, MIM#617100
Review for gene: MSH3 was set to GREEN
Added comment: ClinGen definitive. Colorectal cancers and/or polyposis reported in condition.
Sources: Expert list, Expert Review
Colorectal Cancer and Polyposis v0.27 NTHL1 Chirag Patel gene: NTHL1 was added
gene: NTHL1 was added to Colorectal Cancer and Polyposis. Sources: Expert list,Expert Review
Mode of inheritance for gene: NTHL1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: NTHL1 were set to Colorectal cancer, MONDO:0005575; Polyposis, MONDO:0000147; NTHL1-deficiency tumor predisposition syndrome, MONDO:0100502; Familial adenomatous polyposis 3, MIM#616415
Review for gene: NTHL1 was set to GREEN
Added comment: ClinGen definitive. Colorectal cancers and/or polyposis reported in condition.
Sources: Expert list, Expert Review
Colorectal Cancer and Polyposis v0.26 MUTYH Chirag Patel gene: MUTYH was added
gene: MUTYH was added to Colorectal Cancer and Polyposis. Sources: Expert list,Expert Review
Mode of inheritance for gene: MUTYH was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: MUTYH were set to Colorectal cancer, MONDO:0005575; Polyposis, MONDO:0000147; Familial adenomatous polyposis 2, MONDO:0012041; Adenomas, multiple colorectal, MIM#608456
Review for gene: MUTYH was set to GREEN
Added comment: ClinGen definitive. Colorectal cancers and/or polyposis reported in condition.
Sources: Expert list, Expert Review
Colorectal Cancer and Polyposis v0.25 PMS2 Chirag Patel gene: PMS2 was added
gene: PMS2 was added to Colorectal Cancer and Polyposis. Sources: Expert list,Expert Review
Mode of inheritance for gene: PMS2 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Phenotypes for gene: PMS2 were set to Colorectal cancer, MONDO:0005575; Polyposis, MONDO:0000147; Lynch syndrome 4, MONDO:0013699; Mismatch repair cancer syndrome 4, MONDO:0030843; Lynch syndrome 4, MIM#614337; Mismatch repair cancer syndrome 4, MIM#619101
Review for gene: PMS2 was set to GREEN
Added comment: ClinGen definitive. Colorectal cancers and/or polyposis reported in condition.

Note: there is a high level of homology between PMS2 and pseudogenes
Sources: Expert list, Expert Review
Colorectal Cancer and Polyposis v0.24 MSH6 Chirag Patel gene: MSH6 was added
gene: MSH6 was added to Colorectal Cancer and Polyposis. Sources: Expert list,Expert Review
Mode of inheritance for gene: MSH6 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Phenotypes for gene: MSH6 were set to Colorectal cancer, MONDO:0005575; Polyposis, MONDO:0000147; Lynch syndrome 5, MONDO:0013710; Mismatch repair cancer syndrome 3, MONDO:0030841; Lynch syndrome 5, MIM#614350; Mismatch repair cancer syndrome 3, MIM#619097
Review for gene: MSH6 was set to GREEN
Added comment: ClinGen definitive. Colorectal cancers and/or polyposis reported in condition.
Sources: Expert list, Expert Review
Colorectal Cancer and Polyposis v0.23 MSH2 Chirag Patel gene: MSH2 was added
gene: MSH2 was added to Colorectal Cancer and Polyposis. Sources: Expert list,Expert Review
Mode of inheritance for gene: MSH2 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Phenotypes for gene: MSH2 were set to Colorectal cancer, MONDO:0005575; Polyposis, MONDO:0000147; Lynch syndrome 1, MONDO:0007356; Mismatch repair cancer syndrome 2, MONDO:0030840; Lynch syndrome 1, MIM#120435; Mismatch repair cancer syndrome 2, MIM#619096
Review for gene: MSH2 was set to GREEN
Added comment: ClinGen definitive. Colorectal cancers and/or polyposis reported in condition.
Sources: Expert list, Expert Review
Colorectal Cancer and Polyposis v0.22 MLH1 Chirag Patel gene: MLH1 was added
gene: MLH1 was added to Colorectal Cancer and Polyposis. Sources: Expert list,Expert Review
Mode of inheritance for gene: MLH1 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Phenotypes for gene: MLH1 were set to Colorectal cancer, MONDO:0005575; Polyposis, MONDO:0000147; Lynch syndrome 2, MONDO:0012249; Mismatch repair cancer syndrome 1, MONDO:0010159; Lynch syndrome 2, MIM#609310; Mismatch repair cancer syndrome 1, MIM#276300
Review for gene: MLH1 was set to GREEN
Added comment: ClinGen definitive. Colorectal cancers and/or polyposis reported in condition.
Sources: Expert list, Expert Review
Colorectal Cancer and Polyposis v0.21 TP53 Chirag Patel Classified gene: TP53 as Green List (high evidence)
Colorectal Cancer and Polyposis v0.21 TP53 Chirag Patel Gene: tp53 has been classified as Green List (High Evidence).
Colorectal Cancer and Polyposis v0.20 STK11 Chirag Patel Classified gene: STK11 as Green List (high evidence)
Colorectal Cancer and Polyposis v0.20 STK11 Chirag Patel Gene: stk11 has been classified as Green List (High Evidence).
Colorectal Cancer and Polyposis v0.19 APC Chirag Patel Classified gene: APC as Green List (high evidence)
Colorectal Cancer and Polyposis v0.19 APC Chirag Patel Gene: apc has been classified as Green List (High Evidence).
Colorectal Cancer and Polyposis v0.18 APC Chirag Patel Classified gene: APC as Green List (high evidence)
Colorectal Cancer and Polyposis v0.18 APC Chirag Patel Gene: apc has been classified as Green List (High Evidence).
Colorectal Cancer and Polyposis v0.17 AXIN2 Chirag Patel Classified gene: AXIN2 as Green List (high evidence)
Colorectal Cancer and Polyposis v0.17 AXIN2 Chirag Patel Gene: axin2 has been classified as Green List (High Evidence).
Colorectal Cancer and Polyposis v0.16 BMPR1A Chirag Patel Classified gene: BMPR1A as Green List (high evidence)
Colorectal Cancer and Polyposis v0.16 BMPR1A Chirag Patel Gene: bmpr1a has been classified as Green List (High Evidence).
Colorectal Cancer and Polyposis v0.15 EPCAM Chirag Patel Classified gene: EPCAM as Green List (high evidence)
Colorectal Cancer and Polyposis v0.15 EPCAM Chirag Patel Gene: epcam has been classified as Green List (High Evidence).
Colorectal Cancer and Polyposis v0.14 POLD1 Chirag Patel Classified gene: POLD1 as Green List (high evidence)
Colorectal Cancer and Polyposis v0.14 POLD1 Chirag Patel Gene: pold1 has been classified as Green List (High Evidence).
Colorectal Cancer and Polyposis v0.13 POLE Chirag Patel Classified gene: POLE as Green List (high evidence)
Colorectal Cancer and Polyposis v0.13 POLE Chirag Patel Gene: pole has been classified as Green List (High Evidence).
Colorectal Cancer and Polyposis v0.12 PTEN Chirag Patel Classified gene: PTEN as Green List (high evidence)
Colorectal Cancer and Polyposis v0.12 PTEN Chirag Patel Gene: pten has been classified as Green List (High Evidence).
Colorectal Cancer and Polyposis v0.11 SMAD4 Chirag Patel Classified gene: SMAD4 as Green List (high evidence)
Colorectal Cancer and Polyposis v0.11 SMAD4 Chirag Patel Gene: smad4 has been classified as Green List (High Evidence).
Colorectal Cancer and Polyposis v0.10 SMAD4 Chirag Patel edited their review of gene: SMAD4: Changed phenotypes: Colorectal cancer, MONDO:0005575, Polyposis, MONDO:0000147, Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome, MONDO:0008278, Polyposis, juvenile intestinal, MIM#174900, Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome, MIM#175050
Colorectal Cancer and Polyposis v0.10 PTEN Chirag Patel edited their review of gene: PTEN: Changed phenotypes: Colorectal cancer, MONDO:0005575, Polyposis, MONDO:0000147, PTEN hamartoma tumor syndrome, MONDO:0017623, PTEN hamartoma tumour syndromes, MIM#158350
Colorectal Cancer and Polyposis v0.10 POLE Chirag Patel edited their review of gene: POLE: Changed phenotypes: Colorectal cancer, MONDO:0005575, Polyposis, MONDO:0000147, POLE-related polyposis and colorectal cancer syndrome, MONDO:0100287, POLE-associated polyposis, MIM#615083
Colorectal Cancer and Polyposis v0.10 POLD1 Chirag Patel edited their review of gene: POLD1: Changed phenotypes: Colorectal cancer, MONDO:0005575, Polyposis, MONDO:0000147, POLD1-related polyposis and colorectal cancer syndrome, MONDO:0100351, POLD1-associated polyposis, MIM#612591
Colorectal Cancer and Polyposis v0.10 EPCAM Chirag Patel edited their review of gene: EPCAM: Changed phenotypes: Colorectal cancer, MONDO:0005575, Polyposis, MONDO:0000147, Lynch syndrome 8, MONDO:0013196, Lynch syndrome 8, MIM#613244
Colorectal Cancer and Polyposis v0.10 BMPR1A Chirag Patel edited their review of gene: BMPR1A: Changed phenotypes: Colorectal cancer, MONDO:0005575, Polyposis, MONDO:0000147, Polyposis syndrome, hereditary mixed, 2, MONDO:0012405, Polyposis, juvenile intestinal, MIM#174900
Colorectal Cancer and Polyposis v0.10 AXIN2 Chirag Patel edited their review of gene: AXIN2: Changed phenotypes: Colorectal cancer, MONDO:0005575, Polyposis, MONDO:0000147, AXIN2-related attenuated familial adenomatous polyposis, MONDO:0018426, Oligodontia-cancer predisposition syndrome, MONDO:0012075, Oligodontia-colorectal cancer syndrome, MIM#608615
Colorectal Cancer and Polyposis v0.10 APC Chirag Patel edited their review of gene: APC: Changed phenotypes: Colorectal cancer, MONDO:0005575, Polyposis, MONDO:0000147, APC-related attenuated familial adenomatous polyposis, MONDO:0016613, Classic familial adenomatous polyposis, MONDO:0021055, Familial adenomatous polyposis 1, MONDO:0021056, Adenomatous polyposis coli, MIM#175100
Colorectal Cancer and Polyposis v0.10 STK11 Chirag Patel edited their review of gene: STK11: Changed phenotypes: Colorectal cancer, MONDO:0005575, Polyposis, MONDO:0000147, Peutz-Jeghers syndrome, MONDO:0008280, Peutz-Jeghers syndrome, MIM#175200
Colorectal Cancer and Polyposis v0.10 TP53 Chirag Patel gene: TP53 was added
gene: TP53 was added to Colorectal Cancer and Polyposis. Sources: Expert list,Expert Review
Mode of inheritance for gene: TP53 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: TP53 were set to Colorectal cancer, MONDO:0005575; Polyposis, MONDO:0000147; Li-Fraumeni syndrome, MONDO:0018875; Li-Fraumeni syndrome, MIM#151623
Review for gene: TP53 was set to GREEN
Added comment: ClinGen definitive. Colorectal cancers and/or polyposis reported in condition.

Consider possibility that an identified variant could represent ACE (aberrant clonal expansion), which can be due to clonal haematopoiesis of indeterminate potential (CHIP) or an occult hematologic malignancy, especially in older patients who have undergone prior chemotherapy (PMID: 36040522).
Sources: Expert list, Expert Review
Colorectal Cancer and Polyposis v0.9 STK11 Chirag Patel gene: STK11 was added
gene: STK11 was added to Colorectal Cancer and Polyposis. Sources: Expert list,Expert Review
Mode of inheritance for gene: STK11 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: STK11 were set to Peutz-Jeghers syndrome, MONDO:0008280; Peutz-Jeghers syndrome, MIM#175200
Review for gene: STK11 was set to GREEN
Added comment: ClinGen definitive. Colorectal cancers and/or polyposis reported in condition.

Single gene testing may be more appropriate if clinical features of JPS.
Sources: Expert list, Expert Review
Colorectal Cancer and Polyposis v0.8 SMAD4 Chirag Patel gene: SMAD4 was added
gene: SMAD4 was added to Colorectal Cancer and Polyposis. Sources: Expert list,Expert Review
Mode of inheritance for gene: SMAD4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: SMAD4 were set to Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome, MONDO:0008278; Polyposis, juvenile intestinal, MIM#174900; Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome, MIM#175050
Review for gene: SMAD4 was set to GREEN
Added comment: ClinGen definitive. Colorectal cancers and/or polyposis reported in condition.
Sources: Expert list, Expert Review
Colorectal Cancer and Polyposis v0.7 PTEN Chirag Patel gene: PTEN was added
gene: PTEN was added to Colorectal Cancer and Polyposis. Sources: Expert list,Expert Review
Mode of inheritance for gene: PTEN was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: PTEN were set to PTEN hamartoma tumor syndrome, MONDO:0017623; PTEN hamartoma tumour syndromes, MIM#158350
Review for gene: PTEN was set to GREEN
Added comment: ClinGen definitive. Colorectal cancers and/or polyposis reported in condition.
Sources: Expert list, Expert Review
Colorectal Cancer and Polyposis v0.6 POLE Chirag Patel gene: POLE was added
gene: POLE was added to Colorectal Cancer and Polyposis. Sources: Expert list,Expert Review
Mode of inheritance for gene: POLE was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: POLE were set to POLE-related polyposis and colorectal cancer syndrome, MONDO:0100287; POLE-associated polyposis, MIM#615083
Review for gene: POLE was set to GREEN
Added comment: ClinGen definitive. Colorectal cancers and/or polyposis reported in condition. GOF variants.
Sources: Expert list, Expert Review
Colorectal Cancer and Polyposis v0.5 POLD1 Chirag Patel gene: POLD1 was added
gene: POLD1 was added to Colorectal Cancer and Polyposis. Sources: Expert list,Expert Review
Mode of inheritance for gene: POLD1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: POLD1 were set to POLD1-related polyposis and colorectal cancer syndrome, MONDO:0100351; POLD1-associated polyposis, MIM#612591
Mode of pathogenicity for gene: POLD1 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: POLD1 was set to GREEN
Added comment: ClinGen definitive. Colorectal cancers and/or polyposis reported in condition. GOF variants.
Sources: Expert list, Expert Review
Colorectal Cancer and Polyposis v0.4 EPCAM Chirag Patel gene: EPCAM was added
gene: EPCAM was added to Colorectal Cancer and Polyposis. Sources: Expert list,Expert Review
Mode of inheritance for gene: EPCAM was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: EPCAM were set to Lynch syndrome 8, MONDO:0013196; Lynch syndrome 8, MIM#613244
Review for gene: EPCAM was set to GREEN
Added comment: ClinGen definitive. Colorectal cancers and/or polyposis reported in condition.

Deletion of 3’end of EPCAM gene leading to epigenetic silencing of adjacent downstream MSH2 gene.
Sources: Expert list, Expert Review
Colorectal Cancer and Polyposis v0.3 BMPR1A Chirag Patel gene: BMPR1A was added
gene: BMPR1A was added to Colorectal Cancer and Polyposis. Sources: Expert list,Expert Review
Mode of inheritance for gene: BMPR1A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: BMPR1A were set to Polyposis syndrome, hereditary mixed, 2, MONDO:0012405; Polyposis, juvenile intestinal, MIM#174900
Review for gene: BMPR1A was set to GREEN
Added comment: ClinGen definitive. Colorectal cancers and/or polyposis reported in condition.
Sources: Expert list, Expert Review
Colorectal Cancer and Polyposis v0.2 AXIN2 Chirag Patel gene: AXIN2 was added
gene: AXIN2 was added to Colorectal Cancer and Polyposis. Sources: Expert list,Expert Review
Mode of inheritance for gene: AXIN2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: AXIN2 were set to AXIN2-related attenuated familial adenomatous polyposis, MONDO:0018426; Oligodontia-cancer predisposition syndrome, MONDO:0012075; Oligodontia-colorectal cancer syndrome, MIM#608615
Review for gene: AXIN2 was set to GREEN
Added comment: ClinGen definitive. Colorectal cancers and/or polyposis reported in condition.
Sources: Expert list, Expert Review
Colorectal Cancer and Polyposis v0.1 APC Chirag Patel gene: APC was added
gene: APC was added to Colorectal Cancer and Polyposis. Sources: Expert list,Expert Review
Mode of inheritance for gene: APC was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: APC were set to APC-related attenuated familial adenomatous polyposis, MONDO:0016613; Classic familial adenomatous polyposis, MONDO:0021055; Familial adenomatous polyposis 1, MONDO:0021056; Adenomatous polyposis coli, MIM#175100
Review for gene: APC was set to GREEN
Added comment: ClinGen definitive. Colorectal cancers and/or polyposis reported in condition.
Sources: Expert list, Expert Review
Sarcoma soft tissue v0.32 BUB1B Chirag Patel Classified gene: BUB1B as Green List (high evidence)
Sarcoma soft tissue v0.32 BUB1B Chirag Patel Gene: bub1b has been classified as Green List (High Evidence).
Sarcoma soft tissue v0.31 BUB1B Chirag Patel gene: BUB1B was added
gene: BUB1B was added to Sarcoma soft tissue. Sources: Expert list,Expert Review
Mode of inheritance for gene: BUB1B was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: BUB1B were set to Soft tissue sarcoma, MONDO:0018078; Sarcoma, MONDO:0005089; Mosaic variegated aneuploidy syndrome 1, MONDO:0009759; Mosaic variegated aneuploidy syndrome 1, MIM#257300
Review for gene: BUB1B was set to GREEN
Added comment: ClinGen definitive. Soft-tissue sarcomas reported in condition.
Sources: Expert list, Expert Review
Prepair 1000+ v1.322 TBCE Andrew Coventry reviewed gene: TBCE: Rating: GREEN; Mode of pathogenicity: None; Publications: 27666369 34134906 17699660 34356170 12389028; Phenotypes: Encephalopathy, progressive, with amyotrophy and optic atrophy MIM#617207, Hypoparathyroidism-retardation-dysmorphism syndrome MIM#241410, Kenny-Caffey syndrome, type 1 MIM#244460; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.322 STAR Andrew Coventry reviewed gene: STAR: Rating: GREEN; Mode of pathogenicity: None; Publications: 7892608 8634702 9326645 8948562 9097960 11061515 11297612 14764819 16968793; Phenotypes: Lipoid adrenal hyperplasia MIM#201710; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.322 STAMBP Andrew Coventry reviewed gene: STAMBP: Rating: GREEN; Mode of pathogenicity: None; Publications: 23542699 31638258 29907875 27531570 25692795 25266620 11713295; Phenotypes: Microcephaly-capillary malformation syndrome MIM#614261; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.322 SPEG Andrew Coventry reviewed gene: SPEG: Rating: GREEN; Mode of pathogenicity: None; Publications: 25087613 31625632 30412272 30157964 29614691 29474540 28624463 26578207 25087613 32925938 33794647 19118250 25087613; Phenotypes: Centronuclear myopathy 5 MIM615959; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.322 SPAG1 Andrew Coventry reviewed gene: SPAG1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24055112 32502479; Phenotypes: Ciliary dyskinesia, primary, 28 MIM#615505; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.322 SLC6A3 Andrew Coventry reviewed gene: SLC6A3: Rating: GREEN; Mode of pathogenicity: None; Publications: 21112253 19478460; Phenotypes: Parkinsonism-dystonia, infantile, 1 MIM#613135; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.322 SLC45A2 Andrew Coventry reviewed gene: SLC45A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 11574907 14722913 14961451; Phenotypes: Albinism, oculocutaneous, type IV MIM#606574; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.322 SLC2A10 Andrew Coventry reviewed gene: SLC2A10: Rating: GREEN; Mode of pathogenicity: None; Publications: 30071989 16550171 17935213 22116938; Phenotypes: Arterial tortuosity syndrome MIM#208050; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.322 SLC13A5 Andrew Coventry reviewed gene: SLC13A5: Rating: GREEN; Mode of pathogenicity: None; Publications: 24995870 26384929 27600704 38113697; Phenotypes: Developmental and epileptic encephalopathy 25, with amelogenesis imperfecta MIM#615905; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.322 SARS2 Andrew Coventry reviewed gene: SARS2: Rating: GREEN; Mode of pathogenicity: None; Publications: 24034276 21255763 33751860 34407605 38326069 38264205; Phenotypes: Hyperuricemia, pulmonary hypertension, renal failure, and alkalosis MIM#613845; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.322 RFXAP Andrew Coventry reviewed gene: RFXAP: Rating: GREEN; Mode of pathogenicity: None; Publications: 9118943 32875002 11258423; Phenotypes: MHC class II deficiency 4 MIM#620817; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.322 RBM10 Andrew Coventry reviewed gene: RBM10: Rating: GREEN; Mode of pathogenicity: None; Publications: 20451169 24259342 30450804 30189253 33340101; Phenotypes: TARP syndrome MIM#311900; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Prepair 1000+ v1.322 PRUNE1 Andrew Coventry reviewed gene: PRUNE1: Rating: GREEN; Mode of pathogenicity: None; Publications: 26539891 28334956 33105479 29797509; Phenotypes: Neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies MIM#617481; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.322 PRG4 Andrew Coventry reviewed gene: PRG4: Rating: GREEN; Mode of pathogenicity: None; Publications: 10545950 29397575; Phenotypes: Camptodactyly-arthropathy-coxa vara-pericarditis syndrome MIM#208250; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.322 PQBP1 Andrew Coventry reviewed gene: PQBP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31840929 14634649 20410308 19661183; Phenotypes: Renpenning syndrome MIM#309500; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Prepair 1000+ v1.322 POMGNT1 Andrew Coventry reviewed gene: POMGNT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 27391550 26908613 30961548 30937090; Phenotypes: Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A3, MIM#253280, Muscular dystrophy-dystroglycanopathy (congenital with mental retardation), type B3, MIM#613151, Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 3 MIM#613157; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.322 PNPO Andrew Coventry reviewed gene: PNPO: Rating: GREEN; Mode of pathogenicity: None; Publications: 34769443 33981986 33748042 32888189 24658933 15772097 31261385 31616300 31759955; Phenotypes: Pyridoxamine 5'-phosphate oxidase deficiency MIM#610090; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.322 ATP6V0A2 Clare Hunt reviewed gene: ATP6V0A2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 19401719, 22773132; Phenotypes: Cutis laxa, autosomal recessive, type IIA MIM#219200, Wrinkly skin syndrome, MIM#278250; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.322 HK1 Marta Cifuentes Ochoa reviewed gene: HK1: Rating: ; Mode of pathogenicity: None; Publications: 33361148, 12393545; Phenotypes: Hemolytic anemia due to hexokinase deficiency MIM#235700, Nonspherocytic hemolytic anemia due to hexokinase deficiency (NSHA due to HK1 deficiency) MONDO:0009340 and Neuropathy, hereditary motor and sensory, Russe type MIM#605285, Charcot-Marie-Tooth disease type 4G (CMT4G) MONDO:0011534; Mode of inheritance: None
Prepair 1000+ v1.322 ASPA Clare Hunt reviewed gene: ASPA: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 22750302, 20301412; Phenotypes: Canavan disease MIM#271900; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.322 AMPD2 Clare Hunt reviewed gene: AMPD2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 23911318; Phenotypes: Pontocerebellar hypoplasia type 9 (PCH9); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.322 GATM Marta Cifuentes Ochoa reviewed gene: GATM: Rating: GREEN; Mode of pathogenicity: None; Publications: 11555793, 27604308; Phenotypes: Cerebral creatine deficiency syndrome 3 MIM#612718, AGAT deficiency MONDO:0012996; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.322 ABAT Clare Hunt reviewed gene: ABAT: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 25738457; Phenotypes: GABA-transaminase deficiency, MIM# 613163, mtDNA depletion syndrome (MDS); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.322 GAN Marta Cifuentes Ochoa reviewed gene: GAN: Rating: GREEN; Mode of pathogenicity: None; Publications: 30532362, 11062483; Phenotypes: Giant axonal neuropathy-1, MIM# 256850, MONDO:0009749; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.322 AARS2 Clare Hunt edited their review of gene: AARS2: Added comment: At least 6 families presenting with a severe COXPD phenotype in infancy, primarily with cardiac, muscle and neurological features in addition to lactic acidosis. Further 6 reported with a progressive neurodegenerative disorder characterised by loss of motor and cognitive skills, usually with onset in young adulthood. Some had a history of delayed motor development or learning difficulties in early childhood. Neurologic decline was severe, usually resulting in gait difficulties, ataxia, spasticity, and cognitive decline and dementia. Most individuals lost speech and become wheelchair-bound or bedridden. Brain MRI showed progressive white matter signal abnormalities in the deep white matter. Affected females developed premature ovarian failure. These likely represent a spectrum of severity of a single mitochondrial disorder.
Created: 29 Aug 2020, 4:55 a.m. | Last Modified: 29 Aug 2020, 4:55 a.m.
Panel Version: 0.3999; Changed publications: 27839525
Prepair 1000+ v1.322 ALAD Lauren Thomas reviewed gene: ALAD: Rating: GREEN; Mode of pathogenicity: None; Publications: 16343966, 30724374, 2063868, 1569184, 15303011; Phenotypes: Porphyria, acute hepatic, MIM#612740; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.322 DHCR7 Cassandra Muller reviewed gene: DHCR7: Rating: GREEN; Mode of pathogenicity: None; Publications: 16906538, 10602371, 10677299; Phenotypes: Smith-Lemli-Opitz syndrome (MIM#270400); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early-onset Parkinson disease v2.9 PNPLA6 Bryony Thompson Marked gene: PNPLA6 as ready
Early-onset Parkinson disease v2.9 PNPLA6 Bryony Thompson Gene: pnpla6 has been classified as Amber List (Moderate Evidence).
Early-onset Parkinson disease v2.9 PNPLA6 Bryony Thompson Classified gene: PNPLA6 as Amber List (moderate evidence)
Early-onset Parkinson disease v2.9 PNPLA6 Bryony Thompson Gene: pnpla6 has been classified as Amber List (Moderate Evidence).
Prepair 1000+ v1.322 PKHD1 Andrew Coventry reviewed gene: PKHD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28375157 21945273; Phenotypes: Polycystic kidney disease 4, with or without hepatic disease MIM#263200; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early-onset Parkinson disease v2.8 PNPLA6 Bryony Thompson gene: PNPLA6 was added
gene: PNPLA6 was added to Early-onset Parkinson disease. Sources: Literature
Mode of inheritance for gene: PNPLA6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PNPLA6 were set to 32623594; 36825042
Phenotypes for gene: PNPLA6 were set to PNPLA6-related spastic paraplegia with or without ataxia MONDO:0100149
Review for gene: PNPLA6 was set to AMBER
Added comment: Parkinsonism is a part of the phenotype in at least 2 families, both compound hets including the same missense variant (PNPLA6 c.4003C>T p.Pro1335Ser).
Sources: Literature
Prepair 1000+ v1.322 OCRL Andrew Coventry reviewed gene: OCRL: Rating: GREEN; Mode of pathogenicity: None; Publications: 9199559 15627218 27625797; Phenotypes: Dent disease 2 MIM#300555, Lowe syndrome MIM#309000; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Prepair 1000+ v1.322 CYP7B1 Cassandra Muller reviewed gene: CYP7B1: Rating: GREEN; Mode of pathogenicity: None; Publications: 9802883, 18252231, 31337596, 18252231; Phenotypes: Bile acid synthesis defect, congenital, 3, 613812 (3), Spastic paraplegia 5A, 270800 (3); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.322 CYP27A1 Cassandra Muller reviewed gene: CYP27A1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Cerebrotendinous xanthomatosis, 213700 (3); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.6248 ERCC8 Bryony Thompson Marked gene: ERCC8 as ready
Intellectual disability syndromic and non-syndromic v0.6248 ERCC8 Bryony Thompson Gene: ercc8 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.6248 ERCC8 Bryony Thompson Phenotypes for gene: ERCC8 were changed from to Cockayne syndrome type 1 MONDO:0019569
Intellectual disability syndromic and non-syndromic v0.6247 ERCC8 Bryony Thompson Publications for gene: ERCC8 were set to
Intellectual disability syndromic and non-syndromic v0.6246 ERCC8 Bryony Thompson Mode of inheritance for gene: ERCC8 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.6245 ERCC8 Bryony Thompson reviewed gene: ERCC8: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301516; Phenotypes: Cockayne syndrome type 1 MONDO:0019569; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability syndromic and non-syndromic v0.6245 ERCC6L2 Bryony Thompson Marked gene: ERCC6L2 as ready
Intellectual disability syndromic and non-syndromic v0.6245 ERCC6L2 Bryony Thompson Gene: ercc6l2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.6245 ERCC6L2 Bryony Thompson Phenotypes for gene: ERCC6L2 were changed from to pancytopenia-developmental delay syndrome MONDO:0014317
Intellectual disability syndromic and non-syndromic v0.6244 ERCC6L2 Bryony Thompson Publications for gene: ERCC6L2 were set to
Intellectual disability syndromic and non-syndromic v0.6243 ERCC6L2 Bryony Thompson Mode of inheritance for gene: ERCC6L2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.6242 ERCC6L2 Bryony Thompson reviewed gene: ERCC6L2: Rating: GREEN; Mode of pathogenicity: None; Publications: 36790458; Phenotypes: pancytopenia-developmental delay syndrome MONDO:0014317; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability syndromic and non-syndromic v0.6242 ERCC6 Bryony Thompson Marked gene: ERCC6 as ready
Intellectual disability syndromic and non-syndromic v0.6242 ERCC6 Bryony Thompson Gene: ercc6 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.6242 ERCC6 Bryony Thompson Phenotypes for gene: ERCC6 were changed from to Cockayne spectrum with or without cerebrooculofacioskeletal syndrome MONDO:0100506
Intellectual disability syndromic and non-syndromic v0.6241 ERCC6 Bryony Thompson Publications for gene: ERCC6 were set to
Intellectual disability syndromic and non-syndromic v0.6240 ERCC6 Bryony Thompson Mode of inheritance for gene: ERCC6 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.6239 ERCC3 Bryony Thompson Marked gene: ERCC3 as ready
Intellectual disability syndromic and non-syndromic v0.6239 ERCC3 Bryony Thompson Gene: ercc3 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.6239 ERCC3 Bryony Thompson Phenotypes for gene: ERCC3 were changed from to xeroderma pigmentosum group B MONDO:0012531
Intellectual disability syndromic and non-syndromic v0.6238 ERCC3 Bryony Thompson Publications for gene: ERCC3 were set to
Intellectual disability syndromic and non-syndromic v0.6237 ERCC3 Bryony Thompson Mode of inheritance for gene: ERCC3 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.6236 ERCC2 Bryony Thompson Phenotypes for gene: ERCC2 were changed from xeroderma pigmentosum group D MONDO:0010212 to xeroderma pigmentosum group D MONDO:0010212; trichothiodystrophy 1, photosensitive MONDO:0011125; cerebrooculofacioskeletal syndrome 2 MONDO:0012553
Intellectual disability syndromic and non-syndromic v0.6235 ERCC2 Bryony Thompson Marked gene: ERCC2 as ready
Intellectual disability syndromic and non-syndromic v0.6235 ERCC2 Bryony Thompson Gene: ercc2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.6235 ERCC2 Bryony Thompson Phenotypes for gene: ERCC2 were changed from to xeroderma pigmentosum group D MONDO:0010212
Intellectual disability syndromic and non-syndromic v0.6234 ERCC2 Bryony Thompson Publications for gene: ERCC2 were set to
Intellectual disability syndromic and non-syndromic v0.6233 ERCC2 Bryony Thompson Mode of inheritance for gene: ERCC2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.6232 EP300 Bryony Thompson Marked gene: EP300 as ready
Intellectual disability syndromic and non-syndromic v0.6232 EP300 Bryony Thompson Gene: ep300 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.6232 EP300 Bryony Thompson Phenotypes for gene: EP300 were changed from to Rubinstein-Taybi syndrome MONDO:0019188
Intellectual disability syndromic and non-syndromic v0.6231 EP300 Bryony Thompson Publications for gene: EP300 were set to https://search.clinicalgenome.org/CCID:004751
Intellectual disability syndromic and non-syndromic v0.6230 EP300 Bryony Thompson Publications for gene: EP300 were set to
Intellectual disability syndromic and non-syndromic v0.6229 EP300 Bryony Thompson Mode of inheritance for gene: EP300 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.6228 ELOVL4 Bryony Thompson Marked gene: ELOVL4 as ready
Intellectual disability syndromic and non-syndromic v0.6228 ELOVL4 Bryony Thompson Gene: elovl4 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.6228 ELOVL4 Bryony Thompson Phenotypes for gene: ELOVL4 were changed from to congenital ichthyosis-intellectual disability-spastic quadriplegia syndrome MONDO:0013760
Intellectual disability syndromic and non-syndromic v0.6227 ELOVL4 Bryony Thompson Publications for gene: ELOVL4 were set to
Intellectual disability syndromic and non-syndromic v0.6226 ELOVL4 Bryony Thompson Mode of inheritance for gene: ELOVL4 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.6225 EIF2AK3 Bryony Thompson Marked gene: EIF2AK3 as ready
Intellectual disability syndromic and non-syndromic v0.6225 EIF2AK3 Bryony Thompson Gene: eif2ak3 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.6225 EIF2AK3 Bryony Thompson Mode of inheritance for gene: EIF2AK3 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.6224 EIF2AK3 Bryony Thompson Publications for gene: EIF2AK3 were set to
Intellectual disability syndromic and non-syndromic v0.6223 DIAPH1 Bryony Thompson Publications for gene: DIAPH1 were set to 24781755; 26463574
Intellectual disability syndromic and non-syndromic v0.6222 DIAPH1 Bryony Thompson reviewed gene: DIAPH1: Rating: GREEN; Mode of pathogenicity: None; Publications: 39076976, 24781755, 26463574, 33662367; Phenotypes: progressive microcephaly-seizures-cortical blindness-developmental delay syndrome MONDO:0014714; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Prepair 1000+ v1.322 PNKP Shakira Heerah reviewed gene: PNKP: Rating: GREEN; Mode of pathogenicity: None; Publications: 31436889, 31707899, 20118933, 23224214, 29243230, 2578773, 27066567; Phenotypes: Ataxia-oculomotor apraxia 4, Microcephaly, seizures, and developmental delay, Charcot-Marie-Tooth disease, type 2B2; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2016 PNKP Shakira Heerah Deleted their review
Mendeliome v1.2016 RPS6KB1 Bryony Thompson Classified gene: RPS6KB1 as Amber List (moderate evidence)
Mendeliome v1.2016 RPS6KB1 Bryony Thompson Added comment: Comment on list classification: Comment on list classification: ClinGen HCVD GCEP has classified this gene as Limited for HCM on 13/09/2023 - https://search.clinicalgenome.org/CCID:006034
Mendeliome v1.2016 RPS6KB1 Bryony Thompson Gene: rps6kb1 has been classified as Amber List (Moderate Evidence).
Prepair 1000+ v1.322 LARS Lucy Spencer reviewed gene: LARS: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Infantile liver failure syndrome 1, MIM# 615438; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.322 KCTD7 Lucy Spencer reviewed gene: KCTD7: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Epilepsy, progressive myoclonic 3, with or without intracellular inclusions MIM#611726; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.322 HPS5 Lucy Spencer reviewed gene: HPS5: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hermansky-Pudlak syndrome 5 MIM#614074; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.322 HLCS Lucy Spencer reviewed gene: HLCS: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Holocarboxylase synthetase deficiency MIM#253270; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.322 HADHB Lucy Spencer reviewed gene: HADHB: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Mitochondrial trifunctional protein deficiency 2 MIM#620300; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.322 GSS Lucy Spencer reviewed gene: GSS: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Glutathione synthetase deficiency MIM#266130; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.322 GNPTAB Lucy Spencer reviewed gene: GNPTAB: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Mucolipidosis III alpha/beta MIM#252600, Mucolipidosis II alpha/beta MIM#252500; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.322 FGG Lucy Spencer reviewed gene: FGG: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Afibrinogenemia, congenital MIM#202400; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.322 FGB Lucy Spencer reviewed gene: FGB: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Afibrinogenemia, congenital MIM#202400; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.322 FGA Lucy Spencer reviewed gene: FGA: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Afibrinogenemia, congenital (MIM#202400); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.322 FGA Lucy Spencer Deleted their review
Prepair 1000+ v1.322 FGA Lucy Spencer reviewed gene: FGA: Rating: GREEN; Mode of pathogenicity: None; Publications: Afibrinogenemia, congenital (MIM#202400); Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.6222 ERCC6L2 Ken Lee Wan reviewed gene: ERCC6L2: Rating: AMBER; Mode of pathogenicity: None; Publications: 24507776, 27185855, 28815563, 29633571; Phenotypes: pancytopenia-developmental delay syndrome MONDO:0014317; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability syndromic and non-syndromic v0.6222 ERCC3 Ken Lee Wan reviewed gene: ERCC3: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301571; Phenotypes: xeroderma pigmentosum group B MONDO:0012531; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability syndromic and non-syndromic v0.6222 ERCC2 Ken Lee Wan reviewed gene: ERCC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301571; Phenotypes: xeroderma pigmentosum group D MONDO:0010212, trichothiodystrophy 1, photosensitive MONDO:0011125, cerebrooculofacioskeletal syndrome 2 MONDO:0012553; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability syndromic and non-syndromic v0.6222 EP300 Ken Lee Wan changed review comment from: EP300 is definitively associated with autosomal dominant Rubinstein-Taybi syndrome. Rubinstein-Taybi syndrome is characterized by distinctive facial features, broad and angulated thumbs and halluces, short stature, and intellectual disability (https://search.clinicalgenome.org/CCID:004751).

Mechanism of disease: loss of function; to: EP300 is definitively associated with autosomal dominant Rubinstein-Taybi syndrome. Rubinstein-Taybi syndrome is characterized by distinctive facial features, broad and angulated thumbs and halluces, short stature and intellectual disability (https://search.clinicalgenome.org/CCID:004751).

Mechanism of disease: loss of function
Intellectual disability syndromic and non-syndromic v0.6222 EP300 Ken Lee Wan reviewed gene: EP300: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Rubinstein-Taybi syndrome MONDO:0019188; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability syndromic and non-syndromic v0.6222 ELOVL4 Ken Lee Wan reviewed gene: ELOVL4: Rating: GREEN; Mode of pathogenicity: None; Publications: 37592902; Phenotypes: congenital ichthyosis-intellectual disability-spastic quadriplegia syndrome MONDO:0013760; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Ectodermal Dysplasia v0.86 RSPO4 Paul De Fazio gene: RSPO4 was added
gene: RSPO4 was added to Ectodermal Dysplasia. Sources: Literature
Mode of inheritance for gene: RSPO4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RSPO4 were set to 17041604; 17914448; 18070203
Phenotypes for gene: RSPO4 were set to Anonychia congenita MIM# 206800
Review for gene: RSPO4 was set to GREEN
gene: RSPO4 was marked as current diagnostic
Added comment: Congenital anonychia is defined as the absence of fingernails and toenails. Anonychia and its milder phenotypic variant, hyponychia, usually occur as a feature of genetic syndromes, in association with significant skeletal and limb anomalies. Isolated nonsyndromic congenital anonychia/hyponychia is a rare entity that usually follows autosomal recessive inheritance with variable expression, even within a given family. The nail phenotypes observed range from no nail field to a nail field of reduced size with an absent or rudimentary nail (summary by Bruchle et al., 2008). This form of nail disorder is referred to here as nonsyndromic congenital nail disorder-4 (NDNC4).

Multiple families with homozygous or compound heterozygous variants, in consanguineous and non-consanguineous families.
Sources: Literature
Ovarian Cancer v0.24 TP53 Chirag Patel changed review comment from: ClinGen definitive. Ovarian cancers reported in condition.
Sources: Expert list, Expert Review; to: ClinGen definitive. Ovarian cancers reported in condition.

Consider possibility that an identified variant could represent ACE (aberrant clonal expansion), which can be due to clonal haematopoiesis of indeterminate potential (CHIP) or an occult hematologic malignancy, especially in older patients who have undergone prior chemotherapy (PMID: 36040522).

Sources: Expert list, Expert Review
Ovarian Cancer v0.24 TP53 Chirag Patel Classified gene: TP53 as Green List (high evidence)
Ovarian Cancer v0.24 TP53 Chirag Patel Gene: tp53 has been classified as Green List (High Evidence).
Ovarian Cancer v0.23 RAD51D Chirag Patel Classified gene: RAD51D as Green List (high evidence)
Ovarian Cancer v0.23 RAD51D Chirag Patel Gene: rad51d has been classified as Green List (High Evidence).
Ovarian Cancer v0.22 RAD51C Chirag Patel Classified gene: RAD51C as Green List (high evidence)
Ovarian Cancer v0.22 RAD51C Chirag Patel Gene: rad51c has been classified as Green List (High Evidence).
Ovarian Cancer v0.21 PALB2 Chirag Patel Classified gene: PALB2 as Green List (high evidence)
Ovarian Cancer v0.21 PALB2 Chirag Patel Gene: palb2 has been classified as Green List (High Evidence).
Ovarian Cancer v0.20 EPCAM Chirag Patel Classified gene: EPCAM as Green List (high evidence)
Ovarian Cancer v0.20 EPCAM Chirag Patel Gene: epcam has been classified as Green List (High Evidence).
Ovarian Cancer v0.19 BRIP1 Chirag Patel Classified gene: BRIP1 as Green List (high evidence)
Ovarian Cancer v0.19 BRIP1 Chirag Patel Gene: brip1 has been classified as Green List (High Evidence).
Ovarian Cancer v0.18 BRCA2 Chirag Patel Classified gene: BRCA2 as Green List (high evidence)
Ovarian Cancer v0.18 BRCA2 Chirag Patel Gene: brca2 has been classified as Green List (High Evidence).
Ovarian Cancer v0.17 BRCA1 Chirag Patel Classified gene: BRCA1 as Green List (high evidence)
Ovarian Cancer v0.17 BRCA1 Chirag Patel Gene: brca1 has been classified as Green List (High Evidence).
Ovarian Cancer v0.16 TP53 Chirag Patel gene: TP53 was added
gene: TP53 was added to Ovarian Cancer. Sources: Expert list,Expert Review
Mode of inheritance for gene: TP53 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: TP53 were set to Ovarian cancer, MONDO:0008170; Li-Fraumeni syndrome, MONDO:0018875; Li-Fraumeni syndrome, MIM#151623
Review for gene: TP53 was set to GREEN
Added comment: ClinGen definitive. Ovarian cancers reported in condition.
Sources: Expert list, Expert Review
Ovarian Cancer v0.15 RAD51D Chirag Patel gene: RAD51D was added
gene: RAD51D was added to Ovarian Cancer. Sources: Expert list,Expert Review
Mode of inheritance for gene: RAD51D was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: RAD51D were set to Ovarian cancer, MONDO:0008170; RAD51D-related cancer predisposition, MONDO:0700274; Breast-ovarian cancer, familial, susceptibility to, 4, MONDO:0013669; Breast-ovarian cancer, familial, susceptibility to, 4, MIM#614291
Review for gene: RAD51D was set to GREEN
Added comment: ClinGen definitive. Ovarian cancers reported in condition.
Sources: Expert list, Expert Review
Ovarian Cancer v0.14 RAD51C Chirag Patel gene: RAD51C was added
gene: RAD51C was added to Ovarian Cancer. Sources: Expert list,Expert Review
Mode of inheritance for gene: RAD51C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: RAD51C were set to Ovarian cancer, MONDO:0008170; RAD51C-related cancer predisposition, MONDO:0700273; Breast-ovarian cancer, familial, susceptibility to, 3, MONDO:0013253; Breast-ovarian cancer, familial, susceptibility to, 3, MIM#613399
Review for gene: RAD51C was set to GREEN
Added comment: ClinGen definitive. Ovarian cancers reported in condition.
Sources: Expert list, Expert Review
Ovarian Cancer v0.13 PALB2 Chirag Patel gene: PALB2 was added
gene: PALB2 was added to Ovarian Cancer. Sources: Expert list,Expert Review
Mode of inheritance for gene: PALB2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: PALB2 were set to Ovarian cancer, MONDO:0008170; PALB2-related cancer predisposition, MONDO:0700272; Breast-ovarian cancer, familial, susceptibility to, 5, MIM#620442; Pancreatic cancer, susceptibility to, 3, MIM#613348
Review for gene: PALB2 was set to GREEN
Added comment: ClinGen definitive. Ovarian cancers reported in condition.
Sources: Expert list, Expert Review
Ovarian Cancer v0.12 EPCAM Chirag Patel gene: EPCAM was added
gene: EPCAM was added to Ovarian Cancer. Sources: Expert list,Expert Review
Mode of inheritance for gene: EPCAM was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: EPCAM were set to Ovarian cancer, MONDO:0008170; Lynch syndrome 8, MONDO:0013196; Lynch syndrome 8, MIM#613244
Review for gene: EPCAM was set to GREEN
Added comment: ClinGen definitive. Ovarian cancers reported in condition.

Deletion of 3’end of EPCAM gene leading to epigenetic silencing of adjacent downstream MSH2 gene.
Sources: Expert list, Expert Review
Ovarian Cancer v0.11 BRIP1 Chirag Patel gene: BRIP1 was added
gene: BRIP1 was added to Ovarian Cancer. Sources: Expert list,Expert Review
Mode of inheritance for gene: BRIP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: BRIP1 were set to Ovarian cancer, MONDO:0008170
Review for gene: BRIP1 was set to GREEN
Added comment: ClinGen definitive. Ovarian cancers reported in condition.
Sources: Expert list, Expert Review
Ovarian Cancer v0.10 BRCA2 Chirag Patel gene: BRCA2 was added
gene: BRCA2 was added to Ovarian Cancer. Sources: Expert list,Expert Review
Mode of inheritance for gene: BRCA2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: BRCA2 were set to Ovarian cancer, MONDO:0008170; BRCA2-related cancer predisposition, MONDO:0700269; Breast-ovarian cancer, familial, 2, MIM#612555
Review for gene: BRCA2 was set to GREEN
Added comment: ClinGen definitive. Ovarian cancers reported in condition.
Sources: Expert list, Expert Review
Ovarian Cancer v0.9 BRCA1 Chirag Patel gene: BRCA1 was added
gene: BRCA1 was added to Ovarian Cancer. Sources: Expert list,Expert Review
Mode of inheritance for gene: BRCA1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: BRCA1 were set to Ovarian cancer, MONDO:0008170; BRCA1-related cancer predisposition, MONDO:0700268; Breast-ovarian cancer, familial, 1, MIM#604370
Review for gene: BRCA1 was set to GREEN
Added comment: ClinGen definitive. Ovarian cancers reported in condition.
Sources: Expert list, Expert Review
Ovarian Cancer v0.8 PMS2 Chirag Patel Classified gene: PMS2 as Green List (high evidence)
Ovarian Cancer v0.8 PMS2 Chirag Patel Gene: pms2 has been classified as Green List (High Evidence).
Ovarian Cancer v0.7 MSH6 Chirag Patel Classified gene: MSH6 as Green List (high evidence)
Ovarian Cancer v0.7 MSH6 Chirag Patel Gene: msh6 has been classified as Green List (High Evidence).
Ovarian Cancer v0.6 MSH2 Chirag Patel Classified gene: MSH2 as Green List (high evidence)
Ovarian Cancer v0.6 MSH2 Chirag Patel Gene: msh2 has been classified as Green List (High Evidence).
Ovarian Cancer v0.5 MLH1 Chirag Patel Classified gene: MLH1 as Green List (high evidence)
Ovarian Cancer v0.5 MLH1 Chirag Patel Gene: mlh1 has been classified as Green List (High Evidence).
Ovarian Cancer v0.4 PMS2 Chirag Patel gene: PMS2 was added
gene: PMS2 was added to Ovarian Cancer. Sources: Expert list,Expert Review
Mode of inheritance for gene: PMS2 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Phenotypes for gene: PMS2 were set to Ovarian cancer, MONDO:0008170; Lynch syndrome 4, MONDO:0013699; Mismatch repair cancer syndrome 4, MONDO:0030843; Lynch syndrome 4, MIM#614337; Mismatch repair cancer syndrome 4, MIM#619101
Review for gene: PMS2 was set to GREEN
Added comment: ClinGen definitive. Ovarian cancers reported in condition.

Note: there is a high level of homology between PMS2 and pseudogenes
Sources: Expert list, Expert Review
Ovarian Cancer v0.3 MSH6 Chirag Patel gene: MSH6 was added
gene: MSH6 was added to Ovarian Cancer. Sources: Expert list,Expert Review
Mode of inheritance for gene: MSH6 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Phenotypes for gene: MSH6 were set to Ovarian cancer, MONDO:0008170; Lynch syndrome 5, MONDO:0013710; Mismatch repair cancer syndrome 3, MONDO:0030841; Lynch syndrome 5, MIM#614350; Mismatch repair cancer syndrome 3, MIM#619097
Review for gene: MSH6 was set to GREEN
Added comment: ClinGen definitive. Ovarian cancers reported in condition.
Sources: Expert list, Expert Review
Ovarian Cancer v0.2 MSH2 Chirag Patel gene: MSH2 was added
gene: MSH2 was added to Ovarian Cancer. Sources: Expert list,Expert Review
Mode of inheritance for gene: MSH2 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Phenotypes for gene: MSH2 were set to Ovarian cancer, MONDO:0008170; Lynch syndrome 1, MONDO:0007356; Mismatch repair cancer syndrome 2, MONDO:0030840; Lynch syndrome 1, MIM#120435; Mismatch repair cancer syndrome 2, MIM#619096
Review for gene: MSH2 was set to GREEN
Added comment: ClinGen definitive. Ovarian cancers reported in condition.
Sources: Expert list, Expert Review
Ovarian Cancer v0.1 MLH1 Chirag Patel gene: MLH1 was added
gene: MLH1 was added to Ovarian Cancer. Sources: Expert list,Expert Review
Mode of inheritance for gene: MLH1 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Phenotypes for gene: MLH1 were set to Ovarian cancer, MONDO:0008170; Lynch syndrome 2, MONDO:0012249; Mismatch repair cancer syndrome 1, MONDO:0010159; Lynch syndrome 2, MIM#609310; Mismatch repair cancer syndrome 1, MIM#276300
Review for gene: MLH1 was set to GREEN
Added comment: ClinGen definitive. Ovarian cancers reported in condition.
Sources: Expert list, Expert Review
Endometrial Cancer v0.20 POLE Chirag Patel Classified gene: POLE as Green List (high evidence)
Endometrial Cancer v0.20 POLE Chirag Patel Gene: pole has been classified as Green List (High Evidence).
Endometrial Cancer v0.19 POLD1 Chirag Patel Classified gene: POLD1 as Green List (high evidence)
Endometrial Cancer v0.19 POLD1 Chirag Patel Gene: pold1 has been classified as Green List (High Evidence).
Endometrial Cancer v0.18 TP53 Chirag Patel Classified gene: TP53 as Green List (high evidence)
Endometrial Cancer v0.18 TP53 Chirag Patel Gene: tp53 has been classified as Green List (High Evidence).
Endometrial Cancer v0.17 PTEN Chirag Patel Classified gene: PTEN as Green List (high evidence)
Endometrial Cancer v0.17 PTEN Chirag Patel Gene: pten has been classified as Green List (High Evidence).
Endometrial Cancer v0.16 EPCAM Chirag Patel Classified gene: EPCAM as Green List (high evidence)
Endometrial Cancer v0.16 EPCAM Chirag Patel Gene: epcam has been classified as Green List (High Evidence).
Endometrial Cancer v0.15 BRCA1 Chirag Patel Classified gene: BRCA1 as Green List (high evidence)
Endometrial Cancer v0.15 BRCA1 Chirag Patel Gene: brca1 has been classified as Green List (High Evidence).
Endometrial Cancer v0.14 PMS2 Chirag Patel Classified gene: PMS2 as Green List (high evidence)
Endometrial Cancer v0.14 PMS2 Chirag Patel Gene: pms2 has been classified as Green List (High Evidence).
Endometrial Cancer v0.13 MSH6 Chirag Patel Classified gene: MSH6 as Green List (high evidence)
Endometrial Cancer v0.13 MSH6 Chirag Patel Gene: msh6 has been classified as Green List (High Evidence).
Endometrial Cancer v0.12 MSH2 Chirag Patel Classified gene: MSH2 as Green List (high evidence)
Endometrial Cancer v0.12 MSH2 Chirag Patel Gene: msh2 has been classified as Green List (High Evidence).
Endometrial Cancer v0.11 MLH1 Chirag Patel Classified gene: MLH1 as Green List (high evidence)
Endometrial Cancer v0.11 MLH1 Chirag Patel Gene: mlh1 has been classified as Green List (High Evidence).
Endometrial Cancer v0.10 POLE Chirag Patel gene: POLE was added
gene: POLE was added to Endometrial Cancer. Sources: Expert list,Expert Review
Mode of inheritance for gene: POLE was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: POLE were set to Endometrial cancer, MONDO:0011962; POLE-related polyposis and colorectal cancer syndrome, MONDO:0100287; POLE-associated polyposis, MIM#615083
Mode of pathogenicity for gene: POLE was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: POLE was set to GREEN
Added comment: ClinGen definitive. Endometrial cancers reported in condition. GOF variants.
Sources: Expert list, Expert Review
Endometrial Cancer v0.9 POLD1 Chirag Patel gene: POLD1 was added
gene: POLD1 was added to Endometrial Cancer. Sources: Expert list,Expert Review
Mode of inheritance for gene: POLD1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: POLD1 were set to Endometrial cancer, MONDO:0011962; POLD1-related polyposis and colorectal cancer syndrome, MONDO:0100351; POLD1-associated polyposis, MIM#612591
Mode of pathogenicity for gene: POLD1 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: POLD1 was set to GREEN
Added comment: ClinGen definitive. Endometrial cancers reported in condition. GOF variants.
Sources: Expert list, Expert Review
Endometrial Cancer v0.8 TP53 Chirag Patel gene: TP53 was added
gene: TP53 was added to Endometrial Cancer. Sources: Expert list,Expert Review
Mode of inheritance for gene: TP53 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: TP53 were set to Endometrial cancer, MONDO:0011962; Li-Fraumeni syndrome, MONDO:0018875; Li-Fraumeni syndrome, MIM#151623
Review for gene: TP53 was set to GREEN
Added comment: ClinGen definitive. Endometrial cancers reported in condition.

Consider possibility that an identified variant could represent ACE (aberrant clonal expansion), which can be due to clonal haematopoiesis of indeterminate potential (CHIP) or an occult hematologic malignancy, especially in older patients who have undergone prior chemotherapy (PMID: 36040522).
Sources: Expert list, Expert Review
Endometrial Cancer v0.7 PTEN Chirag Patel gene: PTEN was added
gene: PTEN was added to Endometrial Cancer. Sources: Expert list,Expert Review
Mode of inheritance for gene: PTEN was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: PTEN were set to Endometrial cancer, MONDO:0011962; PTEN hamartoma tumor syndrome, MONDO:0017623; PTEN hamartoma tumour syndromes, MIM#158350
Review for gene: PTEN was set to GREEN
Added comment: ClinGen definitive. Endometrial cancers reported in condition.
Sources: Expert list, Expert Review
Endometrial Cancer v0.6 EPCAM Chirag Patel gene: EPCAM was added
gene: EPCAM was added to Endometrial Cancer. Sources: Expert list,Expert Review
Mode of inheritance for gene: EPCAM was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: EPCAM were set to Endometrial cancer, MONDO:0011962; Lynch syndrome 8, MONDO:0013196; Lynch syndrome 8, MIM#613244
Review for gene: EPCAM was set to GREEN
Added comment: ClinGen definitive. Endometrial cancers reported in condition.

Deletion of 3’end of EPCAM gene leading to epigenetic silencing of adjacent downstream MSH2 gene.
Sources: Expert list, Expert Review
Endometrial Cancer v0.5 BRCA1 Chirag Patel gene: BRCA1 was added
gene: BRCA1 was added to Endometrial Cancer. Sources: Expert list,Expert Review
Mode of inheritance for gene: BRCA1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: BRCA1 were set to Endometrial cancer, MONDO:0011962; BRCA1-related cancer predisposition, MONDO:0700268; Breast-ovarian cancer, familial, 1, MIM#604370
Review for gene: BRCA1 was set to GREEN
Added comment: ClinGen definitive. Endometrial cancers reported in condition.
Sources: Expert list, Expert Review
Endometrial Cancer v0.4 PMS2 Chirag Patel gene: PMS2 was added
gene: PMS2 was added to Endometrial Cancer. Sources: Expert list,Expert Review
Mode of inheritance for gene: PMS2 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Phenotypes for gene: PMS2 were set to Endometrial cancer, MONDO:0011962; Lynch syndrome 4, MONDO:0013699; Mismatch repair cancer syndrome 4, MONDO:0030843; Lynch syndrome 4, MIM#614337; Mismatch repair cancer syndrome 4, MIM#619101
Review for gene: PMS2 was set to GREEN
Added comment: ClinGen definitive. Endometrial cancers reported in condition.

Note: there is a high level of homology between PMS2 and pseudogenes
Sources: Expert list, Expert Review
Endometrial Cancer v0.3 MSH6 Chirag Patel gene: MSH6 was added
gene: MSH6 was added to Endometrial Cancer. Sources: Expert list,Expert Review
Mode of inheritance for gene: MSH6 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Phenotypes for gene: MSH6 were set to Endometrial cancer, MONDO:0011962; Lynch syndrome 5, MONDO:0013710; Mismatch repair cancer syndrome 3, MONDO:0030841; Lynch syndrome 5, MIM#614350; Mismatch repair cancer syndrome 3, MIM#619097
Review for gene: MSH6 was set to GREEN
Added comment: ClinGen definitive. Endometrial cancers reported in condition.
Sources: Expert list, Expert Review
Endometrial Cancer v0.2 MSH2 Chirag Patel gene: MSH2 was added
gene: MSH2 was added to Endometrial Cancer. Sources: Expert list,Expert Review
Mode of inheritance for gene: MSH2 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Phenotypes for gene: MSH2 were set to Endometrial cancer, MONDO:0011962; Lynch syndrome 1, MONDO:0007356; Mismatch repair cancer syndrome 2, MONDO:0030840; Lynch syndrome 1, MIM#120435; Mismatch repair cancer syndrome 2, MIM#619096
Review for gene: MSH2 was set to GREEN
Added comment: ClinGen definitive. Endometrial cancers reported in condition.
Sources: Expert list, Expert Review
Endometrial Cancer v0.1 MLH1 Chirag Patel gene: MLH1 was added
gene: MLH1 was added to Endometrial Cancer. Sources: Expert list,Expert Review
Mode of inheritance for gene: MLH1 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Phenotypes for gene: MLH1 were set to Endometrial cancer, MONDO:0011962; Lynch syndrome 2, MONDO:0012249; Mismatch repair cancer syndrome 1, MONDO:0010159; Lynch syndrome 2, MIM#609310; Mismatch repair cancer syndrome 1, MIM#276300
Review for gene: MLH1 was set to GREEN
Added comment: ClinGen definitive. Endometrial cancers reported in condition.
Sources: Expert list, Expert Review
Prostate Cancer v0.24 HOXB13 Chirag Patel Classified gene: HOXB13 as Green List (high evidence)
Prostate Cancer v0.24 HOXB13 Chirag Patel Gene: hoxb13 has been classified as Green List (High Evidence).
Prostate Cancer v0.23 HOXB13 Chirag Patel gene: HOXB13 was added
gene: HOXB13 was added to Prostate Cancer. Sources: Expert list,Expert Review,Literature
Mode of inheritance for gene: HOXB13 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HOXB13 were set to PMID: 22236224, 30730552, 38766261
Phenotypes for gene: HOXB13 were set to Prostate cancer, MONDO:0008315; Prostate cancer, susceptibility to, MIM#610997
Review for gene: HOXB13 was set to GREEN
Added comment: Established gene-disease association (particularly G84E variant).

Several studies demonstrating the association of the HOXB13 G84E variant with prostate cancer, including a European study that showed an increased frequency of the HOXB13 G84E variant in patients with prostate cancer at 1.4% compared to those without prostate cancer at 0.1%.
Sources: Expert list, Expert Review, Literature
Prostate Cancer v0.22 CHEK2 Chirag Patel Classified gene: CHEK2 as Green List (high evidence)
Prostate Cancer v0.22 CHEK2 Chirag Patel Gene: chek2 has been classified as Green List (High Evidence).
Prostate Cancer v0.21 TP53 Chirag Patel Classified gene: TP53 as Green List (high evidence)
Prostate Cancer v0.21 TP53 Chirag Patel Gene: tp53 has been classified as Green List (High Evidence).
Prostate Cancer v0.20 PALB2 Chirag Patel Classified gene: PALB2 as Green List (high evidence)
Prostate Cancer v0.20 PALB2 Chirag Patel Gene: palb2 has been classified as Green List (High Evidence).
Prostate Cancer v0.19 EPCAM Chirag Patel Classified gene: EPCAM as Green List (high evidence)
Prostate Cancer v0.19 EPCAM Chirag Patel Gene: epcam has been classified as Green List (High Evidence).
Prostate Cancer v0.18 BRCA2 Chirag Patel Classified gene: BRCA2 as Green List (high evidence)
Prostate Cancer v0.18 BRCA2 Chirag Patel Gene: brca2 has been classified as Green List (High Evidence).
Prostate Cancer v0.17 BRCA1 Chirag Patel Classified gene: BRCA1 as Green List (high evidence)
Prostate Cancer v0.17 BRCA1 Chirag Patel Gene: brca1 has been classified as Green List (High Evidence).
Prostate Cancer v0.16 ATM Chirag Patel Classified gene: ATM as Green List (high evidence)
Prostate Cancer v0.16 ATM Chirag Patel Gene: atm has been classified as Green List (High Evidence).
Prostate Cancer v0.15 CHEK2 Chirag Patel gene: CHEK2 was added
gene: CHEK2 was added to Prostate Cancer. Sources: Expert list,Expert Review,Literature
Mode of inheritance for gene: CHEK2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CHEK2 were set to PMID: 33322746, 36529447
Phenotypes for gene: CHEK2 were set to Prostate cancer, MONDO:0008315; CHEK2-related cancer predisposition, MONDO:0700271; Breast/prostate cancer, susceptibility to, MIM#609265
Review for gene: CHEK2 was set to GREEN
Added comment: Established gene-disease association. Prostate cancers reported in condition.

Consider possibility that an identified variant could represent ACE (aberrant clonal expansion), which can be due to clonal haematopoiesis of indeterminate potential (CHIP) or an occult hematologic malignancy, especially in older patients who have undergone prior chemotherapy (PMID: 36040522).
Sources: Expert list, Expert Review, Literature
Prostate Cancer v0.14 TP53 Chirag Patel gene: TP53 was added
gene: TP53 was added to Prostate Cancer. Sources: Expert list,Expert Review
Mode of inheritance for gene: TP53 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: TP53 were set to Prostate cancer, MONDO:0008315; Li-Fraumeni syndrome, MONDO:0018875; Li-Fraumeni syndrome, MIM#151623
Review for gene: TP53 was set to GREEN
Added comment: ClinGen definitive. Prostate cancers reported in condition.

Consider possibility that an identified variant could represent ACE (aberrant clonal expansion), which can be due to clonal haematopoiesis of indeterminate potential (CHIP) or an occult hematologic malignancy, especially in older patients who have undergone prior chemotherapy (PMID: 36040522).
Sources: Expert list, Expert Review
Prostate Cancer v0.13 PALB2 Chirag Patel gene: PALB2 was added
gene: PALB2 was added to Prostate Cancer. Sources: Expert list,Expert Review
Mode of inheritance for gene: PALB2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: PALB2 were set to Prostate cancer, MONDO:0008315; PALB2-related cancer predisposition, MONDO:0700272; Breast-ovarian cancer, familial, susceptibility to, 5, MIM#620442; Pancreatic cancer, susceptibility to, 3, MIM#613348
Review for gene: PALB2 was set to GREEN
Added comment: ClinGen definitive. Prostate cancers reported in condition.
Sources: Expert list, Expert Review
Prostate Cancer v0.12 EPCAM Chirag Patel gene: EPCAM was added
gene: EPCAM was added to Prostate Cancer. Sources: Expert list,Expert Review
Mode of inheritance for gene: EPCAM was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: EPCAM were set to Prostate cancer, MONDO:0008315; Lynch syndrome 8, MONDO:0013196; Lynch syndrome 8, MIM#613244
Review for gene: EPCAM was set to GREEN
Added comment: ClinGen definitive. Prostate cancers reported in condition.

Deletion of 3’end of EPCAM gene leading to epigenetic silencing of adjacent downstream MSH2 gene.
Sources: Expert list, Expert Review
Prostate Cancer v0.11 BRCA2 Chirag Patel gene: BRCA2 was added
gene: BRCA2 was added to Prostate Cancer. Sources: Expert list,Expert Review
Mode of inheritance for gene: BRCA2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: BRCA2 were set to Prostate cancer, MONDO:0008315; BRCA2-related cancer predisposition, MONDO:0700269; Breast-ovarian cancer, familial, 2, MIM#612555
Review for gene: BRCA2 was set to GREEN
Added comment: ClinGen definitive. Prostate cancers reported in condition.
Sources: Expert list, Expert Review
Prostate Cancer v0.10 BRCA1 Chirag Patel gene: BRCA1 was added
gene: BRCA1 was added to Prostate Cancer. Sources: Expert list,Expert Review
Mode of inheritance for gene: BRCA1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: BRCA1 were set to Prostate cancer, MONDO:0008315; BRCA1-related cancer predisposition, MONDO:0700268; Breast-ovarian cancer, familial, 1, MIM#604370
Review for gene: BRCA1 was set to GREEN
Added comment: ClinGen definitive. Prostate cancers reported in condition.
Sources: Expert list, Expert Review
Prostate Cancer v0.9 ATM Chirag Patel gene: ATM was added
gene: ATM was added to Prostate Cancer. Sources: Expert list,Expert Review
Mode of inheritance for gene: ATM was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: ATM were set to Prostate cancer, MONDO:0008315; ATM-related cancer predisposition, MONDO:0700270; Breast cancer, susceptibility to, MIM#114480
Review for gene: ATM was set to GREEN
Added comment: ClinGen definitive. Prostate cancers reported in condition.

Consider possibility that an identified variant could represent ACE (aberrant clonal expansion), which can be due to clonal haematopoiesis of indeterminate potential (CHIP) or an occult hematologic malignancy, especially in older patients who have undergone prior chemotherapy (PMID: 36040522).
Sources: Expert list, Expert Review
Prostate Cancer v0.8 MLH1 Chirag Patel Classified gene: MLH1 as Green List (high evidence)
Prostate Cancer v0.8 MLH1 Chirag Patel Gene: mlh1 has been classified as Green List (High Evidence).
Prostate Cancer v0.7 MSH2 Chirag Patel Classified gene: MSH2 as Green List (high evidence)
Prostate Cancer v0.7 MSH2 Chirag Patel Gene: msh2 has been classified as Green List (High Evidence).
Prostate Cancer v0.6 MSH6 Chirag Patel Classified gene: MSH6 as Green List (high evidence)
Prostate Cancer v0.6 MSH6 Chirag Patel Gene: msh6 has been classified as Green List (High Evidence).
Prostate Cancer v0.5 PMS2 Chirag Patel Classified gene: PMS2 as Green List (high evidence)
Prostate Cancer v0.5 PMS2 Chirag Patel Gene: pms2 has been classified as Green List (High Evidence).
Prostate Cancer v0.4 PMS2 Chirag Patel gene: PMS2 was added
gene: PMS2 was added to Prostate Cancer. Sources: Expert list,Expert Review
Mode of inheritance for gene: PMS2 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Phenotypes for gene: PMS2 were set to Prostate cancer, MONDO:0008315; Lynch syndrome 4, MONDO:0013699; Mismatch repair cancer syndrome 4, MONDO:0030843; Lynch syndrome 4, MIM#614337; Mismatch repair cancer syndrome 4, MIM#619101
Review for gene: PMS2 was set to GREEN
Added comment: ClinGen definitive. Prostate cancers reported in condition.

Note: there is a high level of homology between PMS2 and pseudogenes.
Sources: Expert list, Expert Review
Prostate Cancer v0.3 MSH6 Chirag Patel gene: MSH6 was added
gene: MSH6 was added to Prostate Cancer. Sources: Expert list,Expert Review
Mode of inheritance for gene: MSH6 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Phenotypes for gene: MSH6 were set to Prostate cancer, MONDO:0008315; Lynch syndrome 5, MONDO:0013710; Mismatch repair cancer syndrome 3, MONDO:0030841; Lynch syndrome 5, MIM#614350; Mismatch repair cancer syndrome 3, MIM#619097
Review for gene: MSH6 was set to GREEN
Added comment: ClinGen definitive. Prostate cancers reported in condition.
Sources: Expert list, Expert Review
Prostate Cancer v0.2 MSH2 Chirag Patel gene: MSH2 was added
gene: MSH2 was added to Prostate Cancer. Sources: Expert list,Expert Review
Mode of inheritance for gene: MSH2 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Phenotypes for gene: MSH2 were set to Prostate cancer, MONDO:0008315; Lynch syndrome 1, MONDO:0007356; Mismatch repair cancer syndrome 2, MONDO:0030840; Lynch syndrome 1, MIM#120435; Mismatch repair cancer syndrome 2, MIM#619096
Review for gene: MSH2 was set to GREEN
Added comment: ClinGen definitive. Prostate cancers reported in condition.
Sources: Expert list, Expert Review
Prostate Cancer v0.1 MLH1 Chirag Patel gene: MLH1 was added
gene: MLH1 was added to Prostate Cancer. Sources: Expert list,Expert Review
Mode of inheritance for gene: MLH1 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Phenotypes for gene: MLH1 were set to Prostate cancer, MONDO:0008315; Lynch syndrome 2, MONDO:0012249; Mismatch repair cancer syndrome 1, MONDO:0010159; Lynch syndrome 2, MIM#609310; Mismatch repair cancer syndrome 1, MIM#276300
Review for gene: MLH1 was set to GREEN
Added comment: ClinGen definitive. Prostate cancers reported in condition.
Sources: Expert list, Expert Review
Paraganglioma_phaeochromocytoma v0.30 EGLN1 Chirag Patel gene: EGLN1 was added
gene: EGLN1 was added to Paraganglioma_phaeochromocytoma. Sources: Expert list,Literature,Expert Review
Mode of inheritance for gene: EGLN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: EGLN1 were set to PMID: 19092153, 36013579
Phenotypes for gene: EGLN1 were set to Paraganglioma, MONDO:0000448; Pheochromocytoma, MONDO:0008233; Pheochromocytoma/paraganglioma, susceptibility to, no MIM#; Erythrocytosis, familial, 3, MIM#609820
Review for gene: EGLN1 was set to RED
Added comment: PMID: 19092153
1 patient with erythrocytosis and recurrent paraganglioma with a novel de novo germline EGLN1 gene (PHD2) variant (H374R). There was loss of heterozygosity of PHD2 in the tumour. Wild-type PHD2 caused the dose-related suppression of HIF-α–mediated induction of the reporter gene, whereas the response to the H374R PHD2 mutant was impaired.

PMID: 36013579
1 patient with metastatic pheochromocytoma and chronic myeloid leukaemia (CML) without polycythaemia, and a novel germline EGLN1 gene variant (c.153G>A, p.W51*) inherited from unaffected father. The patient had lower expression of PHD2 and higher levels of HIF2α compared to the healthy adrenal tissues, confirming that PHD2 down-regulation results in HIF2α stabilization.
Sources: Expert list, Literature, Expert Review
Paraganglioma_phaeochromocytoma v0.29 EPAS1 Chirag Patel gene: EPAS1 was added
gene: EPAS1 was added to Paraganglioma_phaeochromocytoma. Sources: Expert list,Expert Review,Literature
Mode of inheritance for gene: EPAS1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: EPAS1 were set to PMID: 22931260, 23418310, 33300499
Phenotypes for gene: EPAS1 were set to Paraganglioma, MONDO:0000448; Pheochromocytoma, MONDO:0008233; Pheochromocytoma/paraganglioma, susceptibility to, no MIM#; Erythrocytosis, familial, 4, MIM#611783
Review for gene: EPAS1 was set to RED
Added comment: PMID: 22931260
2 somatic gain-of-function variants in EPAS1 gene encoding hypoxia-inducible factor 2α (HIF2A) in two patients (1 x paraganglioma, 1 x paraganglioma + somatostatinoma). Both patients had polycythemia (congenital erythrocytosis). The two variants were associated with increased HIF-2α activity and increased protein half-life.

PMID: 23418310
7 patients with somatic variants in EPAS1 gene (4 x multiple PGLs, 3 x single sporadic PCC/PGL). Gene expression analysis of EPAS1-mutated tumours revealed similar mRNA EPAS1 levels to those found in SDH-gene- and VHL-mutated cases and a significant up-regulation of two hypoxia-induced genes (PCSK6 and GNA14). Multiplex-PCR screening for small rearrangements detected a specific EPAS1 gain in another EPAS1-mutated tumour and in 3 non-EPAS1-mutated cases.

PMID: 33300499
6 germline missense variants in EPAS1 gene in patients with PPGL (Arg247Ser, Phe374Tyr, His194Arg, Pro785Thr, Ile789Val, Thr766Pro). In transient transfection studies, EPAS1/HIF-2α Arg247Ser, Phe374Tyr and Pro785Thr were all stable in normoxia. In co-immunoprecipitation assays, only the Arg247Ser variant showed diminished interaction with pVHL. A direct interaction between HIF-2α Arg247 and pVHL was confirmed in structural models. Transactivation was assessed by means of a HRE-containing reporter gene in transiently transfected cells, and significantly higher reporter activity was only observed with EPAS1/HIF-2α Phe374Tyr and Pro785Thr. In conclusion, three germline EPAS1 variants (c.739C>A (p.Arg247Ser), c.1121T>A (p.Phe374Tyr) and c.2353C>A (p.Pro785Thr)) all have some functional features in common with somatic activating mutations. Their findings suggest that these three germline variants are hypermorphic alleles that may act as modifiers to the expression of PPGLs.
Sources: Expert list, Expert Review, Literature
Paraganglioma_phaeochromocytoma v0.28 MDH2 Chirag Patel gene: MDH2 was added
gene: MDH2 was added to Paraganglioma_phaeochromocytoma. Sources: Expert list,Expert Review,Literature
Mode of inheritance for gene: MDH2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MDH2 were set to PMID: 25766404, 30008476
Phenotypes for gene: MDH2 were set to Paraganglioma, MONDO:0000448; Pheochromocytoma, MONDO:0008233; Pheochromocytoma/paraganglioma, susceptibility to, no MIM#; Developmental and epileptic encephalopathy 51, MIM#617339
Review for gene: MDH2 was set to RED
Added comment: PMID: 25766404
WES of tumour in 1 patient with multiple malignant paragangliomas identified a germline splice variant in MDH2 (c.429+1G>T)(variant confirmed in blood). Sanger sequencing of the 4 available primary tumours from the patient revealed loss of the MDH2 wild-type allele in two tumours, indicating loss of heterozygosity. MDH2 mRNA expression analysis revealed 6-14 fold lower levels of MDH2 expression in the four tumors carrying the variant compared with control patients. Substantially lower levels of MDH2 protein were detected in the MDH2-related tumours compared with control patients. Knockdown (KD) of MDH2 in HeLa cells by shRNA triggered the accumulation of both malate and fumarate, which was reversed by transient introduction of WT MDH2 cDNA. Segregation testing found the variant in 2 out of 5 asymptomatic relatives. MDH2 mRNA and protein expression in blood cells were statistically significantly lower in the two carriers compared with control patients. Subsequent clinical testing detected high levels of normetanephrine for one of the carriers, thus confirming the presence of the disease.

PMID: 30008476
Sequencing of MDH2 in 830 patients with PPGLs (negative for the main PPGL driver genes), identified 5 germline variants with potential involvement in pathogenicity (3 x missense, 1 x in-frame deletion, 1 x splice-site). None of the variants was associated with an altered MDH2 localization, or mitochondrial quantity and morphology. LOH was not detected in any of the tumours carrying the missense variants, but was seen in the patient with the inframe deletion.
Sources: Expert list, Expert Review, Literature
Paraganglioma_phaeochromocytoma v0.27 PRKAR1A Chirag Patel gene: PRKAR1A was added
gene: PRKAR1A was added to Paraganglioma_phaeochromocytoma. Sources: Expert list,Expert Review,Literature
Mode of inheritance for gene: PRKAR1A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: PRKAR1A were set to Paraganglioma, MONDO:0000448; Pheochromocytoma, MONDO:0008233; Carney complex, type 1, MIM#160980
Review for gene: PRKAR1A was set to RED
Added comment: ClinGen definitive. BUT paragangliomas and phaeochromocytomas not classically reported in condition.
Sources: Expert list, Expert Review, Literature
Paraganglioma_phaeochromocytoma v0.26 SLC25A11 Chirag Patel gene: SLC25A11 was added
gene: SLC25A11 was added to Paraganglioma_phaeochromocytoma. Sources: Expert list,Expert Review,Literature
Mode of inheritance for gene: SLC25A11 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SLC25A11 were set to PMID: 29431636
Phenotypes for gene: SLC25A11 were set to Paragangliomas 6, MONDO:0032767; Pheochromocytoma, MONDO:0008233; Hereditary pheochromocytoma-paraganglioma, MONDO:0017366; Pheochromocytoma/paraganglioma syndrome 6, MIM#618464
Review for gene: SLC25A11 was set to RED
Added comment: 7 patients with paraganglioma with germline variants in the SLC25A11 gene. The variants were missense, splice site, frameshift, and silent change. The variants were not found in dbSNP or ExAC databases. The missense variants affected highly conserved residues in the signature protein sequence or alpha matrix helix. The variants were associated with loss of heterozygosity, suggesting that SLC25A11 acts as a tumour suppressor gene. Immunohistochemical studies on the tumour tissue showed absence of the SLC25A11 protein and hypermethylation of DNA and histones compared to controls. Pseudohypoxic and hypermethylator phenotypes comparable with those described in SDHx- and FH-related tumours were observed both in tumours with mutated SLC25A11 and in Slc25a11Δ/Δ immortalized mouse chromaffin knockout cells generated by CRISPR-Cas9 technology.
Sources: Expert list, Expert Review, Literature
Paraganglioma_phaeochromocytoma v0.25 DLST Chirag Patel gene: DLST was added
gene: DLST was added to Paraganglioma_phaeochromocytoma. Sources: Expert list,Expert Review,Literature
Mode of inheritance for gene: DLST was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DLST were set to PMID: 30929736, 33180916
Phenotypes for gene: DLST were set to Paragangliomas 7, MONDO:0032771; Pheochromocytoma, MONDO:0008233; Hereditary pheochromocytoma-paraganglioma, MONDO:0017366; Pheochromocytoma/paraganglioma syndrome 7, MIM#618475
Review for gene: DLST was set to RED
Added comment: PMID: 30929736
4 unrelated patients with pheochromocytomas and paragangliomas with the same germline heterozygous missense variant in DLST gene (G374E). Analysis of tumour tissue available from 3 of the patients showed loss of heterozygosity (LOH) for DLST due to uniparental disomy (UPD) of the paternal chromosome. None of the patients had a family history of the disorder, although 3 probands had asymptomatic family members who carried the mutation, consistent with incomplete penetrance. Knockdown of the DLST gene in human H838 cells resulted in a significant block in carbon flow in the tricarboxylic acid (TCA) cycle, which was rescued by wildtype DLST, but not by the G374E mutant. Many PPGL genes encode proteins involved in the tricarboxylic acid (TCA) cycle. In vitro functional expression studies showed that the G374E mutant had compromised catalytic activity compared to wildtype, resulting in a high alpha-KG/fumarate ratio and accumulation of the oncometabolite 2-hydroxyglutaric acid (2HG), particularly the L-2HG enantiomer. Analysis of patient tumours showed strong immunostaining for DLST as well as a hypermethylated phenotype, categorized in the non-CIMP (CpG island methylator phenotype) cluster, and a pseudohypoxic state with increased expression of HIF3A. The findings indicated that DLST can act as a tumour suppression gene. Heterozygous missense variants in DLST (R231Q, D304N, and Y422C) were found in 3 additional probands, but in vitro functional studies of these 3 other missense variants indicated that they behaved similar to wildtype DLST in the assay used. None of the patients besides those with the G374E variant showed LOH in tumour tissue.

PMID: 30929736
2 unrelated patients with pheochromocytomas and paragangliomas with 2 different germline heterozygous missense variants in DLST gene (Pro384Leu, Gly374Glu). Tumour testing in 1 patient identified a second somatic missense variant in DLST (Thr383Ala). They showed the p.(Pro384Leu) variant, located in the catalytic site of DLST, leads to a dramatic but not complete loss of catalytic activity.
Sources: Expert list, Expert Review, Literature
Paraganglioma_phaeochromocytoma v0.24 FH Chirag Patel Classified gene: FH as Green List (high evidence)
Paraganglioma_phaeochromocytoma v0.24 FH Chirag Patel Gene: fh has been classified as Green List (High Evidence).
Paraganglioma_phaeochromocytoma v0.23 MEN1 Chirag Patel Classified gene: MEN1 as Green List (high evidence)
Paraganglioma_phaeochromocytoma v0.23 MEN1 Chirag Patel Gene: men1 has been classified as Green List (High Evidence).
Paraganglioma_phaeochromocytoma v0.22 NF1 Chirag Patel Classified gene: NF1 as Green List (high evidence)
Paraganglioma_phaeochromocytoma v0.22 NF1 Chirag Patel Gene: nf1 has been classified as Green List (High Evidence).
Paraganglioma_phaeochromocytoma v0.21 RET Chirag Patel Classified gene: RET as Green List (high evidence)
Paraganglioma_phaeochromocytoma v0.21 RET Chirag Patel Gene: ret has been classified as Green List (High Evidence).
Paraganglioma_phaeochromocytoma v0.20 RET Chirag Patel gene: RET was added
gene: RET was added to Paraganglioma_phaeochromocytoma. Sources: Expert list,Expert Review
Mode of inheritance for gene: RET was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: RET were set to Paraganglioma, MONDO:0000448; Pheochromocytoma, MONDO:0008233; Multiple endocrine neoplasia type 2A, MONDO:0008234; Multiple endocrine neoplasia type 2B, MONDO:0008082; Multiple endocrine neoplasia, type 2A, MIM#171400; Multiple endocrine neoplasia, type 2B, MIM#162300; Pheochromocytoma, MIM#171300; Medullary thyroid carcinoma, MIM#155240; Pheochromocytoma, susceptibility to, MIM#171300
Mode of pathogenicity for gene: RET was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: RET was set to GREEN
Added comment: ClinGen definitive. Paragangliomas and phaeochromocytomas reported in condition. GOF variants.
Sources: Expert list, Expert Review
Paraganglioma_phaeochromocytoma v0.19 NF1 Chirag Patel gene: NF1 was added
gene: NF1 was added to Paraganglioma_phaeochromocytoma. Sources: Expert list,Expert Review
Mode of inheritance for gene: NF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: NF1 were set to Paraganglioma, MONDO:0000448; Pheochromocytoma, MONDO:0008233; Neurofibromatosis type 1, MONDO:0018975; Neurofibromatosis, type 1, MIM#162200
Review for gene: NF1 was set to GREEN
Added comment: ClinGen definitive. Paragangliomas and phaeochromocytomas reported in condition.

Single gene testing may be more appropriate if clinical features of NF1.
Sources: Expert list, Expert Review
Paraganglioma_phaeochromocytoma v0.18 MEN1 Chirag Patel gene: MEN1 was added
gene: MEN1 was added to Paraganglioma_phaeochromocytoma. Sources: Expert list,Expert Review
Mode of inheritance for gene: MEN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: MEN1 were set to Paraganglioma, MONDO:0000448; Pheochromocytoma, MONDO:0008233; Multiple endocrine neoplasia type 1, MONDO:0007540; Multiple endocrine neoplasia, type 1, MIM#131100
Review for gene: MEN1 was set to GREEN
Added comment: ClinGen definitive. Paragangliomas and phaeochromocytomas reported in condition.
Sources: Expert list, Expert Review
Paraganglioma_phaeochromocytoma v0.17 FH Chirag Patel gene: FH was added
gene: FH was added to Paraganglioma_phaeochromocytoma. Sources: Expert list,Expert Review
Mode of inheritance for gene: FH was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: FH were set to Paraganglioma, MONDO:0000448; Pheochromocytoma, MONDO:0008233; Hereditary leiomyomatosis and renal cell cancer, MONDO:0007888; Leiomyomatosis and renal cell cancer, MIM#150800
Review for gene: FH was set to GREEN
Added comment: ClinGen definitive. Paragangliomas and phaeochromocytomas reported in condition.
Sources: Expert list, Expert Review
Paraganglioma_phaeochromocytoma v0.16 MAX Chirag Patel Classified gene: MAX as Green List (high evidence)
Paraganglioma_phaeochromocytoma v0.16 MAX Chirag Patel Gene: max has been classified as Green List (High Evidence).
Paraganglioma_phaeochromocytoma v0.15 SDHA Chirag Patel Classified gene: SDHA as Green List (high evidence)
Paraganglioma_phaeochromocytoma v0.15 SDHA Chirag Patel Gene: sdha has been classified as Green List (High Evidence).
Paraganglioma_phaeochromocytoma v0.14 SDHAF2 Chirag Patel Classified gene: SDHAF2 as Green List (high evidence)
Paraganglioma_phaeochromocytoma v0.14 SDHAF2 Chirag Patel Gene: sdhaf2 has been classified as Green List (High Evidence).
Paraganglioma_phaeochromocytoma v0.13 SDHB Chirag Patel Classified gene: SDHB as Green List (high evidence)
Paraganglioma_phaeochromocytoma v0.13 SDHB Chirag Patel Gene: sdhb has been classified as Green List (High Evidence).
Paraganglioma_phaeochromocytoma v0.12 SDHC Chirag Patel Classified gene: SDHC as Green List (high evidence)
Paraganglioma_phaeochromocytoma v0.12 SDHC Chirag Patel Gene: sdhc has been classified as Green List (High Evidence).
Paraganglioma_phaeochromocytoma v0.11 SDHD Chirag Patel Classified gene: SDHD as Green List (high evidence)
Paraganglioma_phaeochromocytoma v0.11 SDHD Chirag Patel Gene: sdhd has been classified as Green List (High Evidence).
Paraganglioma_phaeochromocytoma v0.10 TMEM127 Chirag Patel Classified gene: TMEM127 as Green List (high evidence)
Paraganglioma_phaeochromocytoma v0.10 TMEM127 Chirag Patel Gene: tmem127 has been classified as Green List (High Evidence).
Paraganglioma_phaeochromocytoma v0.9 VHL Chirag Patel Classified gene: VHL as Green List (high evidence)
Paraganglioma_phaeochromocytoma v0.9 VHL Chirag Patel Gene: vhl has been classified as Green List (High Evidence).
Paraganglioma_phaeochromocytoma v0.8 VHL Chirag Patel gene: VHL was added
gene: VHL was added to Paraganglioma_phaeochromocytoma. Sources: Expert list,Expert Review
Mode of inheritance for gene: VHL was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: VHL were set to Paraganglioma, MONDO:0000448; Pheochromocytoma, MONDO:0008233; Von Hippel-Lindau disease, MONDO:0008667; von Hippel-Lindau syndrome, MIM#193300; Pheochromocytoma, susceptibility to, MIM#171300
Review for gene: VHL was set to GREEN
Added comment: ClinGen definitive. Paragangliomas and phaeochromocytomas reported in condition.
Sources: Expert list, Expert Review
Paraganglioma_phaeochromocytoma v0.7 TMEM127 Chirag Patel gene: TMEM127 was added
gene: TMEM127 was added to Paraganglioma_phaeochromocytoma. Sources: Expert list,Expert Review
Mode of inheritance for gene: TMEM127 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: TMEM127 were set to Paraganglioma, MONDO:0000448; Pheochromocytoma, MONDO:0008233; Hereditary pheochromocytoma-paraganglioma, MONDO:0017366; Pheochromocytoma, susceptibility to, MIM#171300
Review for gene: TMEM127 was set to GREEN
Added comment: ClinGen definitive.
Sources: Expert list, Expert Review
Paraganglioma_phaeochromocytoma v0.6 SDHD Chirag Patel gene: SDHD was added
gene: SDHD was added to Paraganglioma_phaeochromocytoma. Sources: Expert list,Expert Review
Mode of inheritance for gene: SDHD was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: SDHD were set to Paragangliomas 1, MONDO:0008192; Pheochromocytoma, MONDO:0008233; Hereditary pheochromocytoma-paraganglioma, MONDO:0017366; Pheochromocytoma/paraganglioma syndrome 1, MIM#168000
Review for gene: SDHD was set to GREEN
Added comment: ClinGen definitive.
Sources: Expert list, Expert Review
Paraganglioma_phaeochromocytoma v0.5 SDHC Chirag Patel gene: SDHC was added
gene: SDHC was added to Paraganglioma_phaeochromocytoma. Sources: Expert list,Expert Review
Mode of inheritance for gene: SDHC was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: SDHC were set to Paragangliomas 3, MONDO:0011544; Pheochromocytoma, MONDO:0008233; Hereditary pheochromocytoma-paraganglioma, MONDO:0017366; Pheochromocytoma/paraganglioma syndrome 3, MIM#605373
Review for gene: SDHC was set to GREEN
Added comment: ClinGen definitive.
Sources: Expert list, Expert Review
Paraganglioma_phaeochromocytoma v0.4 SDHB Chirag Patel gene: SDHB was added
gene: SDHB was added to Paraganglioma_phaeochromocytoma. Sources: Expert list,Expert Review
Mode of inheritance for gene: SDHB was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: SDHB were set to Paragangliomas 4, MONDO:0007273; Pheochromocytoma, MONDO:0008233; Hereditary pheochromocytoma-paraganglioma, MONDO:0017366; Pheochromocytoma/paraganglioma syndrome 4, MIM#115310
Review for gene: SDHB was set to GREEN
Added comment: ClinGen definitive.
Sources: Expert list, Expert Review
Paraganglioma_phaeochromocytoma v0.3 SDHAF2 Chirag Patel gene: SDHAF2 was added
gene: SDHAF2 was added to Paraganglioma_phaeochromocytoma. Sources: Expert list,Expert Review
Mode of inheritance for gene: SDHAF2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: SDHAF2 were set to Paragangliomas 2, MONDO:0011121; Pheochromocytoma, MONDO:0008233; Hereditary pheochromocytoma-paraganglioma, MONDO:0017366; Pheochromocytoma/paraganglioma syndrome 2, MIM#601650
Review for gene: SDHAF2 was set to GREEN
Added comment: ClinGen definitive.
Sources: Expert list, Expert Review
Paraganglioma_phaeochromocytoma v0.2 SDHA Chirag Patel gene: SDHA was added
gene: SDHA was added to Paraganglioma_phaeochromocytoma. Sources: Expert list,Expert Review
Mode of inheritance for gene: SDHA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: SDHA were set to Paragangliomas 5, MONDO:0013602; Pheochromocytoma, MONDO:0008233; Hereditary pheochromocytoma-paraganglioma, MONDO:0017366; Pheochromocytoma/paraganglioma syndrome 5, MIM#614165
Review for gene: SDHA was set to GREEN
Added comment: ClinGen definitive.
Sources: Expert list, Expert Review
Paraganglioma_phaeochromocytoma v0.1 MAX Chirag Patel gene: MAX was added
gene: MAX was added to Paraganglioma_phaeochromocytoma. Sources: Expert list,Expert Review
Mode of inheritance for gene: MAX was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: MAX were set to Paraganglioma, MONDO:0000448; Pheochromocytoma, MONDO:0008233; Hereditary pheochromocytoma-paraganglioma, MONDO:0017366; Pheochromocytoma, susceptibility to, MIM#171300
Review for gene: MAX was set to GREEN
Added comment: ClinGen definitive.
Sources: Expert list, Expert Review
Prepair 1000+ v1.322 DYNC2LI1 Lilian Downie Marked gene: DYNC2LI1 as ready
Prepair 1000+ v1.322 DYNC2LI1 Lilian Downie Gene: dync2li1 has been classified as Green List (High Evidence).
Prepair 1000+ v1.322 DYNC2LI1 Lilian Downie Publications for gene: DYNC2LI1 were set to
Prepair 1000+ v1.321 EPCAM Lilian Downie Marked gene: EPCAM as ready
Prepair 1000+ v1.321 EPCAM Lilian Downie Gene: epcam has been classified as Green List (High Evidence).
Prepair 1000+ v1.321 EPCAM Lilian Downie Publications for gene: EPCAM were set to
Prepair 1000+ v1.320 EVC Lilian Downie Marked gene: EVC as ready
Prepair 1000+ v1.320 EVC Lilian Downie Gene: evc has been classified as Green List (High Evidence).
Prepair 1000+ v1.320 EVC Lilian Downie Publications for gene: EVC were set to
Prepair 1000+ v1.319 ERCC2 Lilian Downie Marked gene: ERCC2 as ready
Prepair 1000+ v1.319 ERCC2 Lilian Downie Gene: ercc2 has been classified as Green List (High Evidence).
Prepair 1000+ v1.319 ERCC2 Lilian Downie Phenotypes for gene: ERCC2 were changed from Cerebrooculofacioskeletal syndrome 2, 610756 (3) to Cerebrooculofacioskeletal syndrome 2, MIM# 610756; Trichothiodystrophy 1, photosensitive, MIM# 601675; Xeroderma pigmentosum, group D, MIM# 278730
Prepair 1000+ v1.318 ERCC2 Lilian Downie Publications for gene: ERCC2 were set to
Prepair 1000+ v1.317 ABCD1 Lilian Downie Marked gene: ABCD1 as ready
Prepair 1000+ v1.317 ABCD1 Lilian Downie Gene: abcd1 has been classified as Green List (High Evidence).
Prepair 1000+ v1.317 ABCD1 Lilian Downie Publications for gene: ABCD1 were set to
Prepair 1000+ v1.316 ACOX1 Lilian Downie Marked gene: ACOX1 as ready
Prepair 1000+ v1.316 ACOX1 Lilian Downie Gene: acox1 has been classified as Green List (High Evidence).
Prepair 1000+ v1.316 ACOX1 Lilian Downie Publications for gene: ACOX1 were set to
Prepair 1000+ v1.315 ADAMTS13 Lilian Downie Marked gene: ADAMTS13 as ready
Prepair 1000+ v1.315 ADAMTS13 Lilian Downie Gene: adamts13 has been classified as Green List (High Evidence).
Prepair 1000+ v1.315 ADAMTS13 Lilian Downie Phenotypes for gene: ADAMTS13 were changed from Thrombotic thrombocytopenic purpura, familial, 274150 (3) to Thrombotic thrombocytopenic purpura, hereditary, MIM#274150
Prepair 1000+ v1.314 ADAMTS13 Lilian Downie Publications for gene: ADAMTS13 were set to 16796708; 34702267
Prepair 1000+ v1.313 ADAMTS13 Lilian Downie Publications for gene: ADAMTS13 were set to
Prepair 1000+ v1.312 AIPL1 Lilian Downie Marked gene: AIPL1 as ready
Prepair 1000+ v1.312 AIPL1 Lilian Downie Gene: aipl1 has been classified as Green List (High Evidence).
Prepair 1000+ v1.312 AIPL1 Lilian Downie Phenotypes for gene: AIPL1 were changed from Cone-rod dystrophy, 604393 (3) to Leber congenital amaurosis 4, 604393; Cone-rod dystrophy, 604393; Retinitis pigmentosa, juvenile, 604393
Prepair 1000+ v1.311 AIPL1 Lilian Downie Publications for gene: AIPL1 were set to
Intellectual disability syndromic and non-syndromic v0.6222 IFT172 Sangavi Sivagnanasundram reviewed gene: IFT172: Rating: AMBER; Mode of pathogenicity: None; Publications: 24290075, 26763875; Phenotypes: Bardet-Biedl syndrome MONDO:0015229; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.6222 IFIH1 Sangavi Sivagnanasundram changed review comment from: ID is a prominent feature of this condition in most cases and those affected will likely have severe intellectual and physical disability.

GoF is the mechanism of disease.; to: ID is a prominent feature of this condition in most cases and those affected will likely have severe intellectual and physical disability.

GoF is the mechanism of disease.

Classified as DEFINITIVE by ClinGen's Leukodystrophy and Leukoencephalopathy GCEP on 23/08/2024 - https://search.clinicalgenome.org/CCID:008354
Intellectual disability syndromic and non-syndromic v0.6222 IFIH1 Sangavi Sivagnanasundram reviewed gene: IFIH1: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 20301648, 25620204; Phenotypes: IFIH1-related type 1 interferonopathy MONDO:0700262; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.6222 ERCC6 Mark Cleghorn reviewed gene: ERCC6: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 20301516; Phenotypes: Cockayne syndrome type B, Cerebrooculofacioskeletal syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.6222 IDUA Sangavi Sivagnanasundram reviewed gene: IDUA: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301341; Phenotypes: mucopolysaccharidosis type 1 MONDO:0001586; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.6222 IDH2 Sangavi Sivagnanasundram reviewed gene: IDH2: Rating: GREEN; Mode of pathogenicity: None; Publications: 20847235, 35359529; Phenotypes: mitochondrial disease MONDO:0044970; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability syndromic and non-syndromic v0.6222 HTRA2 Sangavi Sivagnanasundram reviewed gene: HTRA2: Rating: GREEN; Mode of pathogenicity: None; Publications: 27208207, 27696117, 30114719, 32445293; Phenotypes: 3-methylglutaconic aciduria type 8 MONDO:0044723; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.6222 HSPD1 Sangavi Sivagnanasundram reviewed gene: HSPD1: Rating: AMBER; Mode of pathogenicity: None; Publications: 18571143, 27405012; Phenotypes: Leukodystrophy, hypomyelinating, 4, MIM #612233; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.6222 HSD17B10 Sangavi Sivagnanasundram reviewed gene: HSD17B10: Rating: GREEN; Mode of pathogenicity: None; Publications: 22132097, 17618155; Phenotypes: HSD10 mitochondrial disease MONDO:0010327; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Prepair 1000+ v1.310 ALG11 Lilian Downie Marked gene: ALG11 as ready
Prepair 1000+ v1.310 ALG11 Lilian Downie Gene: alg11 has been classified as Green List (High Evidence).
Prepair 1000+ v1.310 ALG11 Lilian Downie Publications for gene: ALG11 were set to
Prepair 1000+ v1.309 ALG8 Lilian Downie Marked gene: ALG8 as ready
Prepair 1000+ v1.309 ALG8 Lilian Downie Gene: alg8 has been classified as Green List (High Evidence).
Prepair 1000+ v1.309 ALG8 Lilian Downie Publications for gene: ALG8 were set to
Prepair 1000+ v1.308 AP3B2 Lilian Downie Marked gene: AP3B2 as ready
Prepair 1000+ v1.308 AP3B2 Lilian Downie Gene: ap3b2 has been classified as Green List (High Evidence).
Prepair 1000+ v1.308 AP3B2 Lilian Downie Phenotypes for gene: AP3B2 were changed from Epileptic encephalopathy, early infantile, 48, 617276 (3), Autosomal recessive to Developmental and epileptic encephalopathy 48 MIM#617276
Prepair 1000+ v1.307 AP3B2 Lilian Downie Publications for gene: AP3B2 were set to
Prepair 1000+ v1.306 ARPC1B Lilian Downie Marked gene: ARPC1B as ready
Prepair 1000+ v1.306 ARPC1B Lilian Downie Gene: arpc1b has been classified as Green List (High Evidence).
Prepair 1000+ v1.306 ARPC1B Lilian Downie Phenotypes for gene: ARPC1B were changed from Platelet abnormalities with eosinophilia and immune-mediated inflammatory disease, 617718 (3), Autosomal recessive to Immunodeficiency 71 with inflammatory disease and congenital thrombocytopenia MIM#617718
Intellectual disability syndromic and non-syndromic v0.6222 HPD Sangavi Sivagnanasundram reviewed gene: HPD: Rating: AMBER; Mode of pathogenicity: None; Publications: 31537781; Phenotypes: tyrosinemia type III MONDO:0010162; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.6222 HMGCL Sangavi Sivagnanasundram reviewed gene: HMGCL: Rating: AMBER; Mode of pathogenicity: None; Publications: 36771238, 35646072; Phenotypes: 3-hydroxy-3-methylglutaric aciduria MONDO:0009520; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.6222 HLCS Sangavi Sivagnanasundram reviewed gene: HLCS: Rating: GREEN; Mode of pathogenicity: None; Publications: 18974016, 18429047, 12124727; Phenotypes: holocarboxylase synthetase deficiency MONDO:0009666; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.6222 HIBCH Sangavi Sivagnanasundram reviewed gene: HIBCH: Rating: GREEN; Mode of pathogenicity: None; Publications: 24299452, 30847210, 17160907, 26163321, 26026795, 31523596, 32022391, 24299452, 32677093; Phenotypes: 3-hydroxyisobutyryl-CoA hydrolase deficiency MONDO:0009603, Leigh syndrome MONDO:0009723; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.6222 HEXB Sangavi Sivagnanasundram reviewed gene: HEXB: Rating: GREEN; Mode of pathogenicity: None; Publications: 35420740; Phenotypes: Sandhoff disease MONDO:0010006; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.6222 HEXA Sangavi Sivagnanasundram reviewed gene: HEXA: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301397; Phenotypes: Tay-Sachs disease MONDO:0010100; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.305 ARPC1B Lilian Downie Publications for gene: ARPC1B were set to
Heterotaxy v1.32 DNAH6 Seb Lunke reviewed gene: DNAH6: Rating: AMBER; Mode of pathogenicity: None; Publications: 34215651; Phenotypes: situs inversus, MONDO:0010029, transposition of the great arteries, MONDO:0000153; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2015 DNAH6 Seb Lunke reviewed gene: DNAH6: Rating: AMBER; Mode of pathogenicity: None; Publications: 34215651; Phenotypes: situs inversus, MONDO:0010029, transposition of the great arteries, MONDO:0000153; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.6222 HESX1 Sangavi Sivagnanasundram reviewed gene: HESX1: Rating: AMBER; Mode of pathogenicity: None; Publications: 19623216, 30888394; Phenotypes: septooptic dysplasia MONDO:0008428, Pituitary hormone deficiency, combined, 5 MONDO:0013099; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.6222 HEPACAM Sangavi Sivagnanasundram reviewed gene: HEPACAM: Rating: GREEN; Mode of pathogenicity: None; Publications: 21419380, 24202401, 27389245, 31372844, 21419380, 24202401, 27322623; Phenotypes: Megalencephalic leukoencephalopathy with subcortical cysts 2A MONDO:0013490, Megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without intellectual disability MONDO:0013491; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.6222 HCCS Sangavi Sivagnanasundram reviewed gene: HCCS: Rating: AMBER; Mode of pathogenicity: None; Publications: 18950397; Phenotypes: linear skin defects with multiple congenital anomalies 1 (MONDO:0024552); Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability syndromic and non-syndromic v0.6222 HADHA Sangavi Sivagnanasundram reviewed gene: HADHA: Rating: AMBER; Mode of pathogenicity: None; Publications: 36063482; Phenotypes: long chain 3-hydroxyacyl-CoA dehydrogenase deficiency MONDO:0012173; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Repeat Disorders v0.168 SCA_THAP11_CAG Zornitza Stark Phenotypes for STR: SCA_THAP11_CAG were changed from autosomal dominant cerebellar ataxia MONDO:0020380 to Spinocerebellar ataxia 51, MIM# 620947
Repeat Disorders v0.167 SCA_THAP11_CAG Zornitza Stark reviewed STR: SCA_THAP11_CAG: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Spinocerebellar ataxia 51, MIM# 620947; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v1.268 EXOC3L2 Zornitza Stark Phenotypes for gene: EXOC3L2 were changed from Dandy-Walker malformation, MONDO:0009072; Meckel-Gruber-like syndrome to Brain malformation renal syndrome, MIM# 620943
Fetal anomalies v1.267 EXOC3L2 Zornitza Stark reviewed gene: EXOC3L2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Brain malformation renal syndrome, MIM# 620943; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2015 EXOC3L2 Zornitza Stark Phenotypes for gene: EXOC3L2 were changed from Dandy-Walker malformation, MONDO:0009072; renal dysplasia; bone marrow failure to Brain malformation renal syndrome, MIM# 620943
Mendeliome v1.2014 EXOC3L2 Zornitza Stark edited their review of gene: EXOC3L2: Changed phenotypes: Brain malformation renal syndrome, MIM# 620943
Ciliopathies v1.61 EXOC3L2 Zornitza Stark Phenotypes for gene: EXOC3L2 were changed from Dandy-Walker malformation; renal dysplasia; bone marrow failure to Brain malformation renal syndrome, MIM# 620943
Ciliopathies v1.60 EXOC3L2 Zornitza Stark edited their review of gene: EXOC3L2: Changed phenotypes: Brain malformation renal syndrome, MIM# 620943
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.139 EXOC3L2 Zornitza Stark Phenotypes for gene: EXOC3L2 were changed from Dandy-Walker malformation; renal dysplasia; bone marrow failure to Brain malformation renal syndrome, MIM# 620943
Congenital anomalies of the kidney and urinary tract (CAKUT) Syndromic v0.138 EXOC3L2 Zornitza Stark edited their review of gene: EXOC3L2: Changed phenotypes: Brain malformation renal syndrome, MIM# 620943
Mendeliome v1.2014 THAP11 Zornitza Stark Phenotypes for gene: THAP11 were changed from Inborn disorder of cobalamin metabolism and transport, MONDO:0019220, THAP11-related to Methylmalonic aciduria, cblC type-like, MIM# 620940; Inborn disorder of cobalamin metabolism and transport, MONDO:0019220, THAP11-related
Mendeliome v1.2013 THAP11 Zornitza Stark edited their review of gene: THAP11: Changed phenotypes: Methylmalonic aciduria, cblC type-like, MIM# 620940, Inborn disorder of cobalamin metabolism and transport, MONDO:0019220, THAP11-related
BabyScreen+ newborn screening v1.115 THAP11 Zornitza Stark Phenotypes for gene: THAP11 were changed from Inborn disorder of cobalamin metabolism and transport, MONDO:0019220, THAP11-related to Methylmalonic aciduria, cblC type-like, MIM# 620940; Inborn disorder of cobalamin metabolism and transport, MONDO:0019220, THAP11-related
BabyScreen+ newborn screening v1.114 THAP11 Zornitza Stark reviewed gene: THAP11: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Methylmalonic aciduria, cblC type-like, MIM# 620940, Inborn disorder of cobalamin metabolism and transport, MONDO:0019220, THAP11-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Vitamin metabolism disorders v1.7 THAP11 Zornitza Stark Phenotypes for gene: THAP11 were changed from Methylmalonic aciduria and homocystinuria MONDO:0016826 to Methylmalonic aciduria, cblC type-like, MIM# 620940; Inborn disorder of cobalamin metabolism and transport, MONDO:0019220, THAP11-related
Vitamin metabolism disorders v1.6 THAP11 Zornitza Stark edited their review of gene: THAP11: Changed phenotypes: Methylmalonic aciduria, cblC type-like, MIM# 620940, Inborn disorder of cobalamin metabolism and transport, MONDO:0019220, THAP11-related
Sarcoma soft tissue v0.30 BRCA1 Chirag Patel Classified gene: BRCA1 as Green List (high evidence)
Sarcoma soft tissue v0.30 BRCA1 Chirag Patel Gene: brca1 has been classified as Green List (High Evidence).
Sarcoma soft tissue v0.29 BRCA2 Chirag Patel Classified gene: BRCA2 as Green List (high evidence)
Sarcoma soft tissue v0.29 BRCA2 Chirag Patel Gene: brca2 has been classified as Green List (High Evidence).
Sarcoma soft tissue v0.28 DICER1 Chirag Patel Classified gene: DICER1 as Green List (high evidence)
Sarcoma soft tissue v0.28 DICER1 Chirag Patel Gene: dicer1 has been classified as Green List (High Evidence).
Sarcoma soft tissue v0.27 HRAS Chirag Patel Classified gene: HRAS as Green List (high evidence)
Sarcoma soft tissue v0.27 HRAS Chirag Patel Gene: hras has been classified as Green List (High Evidence).
Sarcoma soft tissue v0.26 NF1 Chirag Patel Classified gene: NF1 as Green List (high evidence)
Sarcoma soft tissue v0.26 NF1 Chirag Patel Gene: nf1 has been classified as Green List (High Evidence).
Sarcoma soft tissue v0.25 RB1 Chirag Patel Classified gene: RB1 as Green List (high evidence)
Sarcoma soft tissue v0.25 RB1 Chirag Patel Gene: rb1 has been classified as Green List (High Evidence).
Sarcoma soft tissue v0.24 SMARCA4 Chirag Patel Classified gene: SMARCA4 as Green List (high evidence)
Sarcoma soft tissue v0.24 SMARCA4 Chirag Patel Gene: smarca4 has been classified as Green List (High Evidence).
Sarcoma soft tissue v0.23 SMARCB1 Chirag Patel Classified gene: SMARCB1 as Green List (high evidence)
Sarcoma soft tissue v0.23 SMARCB1 Chirag Patel Gene: smarcb1 has been classified as Green List (High Evidence).
Sarcoma soft tissue v0.22 TP53 Chirag Patel Classified gene: TP53 as Green List (high evidence)
Sarcoma soft tissue v0.22 TP53 Chirag Patel Gene: tp53 has been classified as Green List (High Evidence).
Sarcoma soft tissue v0.21 TP53 Chirag Patel gene: TP53 was added
gene: TP53 was added to Sarcoma soft tissue. Sources: Expert list,Expert Review
Mode of inheritance for gene: TP53 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: TP53 were set to Soft tissue sarcoma, MONDO:0018078; Sarcoma, MONDO:0005089; Li-Fraumeni syndrome, MONDO:0018875; Li-Fraumeni syndrome, MIM#151623
Review for gene: TP53 was set to GREEN
Added comment: ClinGen definitive. Soft-tissue sarcomas reported in condition.

Consider possibility that an identified variant could represent ACE (aberrant clonal expansion), which can be due to clonal haematopoiesis of indeterminate potential (CHIP) or an occult hematologic malignancy, especially in older patients who have undergone prior chemotherapy (PMID: 36040522).
Sources: Expert list, Expert Review
Sarcoma soft tissue v0.20 SMARCB1 Chirag Patel gene: SMARCB1 was added
gene: SMARCB1 was added to Sarcoma soft tissue. Sources: Expert list,Expert Review
Mode of inheritance for gene: SMARCB1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: SMARCB1 were set to Soft tissue sarcoma, MONDO:0018078; Sarcoma, MONDO:0005089; Rhabdoid tumor predisposition syndrome 1, MONDO:0012252; Rhabdoid tumor predisposition syndrome 1, MIM#609322
Review for gene: SMARCB1 was set to GREEN
Added comment: ClinGen definitive. Soft-tissue sarcomas reported in condition.
Sources: Expert list, Expert Review
Sarcoma soft tissue v0.19 SMARCA4 Chirag Patel gene: SMARCA4 was added
gene: SMARCA4 was added to Sarcoma soft tissue. Sources: Expert list,Expert Review
Mode of inheritance for gene: SMARCA4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: SMARCA4 were set to Soft tissue sarcoma, MONDO:0018078; Sarcoma, MONDO:0005089; Rhabdoid tumor predisposition syndrome 2, MONDO:0013224; Rhabdoid tumor predisposition syndrome 2, MIM#613325
Review for gene: SMARCA4 was set to GREEN
Added comment: ClinGen definitive. Soft-tissue sarcomas reported in condition.
Sources: Expert list, Expert Review
Sarcoma soft tissue v0.18 RB1 Chirag Patel gene: RB1 was added
gene: RB1 was added to Sarcoma soft tissue. Sources: Expert list,Expert Review
Mode of inheritance for gene: RB1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: RB1 were set to Soft tissue sarcoma, MONDO:0018078; Sarcoma, MONDO:0005089; Retinoblastoma, MONDO:0008380; Retinoblastoma, MIM#180200
Review for gene: RB1 was set to GREEN
Added comment: ClinGen definitive. Soft-tissue sarcomas reported in condition.
Sources: Expert list, Expert Review
Sarcoma soft tissue v0.17 NF1 Chirag Patel gene: NF1 was added
gene: NF1 was added to Sarcoma soft tissue. Sources: Expert list,Expert Review
Mode of inheritance for gene: NF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: NF1 were set to Soft tissue sarcoma, MONDO:0018078; Sarcoma, MONDO:0005089; Neurofibromatosis type 1, MONDO:0018975; Neurofibromatosis, type 1, MIM#162200
Review for gene: NF1 was set to GREEN
Added comment: ClinGen definitive. Soft-tissue sarcomas reported in condition.

Single gene testing may be more appropriate if clinical features of NF1.
Sources: Expert list, Expert Review
Sarcoma soft tissue v0.16 HRAS Chirag Patel gene: HRAS was added
gene: HRAS was added to Sarcoma soft tissue. Sources: Expert list,Expert Review
Mode of inheritance for gene: HRAS was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: HRAS were set to Soft tissue sarcoma, MONDO:0018078; Sarcoma, MONDO:0005089; Costello syndrome, MONDO:0009026; Costello syndrome, MIM#218040
Mode of pathogenicity for gene: HRAS was set to Other
Review for gene: HRAS was set to GREEN
Added comment: ClinGen definitive. Soft-tissue sarcomas reported in condition. GOF variants.
Sources: Expert list, Expert Review
Sarcoma soft tissue v0.15 DICER1 Chirag Patel gene: DICER1 was added
gene: DICER1 was added to Sarcoma soft tissue. Sources: Expert list,Expert Review
Mode of inheritance for gene: DICER1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: DICER1 were set to Soft tissue sarcoma, MONDO:0018078; Sarcoma, MONDO:0005089; DICER1-related tumor predisposition, MONDO:0100216; DICER1 syndrome, MIM#601200
Review for gene: DICER1 was set to GREEN
Added comment: ClinGen definitive. Soft-tissue sarcomas reported in condition.
Sources: Expert list, Expert Review
Sarcoma soft tissue v0.14 BRCA2 Chirag Patel gene: BRCA2 was added
gene: BRCA2 was added to Sarcoma soft tissue. Sources: Expert list,Expert Review
Mode of inheritance for gene: BRCA2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: BRCA2 were set to Soft tissue sarcoma, MONDO:0018078; Sarcoma, MONDO:0005089; BRCA2-related cancer predisposition, MONDO:0700269; Breast-ovarian cancer, familial, 2, MIM#612555
Review for gene: BRCA2 was set to GREEN
Added comment: ClinGen definitive. Soft-tissue sarcomas reported in condition.
Sources: Expert list, Expert Review
Sarcoma soft tissue v0.13 BRCA1 Chirag Patel gene: BRCA1 was added
gene: BRCA1 was added to Sarcoma soft tissue. Sources: Expert list,Expert Review
Mode of inheritance for gene: BRCA1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: BRCA1 were set to Soft tissue sarcoma, MONDO:0018078; Sarcoma, MONDO:0005089; BRCA1-related cancer predisposition, MONDO:0700268; Breast-ovarian cancer, familial, 1, MIM#604370
Review for gene: BRCA1 was set to GREEN
Added comment: ClinGen definitive. Soft-tissue sarcomas reported in condition.
Sources: Expert list, Expert Review
Sarcoma soft tissue v0.12 MLH1 Chirag Patel Classified gene: MLH1 as Green List (high evidence)
Sarcoma soft tissue v0.12 MLH1 Chirag Patel Gene: mlh1 has been classified as Green List (High Evidence).
Sarcoma soft tissue v0.11 MSH2 Chirag Patel Classified gene: MSH2 as Green List (high evidence)
Sarcoma soft tissue v0.11 MSH2 Chirag Patel Gene: msh2 has been classified as Green List (High Evidence).
Sarcoma soft tissue v0.10 MSH6 Chirag Patel Classified gene: MSH6 as Green List (high evidence)
Sarcoma soft tissue v0.10 MSH6 Chirag Patel Gene: msh6 has been classified as Green List (High Evidence).
Sarcoma soft tissue v0.9 NBN Chirag Patel Classified gene: NBN as Green List (high evidence)
Sarcoma soft tissue v0.9 NBN Chirag Patel Gene: nbn has been classified as Green List (High Evidence).
Sarcoma soft tissue v0.8 PMS2 Chirag Patel Classified gene: PMS2 as Green List (high evidence)
Sarcoma soft tissue v0.8 PMS2 Chirag Patel Gene: pms2 has been classified as Green List (High Evidence).
Sarcoma soft tissue v0.7 WRN Chirag Patel Classified gene: WRN as Green List (high evidence)
Sarcoma soft tissue v0.7 WRN Chirag Patel Gene: wrn has been classified as Green List (High Evidence).
Sarcoma soft tissue v0.6 MLH1 Chirag Patel gene: MLH1 was added
gene: MLH1 was added to Sarcoma soft tissue. Sources: Expert list,Expert Review
Mode of inheritance for gene: MLH1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: MLH1 were set to Soft tissue sarcoma, MONDO:0018078; Sarcoma, MONDO:0005089; Mismatch repair cancer syndrome 1, MONDO:0010159; Mismatch repair cancer syndrome 1, MIM#276300
Review for gene: MLH1 was set to GREEN
Added comment: ClinGen definitive. Soft-tissue sarcomas reported in condition.
Sources: Expert list, Expert Review
Sarcoma soft tissue v0.5 MSH2 Chirag Patel gene: MSH2 was added
gene: MSH2 was added to Sarcoma soft tissue. Sources: Expert list,Expert Review
Mode of inheritance for gene: MSH2 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: MSH2 were set to Soft tissue sarcoma, MONDO:0018078; Sarcoma, MONDO:0005089; Mismatch repair cancer syndrome 2, MONDO:0030840; Mismatch repair cancer syndrome 2, MIM#619096
Review for gene: MSH2 was set to GREEN
Added comment: ClinGen definitive. Soft-tissue sarcomas reported in condition.
Sources: Expert list, Expert Review
Sarcoma soft tissue v0.4 MSH6 Chirag Patel gene: MSH6 was added
gene: MSH6 was added to Sarcoma soft tissue. Sources: Expert list,Expert Review
Mode of inheritance for gene: MSH6 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: MSH6 were set to Soft tissue sarcoma, MONDO:0018078; Sarcoma, MONDO:0005089; Mismatch repair cancer syndrome 3, MONDO:0030841; Mismatch repair cancer syndrome 3, MIM#619097
Review for gene: MSH6 was set to GREEN
Added comment: ClinGen definitive. Soft-tissue sarcomas reported in condition.
Sources: Expert list, Expert Review
Sarcoma soft tissue v0.3 NBN Chirag Patel gene: NBN was added
gene: NBN was added to Sarcoma soft tissue. Sources: Expert list,Expert Review
Mode of inheritance for gene: NBN was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: NBN were set to Soft tissue sarcoma, MONDO:0018078; Sarcoma, MONDO:0005089; Nijmegen breakage syndrome, MONDO:0009623; Nijmegen breakage syndrome, MIM#251260
Review for gene: NBN was set to GREEN
Added comment: ClinGen definitive. Soft-tissue sarcomas reported in condition.
Sources: Expert list, Expert Review
Sarcoma soft tissue v0.2 PMS2 Chirag Patel gene: PMS2 was added
gene: PMS2 was added to Sarcoma soft tissue. Sources: Expert list,Expert Review
Mode of inheritance for gene: PMS2 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: PMS2 were set to Soft tissue sarcoma, MONDO:0018078; Sarcoma, MONDO:0005089; Mismatch repair cancer syndrome 4, MONDO:0030843; Mismatch repair cancer syndrome 4, MIM#619101
Review for gene: PMS2 was set to GREEN
Added comment: ClinGen definitive. Soft-tissue sarcomas reported in condition.

Note: there is a high level of homology between PMS2 and pseudogenes
Sources: Expert list, Expert Review
Sarcoma soft tissue v0.1 WRN Chirag Patel gene: WRN was added
gene: WRN was added to Sarcoma soft tissue. Sources: Expert list,Expert Review
Mode of inheritance for gene: WRN was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: WRN were set to Soft tissue sarcoma, MONDO:0018078; Sarcoma, MONDO:0005089; Werner syndrome, MONDO:0010196; Werner syndrome, MIM#277700
Review for gene: WRN was set to GREEN
Added comment: ClinGen definitive. Soft-tissue sarcomas reported in condition.
Sources: Expert list, Expert Review
Sarcoma non-soft tissue v0.15 TP53 Chirag Patel Classified gene: TP53 as Green List (high evidence)
Sarcoma non-soft tissue v0.15 TP53 Chirag Patel Gene: tp53 has been classified as Green List (High Evidence).
Sarcoma non-soft tissue v0.14 RB1 Chirag Patel Classified gene: RB1 as Green List (high evidence)
Sarcoma non-soft tissue v0.14 RB1 Chirag Patel Gene: rb1 has been classified as Green List (High Evidence).
Sarcoma non-soft tissue v0.13 EXT2 Chirag Patel Classified gene: EXT2 as Green List (high evidence)
Sarcoma non-soft tissue v0.13 EXT2 Chirag Patel Gene: ext2 has been classified as Green List (High Evidence).
Sarcoma non-soft tissue v0.12 EXT1 Chirag Patel Classified gene: EXT1 as Green List (high evidence)
Sarcoma non-soft tissue v0.12 EXT1 Chirag Patel Gene: ext1 has been classified as Green List (High Evidence).
Sarcoma non-soft tissue v0.11 WRN Chirag Patel Classified gene: WRN as Green List (high evidence)
Sarcoma non-soft tissue v0.11 WRN Chirag Patel Gene: wrn has been classified as Green List (High Evidence).
Sarcoma non-soft tissue v0.10 RECQL4 Chirag Patel Classified gene: RECQL4 as Green List (high evidence)
Sarcoma non-soft tissue v0.10 RECQL4 Chirag Patel Gene: recql4 has been classified as Green List (High Evidence).
Sarcoma non-soft tissue v0.9 BLM Chirag Patel Classified gene: BLM as Green List (high evidence)
Sarcoma non-soft tissue v0.9 BLM Chirag Patel Gene: blm has been classified as Green List (High Evidence).
Sarcoma non-soft tissue v0.8 TP53 Chirag Patel gene: TP53 was added
gene: TP53 was added to Sarcoma non-soft tissue. Sources: Expert list,Expert Review
Mode of inheritance for gene: TP53 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: TP53 were set to Sarcoma, MONDO:0005089; Li-Fraumeni syndrome, MONDO:0018875; Li-Fraumeni syndrome, MIM#151623
Review for gene: TP53 was set to GREEN
Added comment: ClinGen definitive. Non-soft-tissue sarcomas reported in condition.

Consider possibility that an identified variant could represent ACE (aberrant clonal expansion), which can be due to clonal haematopoiesis of indeterminate potential (CHIP) or an occult hematologic malignancy, especially in older patients who have undergone prior chemotherapy (PMID: 36040522).
Sources: Expert list, Expert Review
Sarcoma non-soft tissue v0.7 RB1 Chirag Patel gene: RB1 was added
gene: RB1 was added to Sarcoma non-soft tissue. Sources: Expert list,Expert Review
Mode of inheritance for gene: RB1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: RB1 were set to Sarcoma, MONDO:0005089; Retinoblastoma, MONDO:0008380; Retinoblastoma, MIM#180200
Review for gene: RB1 was set to GREEN
Added comment: ClinGen definitive. Non-soft-tissue sarcomas reported in condition.
Sources: Expert list, Expert Review
Sarcoma non-soft tissue v0.6 EXT2 Chirag Patel gene: EXT2 was added
gene: EXT2 was added to Sarcoma non-soft tissue. Sources: Expert list,Expert Review
Mode of inheritance for gene: EXT2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: EXT2 were set to Sarcoma, MONDO:0005089; Exostoses, multiple, type 2, MONDO:0007586; Exostoses, multiple, type 2, MIM#133701
Review for gene: EXT2 was set to GREEN
Added comment: ClinGen definitive. Non-soft-tissue sarcomas reported in condition.
Sources: Expert list, Expert Review
Sarcoma non-soft tissue v0.5 EXT1 Chirag Patel gene: EXT1 was added
gene: EXT1 was added to Sarcoma non-soft tissue. Sources: Expert list,Expert Review
Mode of inheritance for gene: EXT1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: EXT1 were set to Sarcoma, MONDO:0005089; Exostoses, multiple, type 1, MONDO:0007585; Exostoses, multiple, type 1, MIM#133700
Review for gene: EXT1 was set to GREEN
Added comment: ClinGen definitive. Non-soft-tissue sarcomas reported in condition.
Sources: Expert list, Expert Review
Sarcoma non-soft tissue v0.4 WRN Chirag Patel gene: WRN was added
gene: WRN was added to Sarcoma non-soft tissue. Sources: Expert list,Expert Review
Mode of inheritance for gene: WRN was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: WRN were set to Sarcoma, MONDO:0005089; Werner syndrome, MONDO:0010196; Werner syndrome, MIM#277700
Review for gene: WRN was set to GREEN
Added comment: ClinGen definitive. Non-soft-tissue sarcomas reported in condition.
Sources: Expert list, Expert Review
Sarcoma non-soft tissue v0.3 RECQL4 Chirag Patel gene: RECQL4 was added
gene: RECQL4 was added to Sarcoma non-soft tissue. Sources: Expert list,Expert Review
Mode of inheritance for gene: RECQL4 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: RECQL4 were set to Sarcoma, MONDO:0005089; Rothmund-Thomson syndrome type 2, MONDO:0016369; Rothmund-Thomson syndrome, type 2, MIM#268400
Review for gene: RECQL4 was set to GREEN
Added comment: ClinGen definitive. Non-soft-tissue sarcomas reported in condition.
Sources: Expert list, Expert Review
Sarcoma non-soft tissue v0.2 BLM Chirag Patel gene: BLM was added
gene: BLM was added to Sarcoma non-soft tissue. Sources: Expert list,Expert Review
Mode of inheritance for gene: BLM was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: BLM were set to Sarcoma, MONDO:0005089; Bloom syndrome, MONDO:0008876; Bloom syndrome, MIM#210900
Review for gene: BLM was set to GREEN
Added comment: ClinGen definitive. Non-soft-tissue sarcomas reported in condition.
Sources: Expert list, Expert Review
Prepair 1000+ v1.304 ARPC1B Crystle Lee edited their review of gene: ARPC1B: Changed publications: 36708766, 33679784
Prepair 1000+ v1.304 ARPC1B Crystle Lee reviewed gene: ARPC1B: Rating: GREEN; Mode of pathogenicity: None; Publications: 36708766; Phenotypes: Immunodeficiency 71 with inflammatory disease and congenital thrombocytopenia, MIM#617718; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.6222 GTF2H5 Sangavi Sivagnanasundram reviewed gene: GTF2H5: Rating: AMBER; Mode of pathogenicity: None; Publications: 30359777, 24986372; Phenotypes: Trichothiodystrophy 3, photosensitive MIM#616395; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.304 AP3B2 Crystle Lee reviewed gene: AP3B2: Rating: GREEN; Mode of pathogenicity: None; Publications: 27889060; Phenotypes: Developmental and epileptic encephalopathy 48, MIM#617276; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.6222 GRM1 Sangavi Sivagnanasundram reviewed gene: GRM1: Rating: AMBER; Mode of pathogenicity: None; Publications: 26308914, 22901947, 31319223, 36675067; Phenotypes: autosomal recessive spinocerebellar ataxia 13 MONDO:0013905; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.6222 GNS Sangavi Sivagnanasundram reviewed gene: GNS: Rating: GREEN; Mode of pathogenicity: None; Publications: 31536183, 25851924, 17998446, 6450420; Phenotypes: mucopolysaccharidosis type 3D MONDO:0009658; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.6222 GNPTAB Sangavi Sivagnanasundram reviewed gene: GNPTAB: Rating: ; Mode of pathogenicity: None; Publications: 20301728; Phenotypes: GNPTAB-mucolipidosis MONDO:0100122; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.6222 GNPAT Sangavi Sivagnanasundram reviewed gene: GNPAT: Rating: GREEN; Mode of pathogenicity: None; Publications: 9843043, 19270340, 21990100; Phenotypes: glyceronephosphate O-acyltransferase deficiency MONDO:0100273; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.304 ALG8 Crystle Lee reviewed gene: ALG8: Rating: GREEN; Mode of pathogenicity: None; Publications: 35716054, 36574950; Phenotypes: Congenital disorder of glycosylation, type Ih, MIM#608104; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.6222 GMPPB Sangavi Sivagnanasundram reviewed gene: GMPPB: Rating: GREEN; Mode of pathogenicity: None; Publications: 23768512, 26133662, 27147698; Phenotypes: myopathy caused by variation in GMPPB MONDO:0700084; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.6222 GMPPA Sangavi Sivagnanasundram reviewed gene: GMPPA: Rating: GREEN; Mode of pathogenicity: None; Publications: 31898852, 35607266; Phenotypes: alacrima, achalasia, and intellectual disability syndrome MONDO:0014219; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.304 ALG11 Crystle Lee reviewed gene: ALG11: Rating: GREEN; Mode of pathogenicity: None; Publications: 36843332, 30676690; Phenotypes: Congenital disorder of glycosylation, type Ip, MIM#613661; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.6222 GM2A Sangavi Sivagnanasundram reviewed gene: GM2A: Rating: GREEN; Mode of pathogenicity: None; Publications: 33819415, 20301397; Phenotypes: Tay-Sachs disease AB variant MONDO:0010099; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.304 AIPL1 Crystle Lee changed review comment from: Biallelic AIPL1 variants are associated with a spectrum of inherited retinal disease, ranging from severe Leber congenital amaurosis (LCA) to later onset retinitis pigmentosa (RP). Heterozygotes present with a milder, later onset cone rod dystrophy and RP.

LCA is a congenital-onset, rapid and progressive disease leading to severe vision impariment and/or loss of vision.; to: Biallelic AIPL1 variants are associated with a spectrum of inherited retinal disease, ranging from severe Leber congenital amaurosis (LCA) to later onset retinitis pigmentosa (RP). Heterozygotes present with a milder, later onset cone rod dystrophy and RP.

LCA is a congenital-onset, rapid and progressive disease leading to severe vision impairment and/or loss of vision.
Prepair 1000+ v1.304 AIPL1 Crystle Lee reviewed gene: AIPL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33067476; Phenotypes: Leber congenital amaurosis 4, 604393, Cone-rod dystrophy, 604393, Retinitis pigmentosa, juvenile, 604393; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.304 ADAMTS13 Crystle Lee reviewed gene: ADAMTS13: Rating: GREEN; Mode of pathogenicity: None; Publications: 16796708, 34702267; Phenotypes: Thrombotic thrombocytopenic purpura, hereditary, MIM#274150; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.304 ACOX1 Crystle Lee reviewed gene: ACOX1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32169171, 17458872; Phenotypes: Peroxisomal acyl-CoA oxidase deficiency, MIM#264470; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.304 ABCD1 Crystle Lee reviewed gene: ABCD1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 35983253; Phenotypes: Adrenoleukodystrophy, MIM#300100; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Prepair 1000+ v1.304 ERCC2 Ee Ming Wong changed review comment from: - Bi-allelic inactivation of XPD protein, a nucleotide excision repair (NER) signaling pathway component encoded by ERCC2 gene, has been associated with several defective DNA repair phenotypes, including xeroderma pigmentosum, photosensitive trichothiodystrophy, and cerebro-oculo-facio-skeletal syndrome.
- Severe, early onset of all three phenotypes have been reported
- Variable expressivity has been reported for Xeroderma pigmentosum, group D, MIM# 278730 where individuals can present with or without mild or severe neurologic abnormalities (GeneReviews)
- OMIM: The location of variants (mutagenic pattern) is consistent in determining the phenotype. Variants shared by both phenotypes are functionally null alleles, and the second / compound heterozygous variant then determines the phenotype. Changes at p.Arg683 are clearly associated with XP, whereas p.Arg112His, p.Arg722Trp, and changes at p.Arg658 are associated with TTD.; to: - Bi-allelic inactivation of XPD protein, a nucleotide excision repair (NER) signaling pathway component encoded by ERCC2 gene, has been associated with several defective DNA repair phenotypes, including xeroderma pigmentosum, photosensitive trichothiodystrophy, and cerebro-oculo-facio-skeletal syndrome.
- Severe, early onset of all three phenotypes have been reported
- Variable expressivity has been reported for Xeroderma pigmentosum, group D, MIM# 278730 where individuals can present with or without mild or severe neurologic abnormalities (GeneReviews)
- OMIM: The location of variants (mutagenic pattern) is consistent in determining the phenotype. Variants shared by both phenotypes are functionally null alleles, and the second / compound heterozygous variant then determines the phenotype. Changes at p.Arg683 are clearly associated with XP, whereas p.Arg112His, p.Arg722Trp, and changes at p.Arg658 are associated with TTD.
Prepair 1000+ v1.304 EVC Ee Ming Wong reviewed gene: EVC: Rating: GREEN; Mode of pathogenicity: None; Publications: 23220543; Phenotypes: Ellis-van Creveld syndrome, MIM# 225500; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Prepair 1000+ v1.304 ERCC2 Ee Ming Wong reviewed gene: ERCC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301571, 32047639, 33369099; Phenotypes: Cerebrooculofacioskeletal syndrome 2, MIM# 610756, Trichothiodystrophy 1, photosensitive, MIM# 601675, Xeroderma pigmentosum, group D, MIM# 278730; Mode of inheritance: None; Current diagnostic: yes
Prepair 1000+ v1.304 EPCAM Ee Ming Wong reviewed gene: EPCAM: Rating: GREEN; Mode of pathogenicity: None; Publications: 24142340; Phenotypes: Diarrhea 5, with tufting enteropathy, congenital, MIM# 613217; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Prepair 1000+ v1.304 DYNC2LI1 Ee Ming Wong reviewed gene: DYNC2LI1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33030252; Phenotypes: Short-rib thoracic dysplasia 15 with polydactyly (MIM#617088); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Fetal anomalies v1.267 NME8 Achchuthan Shanmugasundram changed review comment from: The phenotype listed in the review below, namely, CINCA syndrome, OMIM:607115 is associated with NLRP3 gene rather than NME8 in OMIM. The publications listed below (PMIDs: 12032915, 12483741, 12928894) also reports cases with NLRP3 variants (gene alias: CIAS1) rather than NME8 variants. Hence, this gene should be demoted from green rating and NLRP3 should be added to this panel.; to: The phenotype listed in the review below, namely, CINCA syndrome, OMIM:607115 is associated with NLRP3 gene rather than NME8 in OMIM. The publications listed below (PMIDs: 12032915, 12483741, 12928894) also report cases with NLRP3 variants (gene alias: CIAS1) rather than NME8 variants. Hence, this gene should be demoted from green rating and NLRP3 should be added to this panel.
Mendeliome v1.2013 PHKG2 Sangavi Sivagnanasundram reviewed gene: PHKG2: Rating: GREEN; Mode of pathogenicity: None; Publications: 6962066, 8896567, 9384616, 35549678, 24389071, 25266922, 21646031; Phenotypes: glycogen storage disease IXc MONDO:0013091; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2013 PIH1D3 Sangavi Sivagnanasundram reviewed gene: PIH1D3: Rating: GREEN; Mode of pathogenicity: None; Publications: 28041644, 28176794, 32170493, 38051289, 33106461, 38408845, 33635866; Phenotypes: ciliary dyskinesia, primary, 36, X-linked MONDO:0010517; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v1.2013 IFIH1 Sangavi Sivagnanasundram reviewed gene: IFIH1: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 24686847, 24995871, 25620204, 30219631, 31898846; Phenotypes: IFIH1-related type 1 interferonopathy MONDO:0700262; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2013 IRF4 Sangavi Sivagnanasundram reviewed gene: IRF4: Rating: GREEN; Mode of pathogenicity: None; Publications: 36662884, 36917008, 29537367, 29408330; Phenotypes: combined immunodeficiency MONDO:0015131; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2013 AICDA Sangavi Sivagnanasundram reviewed gene: AICDA: Rating: GREEN; Mode of pathogenicity: None; Publications: 22992148, 12910268, 14564357, 15893695, 32423680, 35570134, 17560278; Phenotypes: hyper-IgM syndrome type 2 MONDO:0011528; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Prepair 1000+ v1.304 PSAT1 Zornitza Stark Marked gene: PSAT1 as ready
Prepair 1000+ v1.304 PSAT1 Zornitza Stark Gene: psat1 has been classified as Green List (High Evidence).
Prepair 1000+ v1.304 PSAT1 Zornitza Stark Phenotypes for gene: PSAT1 were changed from Neu-Laxova syndrome 2, 616038 (3) to Phosphoserine aminotransferase deficiency MIM#610992; Neu-Laxova syndrome 2 MIM#616038
Prepair 1000+ v1.303 PSAT1 Zornitza Stark Publications for gene: PSAT1 were set to
Cerebral Palsy v1.369 TSEN54 Zornitza Stark Marked gene: TSEN54 as ready
Cerebral Palsy v1.369 TSEN54 Zornitza Stark Gene: tsen54 has been classified as Red List (Low Evidence).
Cerebral Palsy v1.369 TSEN54 Zornitza Stark Classified gene: TSEN54 as Red List (low evidence)
Cerebral Palsy v1.369 TSEN54 Zornitza Stark Gene: tsen54 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.6222 DIAPH1 Zornitza Stark Marked gene: DIAPH1 as ready
Intellectual disability syndromic and non-syndromic v0.6222 DIAPH1 Zornitza Stark Gene: diaph1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.6222 DIAPH1 Zornitza Stark Phenotypes for gene: DIAPH1 were changed from to progressive microcephaly-seizures-cortical blindness-developmental delay syndrome MONDO:0014714
Intellectual disability syndromic and non-syndromic v0.6221 DIAPH1 Zornitza Stark Publications for gene: DIAPH1 were set to 24781755; 26463574
Intellectual disability syndromic and non-syndromic v0.6220 DIAPH1 Zornitza Stark Publications for gene: DIAPH1 were set to
Intellectual disability syndromic and non-syndromic v0.6220 DIAPH1 Zornitza Stark Mode of inheritance for gene: DIAPH1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.6219 DIAPH1 Zornitza Stark reviewed gene: DIAPH1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: progressive microcephaly-seizures-cortical blindness-developmental delay syndrome MONDO:0014714; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.6219 EIF2AK3 Ken Lee Wan reviewed gene: EIF2AK3: Rating: GREEN; Mode of pathogenicity: None; Publications: 20202148; Phenotypes: Wolcott-Rallison syndrome MONDO:0009192; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability syndromic and non-syndromic v0.6219 DYNC1H1 Zornitza Stark Marked gene: DYNC1H1 as ready
Intellectual disability syndromic and non-syndromic v0.6219 DYNC1H1 Zornitza Stark Gene: dync1h1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.6219 DYNC1H1 Zornitza Stark Phenotypes for gene: DYNC1H1 were changed from to dyneinopathy MONDO:1040031
Intellectual disability syndromic and non-syndromic v0.6218 DYNC1H1 Zornitza Stark Mode of inheritance for gene: DYNC1H1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Pancreatic Cancer v0.24 TP53 Zornitza Stark Marked gene: TP53 as ready
Pancreatic Cancer v0.24 TP53 Zornitza Stark Gene: tp53 has been classified as Green List (High Evidence).
Pancreatic Cancer v0.24 STK11 Zornitza Stark Marked gene: STK11 as ready
Pancreatic Cancer v0.24 STK11 Zornitza Stark Gene: stk11 has been classified as Green List (High Evidence).
Pancreatic Cancer v0.24 PMS2 Zornitza Stark Marked gene: PMS2 as ready
Pancreatic Cancer v0.24 PMS2 Zornitza Stark Gene: pms2 has been classified as Green List (High Evidence).
Pancreatic Cancer v0.24 PALB2 Zornitza Stark Marked gene: PALB2 as ready
Pancreatic Cancer v0.24 PALB2 Zornitza Stark Gene: palb2 has been classified as Green List (High Evidence).
Pancreatic Cancer v0.24 MSH6 Zornitza Stark Marked gene: MSH6 as ready
Pancreatic Cancer v0.24 MSH6 Zornitza Stark Gene: msh6 has been classified as Green List (High Evidence).
Pancreatic Cancer v0.24 MSH2 Zornitza Stark Marked gene: MSH2 as ready
Pancreatic Cancer v0.24 MSH2 Zornitza Stark Gene: msh2 has been classified as Green List (High Evidence).
Pancreatic Cancer v0.24 MLH1 Zornitza Stark Marked gene: MLH1 as ready
Pancreatic Cancer v0.24 MLH1 Zornitza Stark Gene: mlh1 has been classified as Green List (High Evidence).
Pancreatic Cancer v0.24 EPCAM Zornitza Stark Marked gene: EPCAM as ready
Pancreatic Cancer v0.24 EPCAM Zornitza Stark Gene: epcam has been classified as Green List (High Evidence).
Pancreatic Cancer v0.24 CDKN2A Zornitza Stark Marked gene: CDKN2A as ready
Pancreatic Cancer v0.24 CDKN2A Zornitza Stark Gene: cdkn2a has been classified as Green List (High Evidence).
Pancreatic Cancer v0.24 BRCA2 Zornitza Stark Marked gene: BRCA2 as ready
Pancreatic Cancer v0.24 BRCA2 Zornitza Stark Gene: brca2 has been classified as Green List (High Evidence).
Pancreatic Cancer v0.24 BRCA1 Zornitza Stark Marked gene: BRCA1 as ready
Pancreatic Cancer v0.24 BRCA1 Zornitza Stark Gene: brca1 has been classified as Green List (High Evidence).
Pancreatic Cancer v0.24 ATM Zornitza Stark Marked gene: ATM as ready
Pancreatic Cancer v0.24 ATM Zornitza Stark Gene: atm has been classified as Green List (High Evidence).
Prepair 1000+ v1.302 GMPPA Zornitza Stark Marked gene: GMPPA as ready
Prepair 1000+ v1.302 GMPPA Zornitza Stark Gene: gmppa has been classified as Green List (High Evidence).
Prepair 1000+ v1.302 GMPPA Zornitza Stark Phenotypes for gene: GMPPA were changed from Alacrima, achalasia, and mental retardation syndrome, 615510 (3) to Alacrima, achalasia, and impaired intellectual development syndrome (MIM#615510)
Prepair 1000+ v1.301 GMPPA Zornitza Stark Publications for gene: GMPPA were set to
Prepair 1000+ v1.300 GMPPB Zornitza Stark Marked gene: GMPPB as ready
Prepair 1000+ v1.300 GMPPB Zornitza Stark Gene: gmppb has been classified as Green List (High Evidence).
Prepair 1000+ v1.300 GMPPB Zornitza Stark Phenotypes for gene: GMPPB were changed from Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 14, 615352 (3) to Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 14 615350; Muscular dystrophy-dystroglycanopathy (congenital with impaired intellectual development), type B, 14 615351; Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 14 615352
Prepair 1000+ v1.299 GMPPB Zornitza Stark Publications for gene: GMPPB were set to
Prepair 1000+ v1.298 GMPPB Zornitza Stark reviewed gene: GMPPB: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 14 615350, Muscular dystrophy-dystroglycanopathy (congenital with impaired intellectual development), type B, 14 615351, Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 14 615352; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.298 LCAT Zornitza Stark Marked gene: LCAT as ready
Prepair 1000+ v1.298 LCAT Zornitza Stark Gene: lcat has been classified as Green List (High Evidence).
Prepair 1000+ v1.298 LCAT Zornitza Stark Phenotypes for gene: LCAT were changed from Norum disease, 245900 (3) to Norum disease, MIM#245900; Fish-eye disease, MIM# 136120
Prepair 1000+ v1.297 LCAT Zornitza Stark Publications for gene: LCAT were set to
Prepair 1000+ v1.296 LCAT Zornitza Stark Tag for review tag was added to gene: LCAT.
Prepair 1000+ v1.296 LCAT Zornitza Stark reviewed gene: LCAT: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Fish-eye disease, MIM# 136120; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.6217 DYNC1H1 Ken Lee Wan changed review comment from: DYNC1H1 is definitively associated with autosomal dominant dyneinopathy.

A spectrum of diseases related to monoallelic variants in DYNC1H1 and characterized by variable neuromuscular and/or neurodevelopmental presentations.

DYNC1H1 have been reported with a predominantly neuromuscular presentation, including congenital myopathy, spinal muscular atrophy, Charcot-Marie-Tooth (CMT) and less frequently, intellectual disability and autism.

(https://search.clinicalgenome.org/CCID:004713) (http://purl.obolibrary.org/obo/MONDO_1040031) (OMIM: 600112); to: DYNC1H1 is definitively associated with autosomal dominant dyneinopathy.

A spectrum of diseases related to monoallelic variants in DYNC1H1 and characterized by variable neuromuscular and/or neurodevelopmental presentations.

DYNC1H1 have been reported with a predominantly neuromuscular presentation, including congenital myopathy, spinal muscular atrophy, Charcot-Marie-Tooth (CMT) and less frequently, intellectual disability and autism.

Mechanism of disease: gain of function
(https://search.clinicalgenome.org/CCID:004713) (http://purl.obolibrary.org/obo/MONDO_1040031) (OMIM: 600112)
Prepair 1000+ v1.296 ZMYND10 Zornitza Stark Marked gene: ZMYND10 as ready
Prepair 1000+ v1.296 ZMYND10 Zornitza Stark Gene: zmynd10 has been classified as Green List (High Evidence).
Prepair 1000+ v1.296 ZMYND10 Zornitza Stark Phenotypes for gene: ZMYND10 were changed from Ciliary dyskinesia, primary, 22, 615444 (3) to Ciliary dyskinesia, primary, 22 (MIM#615444)
Prepair 1000+ v1.295 ZMYND10 Zornitza Stark Publications for gene: ZMYND10 were set to
Prepair 1000+ v1.294 MRE11 Zornitza Stark Marked gene: MRE11 as ready
Prepair 1000+ v1.294 MRE11 Zornitza Stark Gene: mre11 has been classified as Green List (High Evidence).
Prepair 1000+ v1.294 MRE11 Zornitza Stark Publications for gene: MRE11 were set to
Prepair 1000+ v1.293 ALDH18A1 Zornitza Stark Marked gene: ALDH18A1 as ready
Prepair 1000+ v1.293 ALDH18A1 Zornitza Stark Gene: aldh18a1 has been classified as Green List (High Evidence).
Prepair 1000+ v1.293 ALDH18A1 Zornitza Stark Phenotypes for gene: ALDH18A1 were changed from Spastic paraplegia 9B, autosomal recessive, 616586 (3) to Cutis laxa, autosomal recessive, type IIIA (MIM#219150); Spastic paraplegia 9B, autosomal recessive (MIM#616586)
Prepair 1000+ v1.292 ALDH18A1 Zornitza Stark Publications for gene: ALDH18A1 were set to
Prepair 1000+ v1.291 ALDH1A3 Zornitza Stark Marked gene: ALDH1A3 as ready
Prepair 1000+ v1.291 ALDH1A3 Zornitza Stark Gene: aldh1a3 has been classified as Green List (High Evidence).
Prepair 1000+ v1.291 ALDH1A3 Zornitza Stark Publications for gene: ALDH1A3 were set to
Prepair 1000+ v1.290 AP1S2 Zornitza Stark Marked gene: AP1S2 as ready
Prepair 1000+ v1.290 AP1S2 Zornitza Stark Gene: ap1s2 has been classified as Green List (High Evidence).
Prepair 1000+ v1.290 AP1S2 Zornitza Stark Publications for gene: AP1S2 were set to
Intellectual disability syndromic and non-syndromic v0.6217 DIS3L2 Zornitza Stark Marked gene: DIS3L2 as ready
Intellectual disability syndromic and non-syndromic v0.6217 DIS3L2 Zornitza Stark Gene: dis3l2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.6217 DIS3L2 Zornitza Stark Phenotypes for gene: DIS3L2 were changed from to Perlman syndrome MONDO:0009965
Intellectual disability syndromic and non-syndromic v0.6216 DIS3L2 Zornitza Stark Publications for gene: DIS3L2 were set to
Intellectual disability syndromic and non-syndromic v0.6215 DIAPH1 Ken Lee Wan changed review comment from: Seizures, cortical blindness, and microcephaly syndrome (SCBMS) is an autosomal recessive neurodevelopmental disorder characterized by microcephaly, early-onset seizures, severely delayed psychomotor development, and cortical blindness. Affected individuals also tend to show poor overall growth with short stature (MIM: 616632).

Biallelic loss-of-function DIAPH1 variants have been reported in 3 Middle Eastern consanguineous families with a unique syndrome of early onset seizures, progressive microcephaly, intellectual disability and severe visual impairment (PMIDs: 24781755; 26463574). Western blot analysis showed lack of the mDia1 protein for affected individuals (PMID: 24781755).; to: Seizures, cortical blindness, and microcephaly syndrome (SCBMS) is an autosomal recessive neurodevelopmental disorder characterized by microcephaly, early-onset seizures, severely delayed psychomotor development and cortical blindness. Affected individuals also tend to show poor overall growth with short stature (MIM: 616632).

Biallelic loss-of-function DIAPH1 variants have been reported in 3 Middle Eastern consanguineous families with a unique syndrome of early onset seizures, progressive microcephaly, intellectual disability and severe visual impairment (PMIDs: 24781755; 26463574). Western blot analysis showed lack of the mDia1 protein for affected individuals (PMID: 24781755).
Intellectual disability syndromic and non-syndromic v0.6215 DIS3L2 Zornitza Stark Mode of inheritance for gene: DIS3L2 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.6214 DNMT3B Ken Lee Wan changed review comment from: DNMT3B is a well-established gene disease association with autosomal recessive immunodeficiency-centromeric instability-facial anomalies syndrome 1 (https://search.clinicalgenome.org/CCID:004692).

Immunodeficiency, centromeric instability, and facial dysmorphism (ICF) syndrome is a rare autosomal recessive disease characterized by facial dysmorphism, immunoglobulin deficiency and branching of chromosomes 1, 9, and 16 after phytohemagglutinin (PHA) stimulation of lymphocytes. The most frequent symptoms of the syndrome are facial dysmorphism, intellectual disability, recurrent and prolonged respiratory infections, infections of the skin and digestive system and variable immune deficiency with a constant decrease of IgA (MIM: 242860).

Mechanism of disease: loss of function; to: DNMT3B is a well-established gene disease association with autosomal recessive immunodeficiency-centromeric instability-facial anomalies syndrome 1 (https://search.clinicalgenome.org/CCID:004692).

Immunodeficiency, centromeric instability and facial dysmorphism (ICF) syndrome is a rare autosomal recessive disease characterized by facial dysmorphism, immunoglobulin deficiency and branching of chromosomes 1, 9 and 16 after phytohemagglutinin (PHA) stimulation of lymphocytes. The most frequent symptoms of the syndrome are facial dysmorphism, intellectual disability, recurrent and prolonged respiratory infections, infections of the skin and digestive system and variable immune deficiency with a constant decrease of IgA (MIM: 242860).

Mechanism of disease: loss of function
Intellectual disability syndromic and non-syndromic v0.6214 DYNC1H1 Ken Lee Wan changed review comment from: DYNC1H1 is definitively associated with autosomal dominant dyneinopathy.

A spectrum of diseases related to monoallelic variants in DYNC1H1 and characterized by variable neuromuscular and/or neurodevelopmental presentations.

DYNC1H1 have been reported with a predominantly neuromuscular presentation, including congenital myopathy, spinal muscular atrophy, Charcot-Marie-Tooth (CMT), and less frequently, intellectual disability and autism.

(https://search.clinicalgenome.org/CCID:004713) (http://purl.obolibrary.org/obo/MONDO_1040031) (OMIM: 600112); to: DYNC1H1 is definitively associated with autosomal dominant dyneinopathy.

A spectrum of diseases related to monoallelic variants in DYNC1H1 and characterized by variable neuromuscular and/or neurodevelopmental presentations.

DYNC1H1 have been reported with a predominantly neuromuscular presentation, including congenital myopathy, spinal muscular atrophy, Charcot-Marie-Tooth (CMT) and less frequently, intellectual disability and autism.

(https://search.clinicalgenome.org/CCID:004713) (http://purl.obolibrary.org/obo/MONDO_1040031) (OMIM: 600112)
Intellectual disability syndromic and non-syndromic v0.6214 DYNC1H1 Ken Lee Wan changed review comment from: DYNC1H1 is definitively associated with autosomal dominant dyneinopathy.

A spectrum of diseases related to monoallelic variants in DYNC1H1 and characterized by variable neuromuscular and/or neurodevelopmental presentations.

DYNC1H1 have been reported with a predominantly neuromuscular presentation, including congenital myopathy, spinal muscular atrophy, Charcot-Marie-Tooth (CMT), and less frequently, intellectual disability and autism.

(https://search.clinicalgenome.org/CCID:004713) (http://purl.obolibrary.org/obo/MONDO_1040031) (OMIM#600112); to: DYNC1H1 is definitively associated with autosomal dominant dyneinopathy.

A spectrum of diseases related to monoallelic variants in DYNC1H1 and characterized by variable neuromuscular and/or neurodevelopmental presentations.

DYNC1H1 have been reported with a predominantly neuromuscular presentation, including congenital myopathy, spinal muscular atrophy, Charcot-Marie-Tooth (CMT), and less frequently, intellectual disability and autism.

(https://search.clinicalgenome.org/CCID:004713) (http://purl.obolibrary.org/obo/MONDO_1040031) (OMIM: 600112)
Intellectual disability syndromic and non-syndromic v0.6214 DYNC1H1 Ken Lee Wan reviewed gene: DYNC1H1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: dyneinopathy MONDO:1040031; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability syndromic and non-syndromic v0.6214 DIS3L2 Zornitza Stark Mode of inheritance for gene: DIS3L2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.6213 DNAJC19 Zornitza Stark Marked gene: DNAJC19 as ready
Intellectual disability syndromic and non-syndromic v0.6213 DNAJC19 Zornitza Stark Gene: dnajc19 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.6213 DNAJC19 Zornitza Stark Phenotypes for gene: DNAJC19 were changed from 3-methylglutaconic aciduria type 5 MONDO:0012435 to 3-methylglutaconic aciduria type 5 MONDO:0012435
Intellectual disability syndromic and non-syndromic v0.6212 DNAJC19 Zornitza Stark Phenotypes for gene: DNAJC19 were changed from to 3-methylglutaconic aciduria type 5 MONDO:0012435
Intellectual disability syndromic and non-syndromic v0.6211 DNAJC19 Zornitza Stark Mode of inheritance for gene: DNAJC19 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.6210 DNAJC19 Zornitza Stark Mode of inheritance for gene: DNAJC19 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.289 PSAT1 Lauren Rogers reviewed gene: PSAT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32077105, 17436247, 25152457; Phenotypes: Phosphoserine aminotransferase deficiency MIM#610992, Neu-Laxova syndrome 2 MIM#616038; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.289 PIP5K1C Zornitza Stark Marked gene: PIP5K1C as ready
Prepair 1000+ v1.289 PIP5K1C Zornitza Stark Gene: pip5k1c has been classified as Amber List (Moderate Evidence).
Prepair 1000+ v1.289 PIP5K1C Zornitza Stark Publications for gene: PIP5K1C were set to
Prepair 1000+ v1.288 PIP5K1C Zornitza Stark Classified gene: PIP5K1C as Amber List (moderate evidence)
Prepair 1000+ v1.288 PIP5K1C Zornitza Stark Gene: pip5k1c has been classified as Amber List (Moderate Evidence).
Prepair 1000+ v1.287 PIP5K1C Zornitza Stark reviewed gene: PIP5K1C: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Lethal congenital contractural syndrome 3 (MIM#611369); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.6209 DNMT3B Zornitza Stark Marked gene: DNMT3B as ready
Intellectual disability syndromic and non-syndromic v0.6209 DNMT3B Zornitza Stark Gene: dnmt3b has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.6209 DNMT3B Zornitza Stark Phenotypes for gene: DNMT3B were changed from to immunodeficiency-centromeric instability-facial anomalies syndrome 1 MONDO:0009454
Intellectual disability syndromic and non-syndromic v0.6208 DNMT3B Zornitza Stark Mode of inheritance for gene: DNMT3B was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.6207 DNMT3B Ken Lee Wan reviewed gene: DNMT3B: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: immunodeficiency-centromeric instability-facial anomalies syndrome 1 MONDO:0009454; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Prepair 1000+ v1.287 PIP5K1C Lauren Rogers reviewed gene: PIP5K1C: Rating: RED; Mode of pathogenicity: None; Publications: 17701898, 38491417; Phenotypes: Lethal congenital contractural syndrome 3 (MIM#611369); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.6207 DNAJC19 Ken Lee Wan reviewed gene: DNAJC19: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: 3-methylglutaconic aciduria type 5 MONDO:0012435; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability syndromic and non-syndromic v0.6207 DIS3L2 Ken Lee Wan changed review comment from: Perlman syndrome is a well-established gene-disease association with autosomal recessive Perlman syndrome (https://search.clinicalgenome.org/CCID:004649)

Perlman syndrome (PRLMNS) is an autosomal recessive congenital overgrowth syndrome with similarities to Beckwith-Wiedemann syndrome (BWS; 130650). Affected children are large at birth, are hypotonic and show organomegaly, characteristic facial dysmorphisms, renal anomalies, frequent neurodevelopmental delay and high neonatal mortality. Perlman syndrome is associated with a high risk of Wilms tumour (OMIM: 267000).

PMID 16278893: 6 out of 22 patients have developmental delay

PMID 22306653: 5 surviving patients with at least one loss-of-function variant identified have developmental delay.

PMID 28328139: 1 surviving patient with compound heterozygous (splice site and missense variants) has developmental delay

Mechanism of disease causation: loss of function; to: DIS3L2 is a well-established gene-disease association with autosomal recessive Perlman syndrome (https://search.clinicalgenome.org/CCID:004649)

Perlman syndrome (PRLMNS) is an autosomal recessive congenital overgrowth syndrome with similarities to Beckwith-Wiedemann syndrome (BWS; 130650). Affected children are large at birth, are hypotonic and show organomegaly, characteristic facial dysmorphisms, renal anomalies, frequent neurodevelopmental delay and high neonatal mortality. Perlman syndrome is associated with a high risk of Wilms tumour (OMIM: 267000).

PMID 16278893: 6 out of 22 patients have developmental delay

PMID 22306653: 5 surviving patients with at least one loss-of-function variant identified have developmental delay.

PMID 28328139: 1 surviving patient with compound heterozygous (splice site and missense variants) has developmental delay

Mechanism of disease causation: loss of function
Intellectual disability syndromic and non-syndromic v0.6207 DIS3L2 Ken Lee Wan reviewed gene: DIS3L2: Rating: GREEN; Mode of pathogenicity: None; Publications: 16278893, 22306653, 28328139; Phenotypes: Perlman syndrome MONDO:0009965; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Prepair 1000+ v1.287 AP1S2 Lauren Rogers reviewed gene: AP1S2: Rating: GREEN; Mode of pathogenicity: None; Publications: 30714330, 23756445, 17186471; Phenotypes: Pettigrew syndrome, MIM# 304340; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Prepair 1000+ v1.287 ALDH1A3 Lauren Rogers reviewed gene: ALDH1A3: Rating: GREEN; Mode of pathogenicity: None; Publications: 23312594, 30200890; Phenotypes: Microphthalmia, isolated 8 (MIM#615113); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.287 ALDH18A1 Lauren Rogers reviewed gene: ALDH18A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24913064, 18478038, 26026163; Phenotypes: Cutis laxa, autosomal recessive, type IIIA (MIM#219150), Spastic paraplegia 9B, autosomal recessive (MIM#616586); Mode of inheritance: None
Prepair 1000+ v1.287 MRE11 Lauren Rogers reviewed gene: MRE11: Rating: GREEN; Mode of pathogenicity: None; Publications: 10612394, 11371508, 15269180, 22863007, 24332946, 21227757; Phenotypes: Ataxia-telangiectasia-like disorder 1 (MIM#604391); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Speech apraxia v1.27 DIP2C Zornitza Stark Classified gene: DIP2C as Amber List (moderate evidence)
Speech apraxia v1.27 DIP2C Zornitza Stark Gene: dip2c has been classified as Amber List (Moderate Evidence).
Speech apraxia v1.26 Zornitza Stark removed gene:TRIM8 from the panel
Speech apraxia v1.25 Zornitza Stark removed gene:TAB2 from the panel
Speech apraxia v1.24 Zornitza Stark removed gene:SPTBN1 from the panel
Speech apraxia v1.23 Zornitza Stark removed gene:SMARCA2 from the panel
Speech apraxia v1.22 Zornitza Stark removed gene:SLC6A1 from the panel
Speech apraxia v1.21 Zornitza Stark removed gene:SETD5 from the panel
Speech apraxia v1.20 Zornitza Stark removed gene:SETD2 from the panel
Speech apraxia v1.19 Zornitza Stark removed gene:SET from the panel
Speech apraxia v1.18 Zornitza Stark removed gene:SCN8A from the panel
Speech apraxia v1.17 Zornitza Stark removed gene:RAF1 from the panel
Speech apraxia v1.16 Zornitza Stark removed gene:PPP2R5D from the panel
Speech apraxia v1.15 Zornitza Stark removed gene:NSD1 from the panel
Speech apraxia v1.14 Zornitza Stark removed gene:KCND3 from the panel
Speech apraxia v1.13 Zornitza Stark removed gene:GNAI1 from the panel
Speech apraxia v1.12 Zornitza Stark removed gene:FOXP1 from the panel
Speech apraxia v1.11 Zornitza Stark removed gene:FBXW7 from the panel
Speech apraxia v1.10 Zornitza Stark removed gene:EHMT1 from the panel
Speech apraxia v1.9 Zornitza Stark removed gene:CAMTA1 from the panel
Speech apraxia v1.8 Zornitza Stark removed gene:CAMK2A from the panel
Speech apraxia v1.7 Zornitza Stark removed gene:CACNA1A from the panel
Prepair 1000+ v1.287 ZMYND10 Lauren Rogers reviewed gene: ZMYND10: Rating: GREEN; Mode of pathogenicity: None; Publications: 23891471, 23891469; Phenotypes: Ciliary dyskinesia, primary, 22 (MIM#615444); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.287 LCAT Lauren Rogers changed review comment from: Well established gene-disease association.

A disorder of lipoprotein metabolism that causes a typical triad of diffuse corneal opacities, target cell hemolytic anemia, and proteinuria with renal failure.

Onset is generally in adulthood; to: Well established gene-disease association.

A disorder of lipoprotein metabolism that causes a typical triad of diffuse corneal opacities, target cell hemolytic anemia, and proteinuria with renal failure.

Onset/diagnosis is generally in adulthood
Prepair 1000+ v1.287 LCAT Lauren Rogers reviewed gene: LCAT: Rating: AMBER; Mode of pathogenicity: None; Publications: 30720493, 6624548, 34256778; Phenotypes: Norum disease (MIM#245900); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.287 LCAT Lauren Rogers Deleted their review
Prepair 1000+ v1.287 LCAT Lauren Rogers reviewed gene: LCAT: Rating: GREEN; Mode of pathogenicity: None; Publications: 30720493, 6624548; Phenotypes: Norum disease (MIM#245900); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.287 GMPPB Lauren Rogers reviewed gene: GMPPB: Rating: ; Mode of pathogenicity: None; Publications: 36833299; Phenotypes: Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 14 615350, Muscular dystrophy-dystroglycanopathy (congenital with impaired intellectual development), type B, 14 615351, Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 14 615352; Mode of inheritance: None
Prepair 1000+ v1.287 GMPPA Lauren Rogers reviewed gene: GMPPA: Rating: GREEN; Mode of pathogenicity: None; Publications: 24035193, 28574218; Phenotypes: Alacrima, achalasia, and impaired intellectual development syndrome (MIM#615510); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Pancreatic Cancer v0.24 ATM Chirag Patel changed review comment from: ClinGen definitive. Pancreatic cancer reported in condition.
Sources: Expert list, Expert Review; to: ClinGen definitive. Pancreatic cancer reported in condition.

Consider possibility that an identified variant could represent ACE (aberrant clonal expansion), which can be due to clonal haematopoiesis of indeterminate potential (CHIP) or an occult hematologic malignancy, especially in older patients who have undergone prior chemotherapy (PMID: 36040522).

Sources: Expert list, Expert Review
Pancreatic Cancer v0.24 TP53 Chirag Patel changed review comment from: ClinGen definitive. Pancreatic cancer reported in condition.

Consider possibility that an identified variant could represent ACE (aberrant clonal expansion), which can be due to clonal haematopoiesis of indeterminate potential (CHIP) or an occult hematologic malignancy, especially in older patients who have undergone prior chemotherapy. Genes most commonly associated with ACE include ATM, CHEK2, and TP53 (PMID: 36040522).

Sources: Expert list, Expert Review; to: ClinGen definitive. Pancreatic cancer reported in condition.

Consider possibility that an identified variant could represent ACE (aberrant clonal expansion), which can be due to clonal haematopoiesis of indeterminate potential (CHIP) or an occult hematologic malignancy, especially in older patients who have undergone prior chemotherapy (PMID: 36040522).

Sources: Expert list, Expert Review
Medulloblastoma v0.25 TP53 Chirag Patel changed review comment from: ClinGen definitive. Medulloblastoma reported in condition.

Consider possibility that an identified variant could represent ACE (aberrant clonal expansion), which can be due to clonal haematopoiesis of indeterminate potential (CHIP) or an occult hematologic malignancy, especially in older patients who have undergone prior chemotherapy. Genes most commonly associated with ACE include ATM, CHEK2, and TP53 (PMID: 36040522).; to: ClinGen definitive. Medulloblastoma reported in condition.

Consider possibility that an identified variant could represent ACE (aberrant clonal expansion), which can be due to clonal haematopoiesis of indeterminate potential (CHIP) or an occult hematologic malignancy, especially in older patients who have undergone prior chemotherapy (PMID: 36040522).
Intellectual disability syndromic and non-syndromic v0.6207 DIAPH1 Ken Lee Wan reviewed gene: DIAPH1: Rating: AMBER; Mode of pathogenicity: None; Publications: 24781755, 26463574; Phenotypes: progressive microcephaly-seizures-cortical blindness-developmental delay syndrome MONDO:0014714; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Prepair 1000+ v1.287 GAS8 Lauren Rogers reviewed gene: GAS8: Rating: GREEN; Mode of pathogenicity: None; Publications: 38873586, 26387594, 27120127; Phenotypes: Ciliary dyskinesia, primary, 33 MIM#616726; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Pancreatic Cancer v0.24 TP53 Chirag Patel changed review comment from: ClinGen definitive. Pancreatic cancer reported in condition.
Sources: Expert list, Expert Review; to: ClinGen definitive. Pancreatic cancer reported in condition.

Consider possibility that an identified variant could represent ACE (aberrant clonal expansion), which can be due to clonal haematopoiesis of indeterminate potential (CHIP) or an occult hematologic malignancy, especially in older patients who have undergone prior chemotherapy. Genes most commonly associated with ACE include ATM, CHEK2, and TP53 (PMID: 36040522).

Sources: Expert list, Expert Review
Medulloblastoma v0.25 TP53 Chirag Patel changed review comment from: ClinGen definitive. Medulloblastoma reported in condition.; to: ClinGen definitive. Medulloblastoma reported in condition.

Consider possibility that an identified variant could represent ACE (aberrant clonal expansion), which can be due to clonal haematopoiesis of indeterminate potential (CHIP) or an occult hematologic malignancy, especially in older patients who have undergone prior chemotherapy. Genes most commonly associated with ACE include ATM, CHEK2, and TP53 (PMID: 36040522).
Medulloblastoma v0.25 ELP1 Chirag Patel reviewed gene: ELP1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 32296180, 39184053; Phenotypes: Medulloblastoma, MONDO:0007959, Medulloblastoma predisposition syndrome, MIM#155255; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Medulloblastoma v0.25 GPR161 Chirag Patel reviewed gene: GPR161: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 31609649, 39184053; Phenotypes: Medulloblastoma, MONDO:0007959, Medulloblastoma predisposition syndrome, MIM#155255; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Melanoma v0.15 Chirag Patel Panel status changed from public to internal
Medulloblastoma v0.25 Chirag Patel Panel status changed from public to internal
Medulloblastoma v0.24 BRCA2 Chirag Patel Classified gene: BRCA2 as Green List (high evidence)
Medulloblastoma v0.24 BRCA2 Chirag Patel Gene: brca2 has been classified as Green List (High Evidence).
Medulloblastoma v0.23 EPCAM Chirag Patel Classified gene: EPCAM as Green List (high evidence)
Medulloblastoma v0.23 EPCAM Chirag Patel Gene: epcam has been classified as Green List (High Evidence).
Medulloblastoma v0.22 MLH1 Chirag Patel Classified gene: MLH1 as Green List (high evidence)
Medulloblastoma v0.22 MLH1 Chirag Patel Gene: mlh1 has been classified as Green List (High Evidence).
Medulloblastoma v0.21 MSH2 Chirag Patel Classified gene: MSH2 as Green List (high evidence)
Medulloblastoma v0.21 MSH2 Chirag Patel Gene: msh2 has been classified as Green List (High Evidence).
Medulloblastoma v0.20 MSH6 Chirag Patel Classified gene: MSH6 as Green List (high evidence)
Medulloblastoma v0.20 MSH6 Chirag Patel Gene: msh6 has been classified as Green List (High Evidence).
Medulloblastoma v0.19 PMS2 Chirag Patel Classified gene: PMS2 as Green List (high evidence)
Medulloblastoma v0.19 PMS2 Chirag Patel Gene: pms2 has been classified as Green List (High Evidence).
Medulloblastoma v0.18 PMS2 Chirag Patel gene: PMS2 was added
gene: PMS2 was added to Medulloblastoma. Sources: Expert list,Expert Review
Mode of inheritance for gene: PMS2 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Phenotypes for gene: PMS2 were set to Medulloblastoma, MONDO:0007959; Lynch syndrome 4, MONDO:0013699; Mismatch repair cancer syndrome 4, MONDO:0030843; Lynch syndrome 4, MIM#614337; Mismatch repair cancer syndrome 4, MIM#619101
Review for gene: PMS2 was set to GREEN
Added comment: ClinGen definitive. Medulloblastoma reported in condition.

Note: there is a high level of homology between PMS2 and pseudogenes.
Sources: Expert list, Expert Review
Medulloblastoma v0.17 MSH6 Chirag Patel gene: MSH6 was added
gene: MSH6 was added to Medulloblastoma. Sources: Expert list,Expert Review
Mode of inheritance for gene: MSH6 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Phenotypes for gene: MSH6 were set to Medulloblastoma, MONDO:0007959; Lynch syndrome 5, MONDO:0013710; Mismatch repair cancer syndrome 3, MONDO:0030841; Lynch syndrome 5, MIM#614350; Mismatch repair cancer syndrome 3, MIM#619097
Review for gene: MSH6 was set to GREEN
Added comment: ClinGen definitive. Medulloblastoma reported in condition.
Sources: Expert list, Expert Review
Medulloblastoma v0.16 MSH2 Chirag Patel gene: MSH2 was added
gene: MSH2 was added to Medulloblastoma. Sources: Expert list,Expert Review
Mode of inheritance for gene: MSH2 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Phenotypes for gene: MSH2 were set to Medulloblastoma, MONDO:0007959; Lynch syndrome 1, MONDO:0007356; Mismatch repair cancer syndrome 2, MONDO:0030840; Lynch syndrome 1, MIM#120435; Mismatch repair cancer syndrome 2, MIM#619096
Review for gene: MSH2 was set to GREEN
Added comment: ClinGen definitive. Medulloblastoma reported in condition.
Sources: Expert list, Expert Review
Medulloblastoma v0.15 MLH1 Chirag Patel gene: MLH1 was added
gene: MLH1 was added to Medulloblastoma. Sources: Expert list,Expert Review
Mode of inheritance for gene: MLH1 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Phenotypes for gene: MLH1 were set to Medulloblastoma, MONDO:0007959; Lynch syndrome 2, MONDO:0012249; Mismatch repair cancer syndrome 1, MONDO:0010159; Lynch syndrome 2, MIM#609310; Mismatch repair cancer syndrome 1, MIM#276300
Review for gene: MLH1 was set to GREEN
Added comment: ClinGen definitive. Medulloblastoma reported in condition.
Sources: Expert list, Expert Review
Medulloblastoma v0.14 EPCAM Chirag Patel gene: EPCAM was added
gene: EPCAM was added to Medulloblastoma. Sources: Expert list,Expert Review
Mode of inheritance for gene: EPCAM was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: EPCAM were set to Medulloblastoma, MONDO:0007959; Lynch syndrome 8, MONDO:0013196; Lynch syndrome 8, MIM#613244
Review for gene: EPCAM was set to GREEN
Added comment: ClinGen definitive. Medulloblastoma reported in condition.

Deletion of 3’end of EPCAM gene leading to epigenetic silencing of adjacent downstream MSH2 gene.
Sources: Expert list, Expert Review
Medulloblastoma v0.13 BRCA2 Chirag Patel gene: BRCA2 was added
gene: BRCA2 was added to Medulloblastoma. Sources: Expert list,Expert Review
Mode of inheritance for gene: BRCA2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: BRCA2 were set to Medulloblastoma, MONDO:0007959; BRCA2-related cancer predisposition, MONDO:0700269; Breast-ovarian cancer, familial, 2, MIM#612555
Review for gene: BRCA2 was set to GREEN
Added comment: ClinGen definitive. Medulloblastoma reported in condition.
Sources: Expert list, Expert Review
Medulloblastoma v0.12 TP53 Chirag Patel reviewed gene: TP53: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Medulloblastoma, MONDO:0007959, Li-Fraumeni syndrome, MONDO:0018875, Li-Fraumeni syndrome, MIM#151623; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Medulloblastoma v0.12 SUFU Chirag Patel reviewed gene: SUFU: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Medulloblastoma, MONDO:0007959, Basal cell nevus syndrome 2, MONDO:0958189, Basal cell nevus syndrome 2, MIM#620343, Meningioma, familial, susceptibility to, MIM#607174, Medulloblastoma predisposition syndrome, MIM#155255; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Medulloblastoma v0.12 PTCH1 Chirag Patel reviewed gene: PTCH1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Medulloblastoma, MONDO:0007959, Basal cell nevus syndrome 1, MONDO:0958174, Basal cell nevus syndrome 1, MIM#109400; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Medulloblastoma v0.12 APC Chirag Patel reviewed gene: APC: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Medulloblastoma, MONDO:0007959, Familial adenomatous polyposis 1, MONDO:0021056, Adenomatous polyposis coli, MIM#175100; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Medulloblastoma v0.12 Chirag Patel Panel status changed from retired to public
Pancreatic Cancer v0.24 ATM Chirag Patel Classified gene: ATM as Green List (high evidence)
Pancreatic Cancer v0.24 ATM Chirag Patel Gene: atm has been classified as Green List (High Evidence).
Pancreatic Cancer v0.23 STK11 Chirag Patel Classified gene: STK11 as Green List (high evidence)
Pancreatic Cancer v0.23 STK11 Chirag Patel Gene: stk11 has been classified as Green List (High Evidence).
Pancreatic Cancer v0.22 TP53 Chirag Patel Classified gene: TP53 as Green List (high evidence)
Pancreatic Cancer v0.22 TP53 Chirag Patel Gene: tp53 has been classified as Green List (High Evidence).
Pancreatic Cancer v0.21 PALB2 Chirag Patel Classified gene: PALB2 as Green List (high evidence)
Pancreatic Cancer v0.21 PALB2 Chirag Patel Gene: palb2 has been classified as Green List (High Evidence).
Pancreatic Cancer v0.20 BRCA1 Chirag Patel Classified gene: BRCA1 as Green List (high evidence)
Pancreatic Cancer v0.20 BRCA1 Chirag Patel Gene: brca1 has been classified as Green List (High Evidence).
Pancreatic Cancer v0.19 BRCA2 Chirag Patel Classified gene: BRCA2 as Green List (high evidence)
Pancreatic Cancer v0.19 BRCA2 Chirag Patel Gene: brca2 has been classified as Green List (High Evidence).
Pancreatic Cancer v0.18 CDKN2A Chirag Patel Classified gene: CDKN2A as Green List (high evidence)
Pancreatic Cancer v0.18 CDKN2A Chirag Patel Gene: cdkn2a has been classified as Green List (High Evidence).
Pancreatic Cancer v0.17 CDKN2A Chirag Patel gene: CDKN2A was added
gene: CDKN2A was added to Pancreatic Cancer. Sources: Expert list,Expert Review
Mode of inheritance for gene: CDKN2A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: CDKN2A were set to Malignant pancreatic neoplasm, MONDO:0009831; Melanoma-pancreatic cancer syndrome, MONDO:0011713; Melanoma and neural system tumor syndrome, MONDO:0007967; Melanoma cutaneous malignant susceptibility to 2, MONDO:0007964; Melanoma, cutaneous malignant, 2, MIM#155601; Melanoma-pancreatic cancer syndrome, MIM#606719; Melanoma and neural system tumor syndrome, MIM#155755
Review for gene: CDKN2A was set to GREEN
Added comment: ClinGen definitive. Pancreatic cancer reported in condition
Sources: Expert list, Expert Review
Pancreatic Cancer v0.16 BRCA1 Chirag Patel gene: BRCA1 was added
gene: BRCA1 was added to Pancreatic Cancer. Sources: Expert list,Expert Review
Mode of inheritance for gene: BRCA1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: BRCA1 were set to Malignant pancreatic neoplasm, MONDO:0009831; BRCA1-related cancer predisposition, MONDO:0700268; Breast-ovarian cancer, familial, 1, MIM#604370
Review for gene: BRCA1 was set to GREEN
Added comment: ClinGen definitive. Pancreatic cancer reported in condition.
Sources: Expert list, Expert Review
Pancreatic Cancer v0.15 BRCA2 Chirag Patel gene: BRCA2 was added
gene: BRCA2 was added to Pancreatic Cancer. Sources: Expert list,Expert Review
Mode of inheritance for gene: BRCA2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: BRCA2 were set to Malignant pancreatic neoplasm, MONDO:0009831; BRCA2-related cancer predisposition, MONDO:0700269; Breast-ovarian cancer, familial, 2, MIM#612555
Review for gene: BRCA2 was set to GREEN
Added comment: ClinGen definitive. Pancreatic cancer reported in condition.
Sources: Expert list, Expert Review
Pancreatic Cancer v0.14 PALB2 Chirag Patel gene: PALB2 was added
gene: PALB2 was added to Pancreatic Cancer. Sources: Expert list,Expert Review
Mode of inheritance for gene: PALB2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: PALB2 were set to Malignant pancreatic neoplasm, MONDO:0009831; PALB2-related cancer predisposition, MONDO:0700272; Breast-ovarian cancer, familial, susceptibility to, 5, MIM#620442; Pancreatic cancer, susceptibility to, 3, MIM#613348
Review for gene: PALB2 was set to GREEN
Added comment: ClinGen definitive. Pancreatic cancer reported in condition.
Sources: Expert list, Expert Review
Pancreatic Cancer v0.13 TP53 Chirag Patel gene: TP53 was added
gene: TP53 was added to Pancreatic Cancer. Sources: Expert list,Expert Review
Mode of inheritance for gene: TP53 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: TP53 were set to Malignant pancreatic neoplasm, MONDO:0009831; Li-Fraumeni syndrome, MONDO:0018875; Li-Fraumeni syndrome, MIM#151623
Review for gene: TP53 was set to GREEN
Added comment: ClinGen definitive. Pancreatic cancer reported in condition.
Sources: Expert list, Expert Review
Pancreatic Cancer v0.12 STK11 Chirag Patel gene: STK11 was added
gene: STK11 was added to Pancreatic Cancer. Sources: Expert list,Expert Review
Mode of inheritance for gene: STK11 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: STK11 were set to Malignant pancreatic neoplasm, MONDO:0009831; Peutz-Jeghers syndrome, MONDO:0008280; Peutz-Jeghers syndrome, MIM#175200
Review for gene: STK11 was set to GREEN
Added comment: ClinGen definitive. Pancreatic cancer reported in condition.
Single gene testing may be more appropriate if clinical features of JPS.
Sources: Expert list, Expert Review
Pancreatic Cancer v0.11 ATM Chirag Patel gene: ATM was added
gene: ATM was added to Pancreatic Cancer. Sources: Expert list,Expert Review
Mode of inheritance for gene: ATM was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: ATM were set to Malignant pancreatic neoplasm, MONDO:0009831; ATM-related cancer predisposition, MONDO:0700270; Breast cancer, susceptibility to, MIM#114480
Review for gene: ATM was set to GREEN
Added comment: ClinGen definitive. Pancreatic cancer reported in condition.
Sources: Expert list, Expert Review
Pancreatic Cancer v0.10 EPCAM Chirag Patel Classified gene: EPCAM as Green List (high evidence)
Pancreatic Cancer v0.10 EPCAM Chirag Patel Gene: epcam has been classified as Green List (High Evidence).
Pancreatic Cancer v0.9 PMS2 Chirag Patel Classified gene: PMS2 as Green List (high evidence)
Pancreatic Cancer v0.9 PMS2 Chirag Patel Gene: pms2 has been classified as Green List (High Evidence).
Pancreatic Cancer v0.8 MSH6 Chirag Patel Classified gene: MSH6 as Green List (high evidence)
Pancreatic Cancer v0.8 MSH6 Chirag Patel Gene: msh6 has been classified as Green List (High Evidence).
Pancreatic Cancer v0.7 MSH2 Chirag Patel Classified gene: MSH2 as Green List (high evidence)
Pancreatic Cancer v0.7 MSH2 Chirag Patel Gene: msh2 has been classified as Green List (High Evidence).
Pancreatic Cancer v0.6 MLH1 Chirag Patel Classified gene: MLH1 as Green List (high evidence)
Pancreatic Cancer v0.6 MLH1 Chirag Patel Gene: mlh1 has been classified as Green List (High Evidence).
Pancreatic Cancer v0.5 PMS2 Chirag Patel gene: PMS2 was added
gene: PMS2 was added to Pancreatic Cancer. Sources: Expert list,Expert Review
Mode of inheritance for gene: PMS2 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Phenotypes for gene: PMS2 were set to Malignant pancreatic neoplasm, MONDO:0009831; Lynch syndrome 4, MONDO:0013699; Mismatch repair cancer syndrome 4, MONDO:0030843; Lynch syndrome 4, MIM#614337; Mismatch repair cancer syndrome 4, MIM#619101
Review for gene: PMS2 was set to GREEN
Added comment: ClinGen definitive. Pancreatic cancer reported in condition.

Note: there is a high level of homology between PMS2 and pseudogenes.
Sources: Expert list, Expert Review
Pancreatic Cancer v0.4 MSH6 Chirag Patel gene: MSH6 was added
gene: MSH6 was added to Pancreatic Cancer. Sources: Expert list,Expert Review
Mode of inheritance for gene: MSH6 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Phenotypes for gene: MSH6 were set to Malignant pancreatic neoplasm, MONDO:0009831; Lynch syndrome 5, MONDO:0013710; Mismatch repair cancer syndrome 3, MONDO:0030841; Lynch syndrome 5, MIM#614350; Mismatch repair cancer syndrome 3, MIM#619097
Review for gene: MSH6 was set to GREEN
Added comment: ClinGen definitive. Pancreatic cancer reported in condition.
Sources: Expert list, Expert Review
Pancreatic Cancer v0.3 MSH2 Chirag Patel gene: MSH2 was added
gene: MSH2 was added to Pancreatic Cancer. Sources: Expert list,Expert Review
Mode of inheritance for gene: MSH2 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Phenotypes for gene: MSH2 were set to Malignant pancreatic neoplasm, MONDO:0009831; Lynch syndrome 1, MONDO:0007356; Mismatch repair cancer syndrome 2, MONDO:0030840; Lynch syndrome 1, MIM#120435; Mismatch repair cancer syndrome 2, MIM#619096
Review for gene: MSH2 was set to GREEN
Added comment: ClinGen definitive. Pancreatic cancer reported in condition.
Sources: Expert list, Expert Review
Pancreatic Cancer v0.2 MLH1 Chirag Patel gene: MLH1 was added
gene: MLH1 was added to Pancreatic Cancer. Sources: Expert list,Expert Review
Mode of inheritance for gene: MLH1 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Phenotypes for gene: MLH1 were set to Malignant pancreatic neoplasm, MONDO:0009831; Lynch syndrome 2, MONDO:0012249; Mismatch repair cancer syndrome 1, MONDO:0010159; Lynch syndrome 2, MIM#609310; Mismatch repair cancer syndrome 1, MIM#276300
Review for gene: MLH1 was set to GREEN
Added comment: ClinGen definitive. Pancreatic cancer reported in condition.
Sources: Expert list, Expert Review
Pancreatic Cancer v0.1 EPCAM Chirag Patel gene: EPCAM was added
gene: EPCAM was added to Pancreatic Cancer. Sources: Expert list,Expert Review
Mode of inheritance for gene: EPCAM was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: EPCAM were set to Malignant pancreatic neoplasm, MONDO:0009831; Lynch syndrome 8, MONDO:0013196; Lynch syndrome 8, MIM#613244
Review for gene: EPCAM was set to GREEN
Added comment: ClinGen definitive. Pancreatic cancer reported in condition.

Deletion of 3’end of EPCAM gene leading to epigenetic silencing of adjacent downstream MSH2 gene.
Sources: Expert list, Expert Review
Parathyroid Tumour v0.13 Chirag Patel Panel name changed from Parathyroid Neoplasm to Parathyroid Cancer
Speech apraxia v1.6 CACNA1A Thomas Scerri Deleted their review
Speech apraxia v1.6 CAMK2A Thomas Scerri Deleted their review
Speech apraxia v1.6 CAMTA1 Thomas Scerri Deleted their review
Speech apraxia v1.6 EHMT1 Thomas Scerri Deleted their review
Speech apraxia v1.6 FBXW7 Thomas Scerri Deleted their review
Speech apraxia v1.6 FOXP1 Thomas Scerri Deleted their review
Speech apraxia v1.6 GNAI1 Thomas Scerri Deleted their review
Speech apraxia v1.6 KCND3 Thomas Scerri Deleted their review
Speech apraxia v1.6 NSD1 Thomas Scerri Deleted their review
Speech apraxia v1.6 PPP2R5D Thomas Scerri Deleted their review
Speech apraxia v1.6 RAF1 Thomas Scerri Deleted their review
Speech apraxia v1.6 SCN8A Thomas Scerri Deleted their review
Speech apraxia v1.6 SET Thomas Scerri Deleted their review
Speech apraxia v1.6 SETD2 Thomas Scerri Deleted their review
Speech apraxia v1.6 SETD5 Thomas Scerri Deleted their review
Speech apraxia v1.6 SLC6A1 Thomas Scerri Deleted their review
Speech apraxia v1.6 SMARCA2 Thomas Scerri Deleted their review
Speech apraxia v1.6 SPTBN1 Thomas Scerri Deleted their review
Speech apraxia v1.6 TAB2 Thomas Scerri Deleted their review
Speech apraxia v1.6 TRIM8 Thomas Scerri Deleted their review
Speech apraxia v1.6 FOXP1 Thomas Scerri changed review comment from: An in-house (as yet unpublished) CAS proband with a pathogenic variant. The proband shows mild CAS.

Another in-house (unpublished) CAS proband with a de novo splice variant that is listed as pathogenic in ClinVar.

Braden et al., (2021; 34109629) examined 29 probands with pathogenic FOXP1 variants, and reported that "All verbal patients had dysarthric and apraxic features, with phonologicaldeficits in most (14 out of 16)."
Sources: Expert list, Expert Review; to: An in-house (as yet unpublished) CAS proband with a pathogenic variant. The proband shows mild CAS.

Another in-house (unpublished) CAS proband with a de novo splice variant that is listed as pathogenic in ClinVar.

Braden et al., (2021; PMID: 34109629) examined 29 probands with pathogenic FOXP1 variants, and reported that "All verbal patients had dysarthric and apraxic features, with phonologicaldeficits in most (14 out of 16)."
Sources: Expert list, Expert Review
Speech apraxia v1.6 FOXP1 Thomas Scerri gene: FOXP1 was added
gene: FOXP1 was added to Speech apraxia. Sources: Expert list,Expert Review
Mode of inheritance for gene: FOXP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FOXP1 were set to 34109629
Phenotypes for gene: FOXP1 were set to Intellectual developmental disorder with language impairment with or without autistic features, MIM# 613670
Review for gene: FOXP1 was set to GREEN
Added comment: An in-house (as yet unpublished) CAS proband with a pathogenic variant. The proband shows mild CAS.

Another in-house (unpublished) CAS proband with a de novo splice variant that is listed as pathogenic in ClinVar.

Braden et al., (2021; 34109629) examined 29 probands with pathogenic FOXP1 variants, and reported that "All verbal patients had dysarthric and apraxic features, with phonologicaldeficits in most (14 out of 16)."
Sources: Expert list, Expert Review
Speech apraxia v1.6 TRIM8 Thomas Scerri gene: TRIM8 was added
gene: TRIM8 was added to Speech apraxia. Sources: Expert list,Expert Review
Mode of inheritance for gene: TRIM8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: TRIM8 were set to Focal segmental glomerulosclerosis and neurodevelopmental syndrome, MIM# 619428
Review for gene: TRIM8 was set to RED
Added comment: An in-house (as yet unpublished) CAS proband with a pathogenic variant.
Sources: Expert list, Expert Review
Speech apraxia v1.6 TAB2 Thomas Scerri gene: TAB2 was added
gene: TAB2 was added to Speech apraxia. Sources: Expert list,Expert Review
Mode of inheritance for gene: TAB2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: TAB2 were set to Congenital heart defects, nonsyndromic, 2, MIM# 614980
Review for gene: TAB2 was set to RED
Added comment: An in-house (as yet unpublished) CAS proband with a pathogenic variant.
Sources: Expert list, Expert Review
Speech apraxia v1.6 SPTBN1 Thomas Scerri gene: SPTBN1 was added
gene: SPTBN1 was added to Speech apraxia. Sources: Expert list,Expert Review
Mode of inheritance for gene: SPTBN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: SPTBN1 were set to Developmental delay, impaired speech, and behavioral abnormalities, MIM# 619475
Review for gene: SPTBN1 was set to RED
Added comment: An in-house (as yet unpublished) CAS proband with a pathogenic variant.
Sources: Expert list, Expert Review
Speech apraxia v1.6 SMARCA2 Thomas Scerri gene: SMARCA2 was added
gene: SMARCA2 was added to Speech apraxia. Sources: Expert list,Expert Review
Mode of inheritance for gene: SMARCA2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: SMARCA2 were set to Blepharophimosis-impaired intellectual development syndrome, MIM# 619293; Nicolaides-Baraitser syndrome, MIM# 601358
Review for gene: SMARCA2 was set to RED
Added comment: Two in-house (as yet unpublished) CAS probands with pathogenic variants.
Sources: Expert list, Expert Review
Speech apraxia v1.6 SLC6A1 Thomas Scerri gene: SLC6A1 was added
gene: SLC6A1 was added to Speech apraxia. Sources: Expert list,Expert Review
Mode of inheritance for gene: SLC6A1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: SLC6A1 were set to Myoclonic-atonic epilepsy, MIM# 616421
Review for gene: SLC6A1 was set to RED
Added comment: An in-house (as yet unpublished) CAS proband with a pathogenic variant.
Sources: Expert list, Expert Review
Speech apraxia v1.6 SETD5 Thomas Scerri gene: SETD5 was added
gene: SETD5 was added to Speech apraxia. Sources: Expert list,Expert Review
Mode of inheritance for gene: SETD5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: SETD5 were set to Intellectual developmental disorder, autosomal dominant 23, MIM# 615761
Review for gene: SETD5 was set to RED
Added comment: An in-house (as yet unpublished) CAS proband with a pathogenic variant.
Sources: Expert list, Expert Review
Speech apraxia v1.6 SETD2 Thomas Scerri gene: SETD2 was added
gene: SETD2 was added to Speech apraxia. Sources: Expert list,Expert Review
Mode of inheritance for gene: SETD2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: SETD2 were set to Intellectual developmental disorder, autosomal dominant 70, MIM# 620157; Luscan-Lumish syndrome, MIM# 616831; Rabin-Pappas syndrome, MIM# 620155
Review for gene: SETD2 was set to RED
Added comment: An in-house (as yet unpublished) CAS proband with a pathogenic variant.
Sources: Expert list, Expert Review
Speech apraxia v1.6 SET Thomas Scerri gene: SET was added
gene: SET was added to Speech apraxia. Sources: Expert list,Expert Review
Mode of inheritance for gene: SET was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: SET were set to Intellectual developmental disorder, autosomal dominant 58, MIM# 618106
Review for gene: SET was set to RED
Added comment: An in-house (as yet unpublished) CAS proband with a pathogenic variant.
Sources: Expert list, Expert Review
Speech apraxia v1.6 SCN8A Thomas Scerri gene: SCN8A was added
gene: SCN8A was added to Speech apraxia. Sources: Expert list,Expert Review
Mode of inheritance for gene: SCN8A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: SCN8A were set to Cognitive impairment with or without cerebellar ataxia, MIM# 614306; Developmental and epileptic encephalopathy 13, MIM# 614558; Seizures, benign familial infantile, 5, MIM# 617080
Review for gene: SCN8A was set to RED
Added comment: An in-house (as yet unpublished) CAS proband with a pathogenic variant.
Sources: Expert list, Expert Review
Speech apraxia v1.6 RAF1 Thomas Scerri gene: RAF1 was added
gene: RAF1 was added to Speech apraxia. Sources: Expert list,Expert Review
Mode of inheritance for gene: RAF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: RAF1 were set to Cardiomyopathy, dilated, 1NN, MIM# 615916; LEOPARD syndrome 2, MIM# 611554; Noonan syndrome 5, MIM# 611553
Review for gene: RAF1 was set to RED
Added comment: An in-house (as yet unpublished) CAS proband with a pathogenic variant.
Sources: Expert list, Expert Review
Speech apraxia v1.6 PPP2R5D Thomas Scerri gene: PPP2R5D was added
gene: PPP2R5D was added to Speech apraxia. Sources: Expert list,Expert Review
Mode of inheritance for gene: PPP2R5D was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: PPP2R5D were set to Houge-Janssens syndrome 1, MIM# 616355
Review for gene: PPP2R5D was set to RED
Added comment: An in-house (as yet unpublished) CAS proband with a pathogenic variant.
Sources: Expert list, Expert Review
Speech apraxia v1.6 NSD1 Thomas Scerri gene: NSD1 was added
gene: NSD1 was added to Speech apraxia. Sources: Expert list,Expert Review
Mode of inheritance for gene: NSD1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: NSD1 were set to Sotos syndrome, MIM# 117550
Review for gene: NSD1 was set to RED
Added comment: An in-house (as yet unpublished) CAS proband with a pathogenic variant.
Sources: Expert list, Expert Review
Speech apraxia v1.6 KDM5C Thomas Scerri commented on gene: KDM5C: An in-house (as yet unpublished) CAS proband with a pathogenic variant.
Speech apraxia v1.6 KCND3 Thomas Scerri gene: KCND3 was added
gene: KCND3 was added to Speech apraxia. Sources: Expert list,Expert Review
Mode of inheritance for gene: KCND3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: KCND3 were set to Brugada syndrome 9, MIM# 616399; Spinocerebellar ataxia 19, MIM# 607346
Review for gene: KCND3 was set to RED
Added comment: An in-house (as yet unpublished) CAS proband with a pathogenic variant.
Sources: Expert list, Expert Review
Speech apraxia v1.6 GNAI1 Thomas Scerri gene: GNAI1 was added
gene: GNAI1 was added to Speech apraxia. Sources: Expert list,Expert Review
Mode of inheritance for gene: GNAI1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: GNAI1 were set to Neurodevelopmental disorder with hypotonia, impaired speech, and behavioral abnormalities, MIM# 619854
Review for gene: GNAI1 was set to RED
Added comment: An in-house (as yet unpublished) CAS proband with a pathogenic variant.
Sources: Expert list, Expert Review
Speech apraxia v1.6 FBXW7 Thomas Scerri gene: FBXW7 was added
gene: FBXW7 was added to Speech apraxia. Sources: Expert list,Expert Review
Mode of inheritance for gene: FBXW7 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: FBXW7 were set to Developmental delay, hypotonia, and impaired language, MIM# 620012
Review for gene: FBXW7 was set to RED
Added comment: An in-house (as yet unpublished) CAS proband with a pathogenic variant.
Sources: Expert list, Expert Review
Speech apraxia v1.6 EHMT1 Thomas Scerri gene: EHMT1 was added
gene: EHMT1 was added to Speech apraxia. Sources: Expert list,Expert Review
Mode of inheritance for gene: EHMT1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: EHMT1 were set to Kleefstra syndrome 1, MIM# 610253
Review for gene: EHMT1 was set to RED
Added comment: Two in-house (as yet unpublished) CAS probands with a pathogenic variant.
Sources: Expert list, Expert Review
Speech apraxia v1.6 CAMTA1 Thomas Scerri gene: CAMTA1 was added
gene: CAMTA1 was added to Speech apraxia. Sources: Expert list,Expert Review
Mode of inheritance for gene: CAMTA1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: CAMTA1 were set to Cerebellar dysfunction with variable cognitive and behavioral abnormalities, MIM# 614756
Review for gene: CAMTA1 was set to RED
Added comment: An in-house (as yet unpublished) CAS proband with a pathogenic variant.
Sources: Expert list, Expert Review
Speech apraxia v1.6 CAMK2A Thomas Scerri gene: CAMK2A was added
gene: CAMK2A was added to Speech apraxia. Sources: Expert list,Expert Review
Mode of inheritance for gene: CAMK2A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: CAMK2A were set to Intellectual developmental disorder, autosomal dominant 53, MIM# 617798
Review for gene: CAMK2A was set to RED
Added comment: An in-house (as yet unpublished) CAS proband with a pathogenic variant.
Sources: Expert list, Expert Review
Speech apraxia v1.6 CACNA1A Thomas Scerri gene: CACNA1A was added
gene: CACNA1A was added to Speech apraxia. Sources: Expert list,Expert Review
Mode of inheritance for gene: CACNA1A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CACNA1A were set to 38712155
Phenotypes for gene: CACNA1A were set to Developmental and epileptic encephalopathy 42, MIM# 617106; Episodic ataxia, type 2, MIM# 108500; Migraine, familial hemiplegic, 1, MIM# 141500; Migraine, familial hemiplegic, 1, with progressive cerebellar ataxia, MIM# 141500; Spinocerebellar ataxia 6, MIM# 183086
Review for gene: CACNA1A was set to GREEN
Added comment: Three in-house (as yet unpublished) CAS probands with pathogenic variants.

Magielski et al. (2024; PMID: 38712155) report 1 individual with speech apraxia and a CACNA1C genetic diagnosis.
Sources: Expert list, Expert Review
Parathyroid Tumour v0.12 RET Zornitza Stark Marked gene: RET as ready
Parathyroid Tumour v0.12 RET Zornitza Stark Gene: ret has been classified as Green List (High Evidence).
Parathyroid Tumour v0.12 MEN1 Zornitza Stark Marked gene: MEN1 as ready
Parathyroid Tumour v0.12 MEN1 Zornitza Stark Gene: men1 has been classified as Green List (High Evidence).
Parathyroid Tumour v0.12 GCM2 Zornitza Stark Marked gene: GCM2 as ready
Parathyroid Tumour v0.12 GCM2 Zornitza Stark Gene: gcm2 has been classified as Green List (High Evidence).
Parathyroid Tumour v0.12 CDKN1B Zornitza Stark Marked gene: CDKN1B as ready
Parathyroid Tumour v0.12 CDKN1B Zornitza Stark Gene: cdkn1b has been classified as Green List (High Evidence).
Parathyroid Tumour v0.12 CDC73 Zornitza Stark Marked gene: CDC73 as ready
Parathyroid Tumour v0.12 CDC73 Zornitza Stark Gene: cdc73 has been classified as Green List (High Evidence).
Parathyroid Tumour v0.12 CASR Zornitza Stark Marked gene: CASR as ready
Parathyroid Tumour v0.12 CASR Zornitza Stark Gene: casr has been classified as Green List (High Evidence).
Thyroid Cancer v0.13 Zornitza Stark Panel name changed from Thyroid Neoplasm to Thyroid Cancer
Thyroid Cancer v0.12 RET Zornitza Stark Marked gene: RET as ready
Thyroid Cancer v0.12 RET Zornitza Stark Gene: ret has been classified as Green List (High Evidence).
Thyroid Cancer v0.12 PTEN Zornitza Stark Marked gene: PTEN as ready
Thyroid Cancer v0.12 PTEN Zornitza Stark Gene: pten has been classified as Green List (High Evidence).
Thyroid Cancer v0.12 PRKAR1A Zornitza Stark Marked gene: PRKAR1A as ready
Thyroid Cancer v0.12 PRKAR1A Zornitza Stark Gene: prkar1a has been classified as Green List (High Evidence).
Thyroid Cancer v0.12 DICER1 Zornitza Stark Marked gene: DICER1 as ready
Thyroid Cancer v0.12 DICER1 Zornitza Stark Gene: dicer1 has been classified as Green List (High Evidence).
Thyroid Cancer v0.12 CDKN1B Zornitza Stark Marked gene: CDKN1B as ready
Thyroid Cancer v0.12 CDKN1B Zornitza Stark Gene: cdkn1b has been classified as Green List (High Evidence).
Thyroid Cancer v0.12 APC Zornitza Stark Marked gene: APC as ready
Thyroid Cancer v0.12 APC Zornitza Stark Gene: apc has been classified as Green List (High Evidence).
Speech apraxia v1.6 ANK2 Zornitza Stark Marked gene: ANK2 as ready
Speech apraxia v1.6 ANK2 Zornitza Stark Gene: ank2 has been classified as Red List (Low Evidence).
Speech apraxia v1.6 ANK2 Zornitza Stark Phenotypes for gene: ANK2 were changed from Cardiac arrhythmia, ankyrin-B-relatedNeurodevelopmental disorder (MONDO:0700092), gene-related to Neurodevelopmental disorder (MONDO:0700092), gene-related
Speech apraxia v1.5 ANK2 Zornitza Stark Classified gene: ANK2 as Red List (low evidence)
Speech apraxia v1.5 ANK2 Zornitza Stark Gene: ank2 has been classified as Red List (Low Evidence).
Speech apraxia v1.4 BPTF Zornitza Stark Marked gene: BPTF as ready
Speech apraxia v1.4 BPTF Zornitza Stark Gene: bptf has been classified as Red List (Low Evidence).
Speech apraxia v1.4 BPTF Zornitza Stark Classified gene: BPTF as Red List (low evidence)
Speech apraxia v1.4 BPTF Zornitza Stark Gene: bptf has been classified as Red List (Low Evidence).
Kidney Cancer v0.26 VHL Zornitza Stark Marked gene: VHL as ready
Kidney Cancer v0.26 VHL Zornitza Stark Gene: vhl has been classified as Green List (High Evidence).
Kidney Cancer v0.26 TSC2 Zornitza Stark Marked gene: TSC2 as ready
Kidney Cancer v0.26 TSC2 Zornitza Stark Gene: tsc2 has been classified as Green List (High Evidence).
Kidney Cancer v0.26 TSC1 Zornitza Stark Marked gene: TSC1 as ready
Kidney Cancer v0.26 TSC1 Zornitza Stark Gene: tsc1 has been classified as Green List (High Evidence).
Kidney Cancer v0.26 SDHD Zornitza Stark Marked gene: SDHD as ready
Kidney Cancer v0.26 SDHD Zornitza Stark Gene: sdhd has been classified as Green List (High Evidence).
Kidney Cancer v0.26 SDHC Zornitza Stark Marked gene: SDHC as ready
Kidney Cancer v0.26 SDHC Zornitza Stark Gene: sdhc has been classified as Green List (High Evidence).
Kidney Cancer v0.26 SDHB Zornitza Stark Marked gene: SDHB as ready
Kidney Cancer v0.26 SDHB Zornitza Stark Gene: sdhb has been classified as Green List (High Evidence).
Kidney Cancer v0.26 SDHAF2 Zornitza Stark Marked gene: SDHAF2 as ready
Kidney Cancer v0.26 SDHAF2 Zornitza Stark Gene: sdhaf2 has been classified as Green List (High Evidence).
Kidney Cancer v0.26 SDHA Zornitza Stark Marked gene: SDHA as ready
Kidney Cancer v0.26 SDHA Zornitza Stark Gene: sdha has been classified as Green List (High Evidence).
Kidney Cancer v0.26 PTEN Zornitza Stark Marked gene: PTEN as ready
Kidney Cancer v0.26 PTEN Zornitza Stark Gene: pten has been classified as Green List (High Evidence).
Kidney Cancer v0.26 MET Zornitza Stark Marked gene: MET as ready
Kidney Cancer v0.26 MET Zornitza Stark Gene: met has been classified as Green List (High Evidence).
Kidney Cancer v0.26 FLCN Zornitza Stark Marked gene: FLCN as ready
Kidney Cancer v0.26 FLCN Zornitza Stark Gene: flcn has been classified as Green List (High Evidence).
Kidney Cancer v0.26 FH Zornitza Stark Marked gene: FH as ready
Kidney Cancer v0.26 FH Zornitza Stark Gene: fh has been classified as Green List (High Evidence).
Kidney Cancer v0.26 BAP1 Zornitza Stark Marked gene: BAP1 as ready
Kidney Cancer v0.26 BAP1 Zornitza Stark Gene: bap1 has been classified as Green List (High Evidence).
Speech apraxia v1.3 BPTF Thomas Scerri gene: BPTF was added
gene: BPTF was added to Speech apraxia. Sources: Expert Review,Expert list
Mode of inheritance for gene: BPTF was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: BPTF were set to Neurodevelopmental disorder with dysmorphic facies and distal limb anomalies, MIM# 617755
Review for gene: BPTF was set to RED
Added comment: An in-house (as yet unpublished) CAS proband with a pathogenic variant.
Sources: Expert Review, Expert list
Speech apraxia v1.3 ANK2 Thomas Scerri changed review comment from: An in-house (as yet unpublished) CAS proband with a pathogenic variant.
Sources: Expert Review; to: An in-house (as yet unpublished) CAS proband with a pathogenic variant.
Sources: Expert list, Expert Review
Speech apraxia v1.3 ANK2 Thomas Scerri edited their review of gene: ANK2: Changed phenotypes: Cardiac arrhythmia, ankyrin-B-related, MIM# 600919, Long QT syndrome 4, MIM# 600919, Neurodevelopmental disorder (MONDO:0700092), ANK2-related
Speech apraxia v1.3 ANK2 Thomas Scerri edited their review of gene: ANK2: Changed phenotypes: Cardiac arrhythmia, ankyrin-B-related, MIM# 600919, Long QT syndrome 4, MIM# 600919, Neurodevelopmental disorder (MONDO:0700092), gene-related
Speech apraxia v1.3 ANK2 Thomas Scerri gene: ANK2 was added
gene: ANK2 was added to Speech apraxia. Sources: Expert Review
Mode of inheritance for gene: ANK2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ANK2 were set to 37195288
Phenotypes for gene: ANK2 were set to Cardiac arrhythmia, ankyrin-B-relatedNeurodevelopmental disorder (MONDO:0700092), gene-related
Review for gene: ANK2 was set to RED
Added comment: An in-house (as yet unpublished) CAS proband with a pathogenic variant.
Sources: Expert Review
Speech apraxia v1.3 SETBP1 Thomas Scerri commented on gene: SETBP1: Two in-house (as yet unpublished) CAS probands with pathogenic variants.
Speech apraxia v1.3 FOXP2 Thomas Scerri changed review comment from: An unpublished CAS proband with a pathogenic variant.; to: An in-house (as yet unpublished) CAS proband with a pathogenic variant.
Speech apraxia v1.3 FOXP2 Thomas Scerri commented on gene: FOXP2: An unpublished CAS proband with a pathogenic variant.
Speech apraxia v1.3 SHANK3 Zornitza Stark Classified gene: SHANK3 as Amber List (moderate evidence)
Speech apraxia v1.3 SHANK3 Zornitza Stark Gene: shank3 has been classified as Amber List (Moderate Evidence).
Speech apraxia v1.2 WDR5 Zornitza Stark Classified gene: WDR5 as Amber List (moderate evidence)
Speech apraxia v1.2 WDR5 Zornitza Stark Gene: wdr5 has been classified as Amber List (Moderate Evidence).
Speech apraxia v1.1 SETD1A Zornitza Stark Classified gene: SETD1A as Green List (high evidence)
Speech apraxia v1.1 SETD1A Zornitza Stark Gene: setd1a has been classified as Green List (High Evidence).
Kidney Cancer v0.26 BAP1 Chirag Patel Classified gene: BAP1 as Green List (high evidence)
Kidney Cancer v0.26 BAP1 Chirag Patel Gene: bap1 has been classified as Green List (High Evidence).
Kidney Cancer v0.25 FH Chirag Patel Classified gene: FH as Green List (high evidence)
Kidney Cancer v0.25 FH Chirag Patel Gene: fh has been classified as Green List (High Evidence).
Kidney Cancer v0.24 FLCN Chirag Patel Classified gene: FLCN as Green List (high evidence)
Kidney Cancer v0.24 FLCN Chirag Patel Gene: flcn has been classified as Green List (High Evidence).
Kidney Cancer v0.23 PTEN Chirag Patel Classified gene: PTEN as Green List (high evidence)
Kidney Cancer v0.23 PTEN Chirag Patel Gene: pten has been classified as Green List (High Evidence).
Kidney Cancer v0.22 MET Chirag Patel Classified gene: MET as Green List (high evidence)
Kidney Cancer v0.22 MET Chirag Patel Gene: met has been classified as Green List (High Evidence).
Kidney Cancer v0.21 MET Chirag Patel gene: MET was added
gene: MET was added to Kidney Cancer. Sources: Expert list,Expert Review
Mode of inheritance for gene: MET was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: MET were set to Renal carcinoma, MONDO:0005206; Papillary renal cell carcinoma, MONDO:0017884; Renal cell carcinoma, papillary, 1, familial, MIM#605074
Mode of pathogenicity for gene: MET was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: MET was set to GREEN
Added comment: ClinGen definitive. GOF variants.
Sources: Expert list, Expert Review
Kidney Cancer v0.20 PTEN Chirag Patel gene: PTEN was added
gene: PTEN was added to Kidney Cancer. Sources: Expert list,Expert Review
Mode of inheritance for gene: PTEN was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: PTEN were set to Renal carcinoma, MONDO:0005206; PTEN hamartoma tumor syndrome, MONDO:0017623; PTEN hamartoma tumour syndromes, MIM#158350
Review for gene: PTEN was set to GREEN
Added comment: ClinGen definitive. Renal carcinoma reported in condition.
Sources: Expert list, Expert Review
Kidney Cancer v0.19 FLCN Chirag Patel gene: FLCN was added
gene: FLCN was added to Kidney Cancer. Sources: Expert list,Expert Review
Mode of inheritance for gene: FLCN was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: FLCN were set to Renal carcinoma, MONDO:0005206; Birt-Hogg-Dube syndrome 1, MONDO:0800445; Birt-Hogg-Dube syndrome, MIM#135150
Review for gene: FLCN was set to GREEN
Added comment: ClinGen definitive. Renal carcinoma reported in condition.
Sources: Expert list, Expert Review
Kidney Cancer v0.18 FH Chirag Patel gene: FH was added
gene: FH was added to Kidney Cancer. Sources: Expert list,Expert Review
Mode of inheritance for gene: FH was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: FH were set to Renal carcinoma, MONDO:0005206; Hereditary leiomyomatosis and renal cell cancer, MONDO:0007888; Leiomyomatosis and renal cell cancer, MIM#150800
Review for gene: FH was set to GREEN
Added comment: ClinGen definitive. Renal carcinoma reported in condition.
Sources: Expert list, Expert Review
Kidney Cancer v0.17 BAP1 Chirag Patel gene: BAP1 was added
gene: BAP1 was added to Kidney Cancer. Sources: Expert list,Expert Review
Mode of inheritance for gene: BAP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: BAP1 were set to Renal carcinoma, MONDO:0005206; BAP1-related tumor predisposition syndrome, MONDO:0013692; BAP1-tumour predisposition syndrome, MIM#614327
Review for gene: BAP1 was set to GREEN
Added comment: ClinGen definitive. Renal carcinoma reported in condition.
Sources: Expert list, Expert Review
Kidney Cancer v0.16 TSC1 Chirag Patel Classified gene: TSC1 as Green List (high evidence)
Kidney Cancer v0.16 TSC1 Chirag Patel Gene: tsc1 has been classified as Green List (High Evidence).
Kidney Cancer v0.15 TSC2 Chirag Patel Classified gene: TSC2 as Green List (high evidence)
Kidney Cancer v0.15 TSC2 Chirag Patel Gene: tsc2 has been classified as Green List (High Evidence).
Kidney Cancer v0.14 VHL Chirag Patel Classified gene: VHL as Green List (high evidence)
Kidney Cancer v0.14 VHL Chirag Patel Gene: vhl has been classified as Green List (High Evidence).
Kidney Cancer v0.13 VHL Chirag Patel gene: VHL was added
gene: VHL was added to Kidney Cancer. Sources: Expert list,Expert Review
Mode of inheritance for gene: VHL was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: VHL were set to Renal carcinoma, MONDO:0005206; Von Hippel-Lindau disease, MONDO:0008667; von Hippel-Lindau syndrome, MIM#193300; Pheochromocytoma, susceptibility to, MIM#171300
Review for gene: VHL was set to GREEN
Added comment: ClinGen definitive. Renal carcinoma reported in condition.
Sources: Expert list, Expert Review
Kidney Cancer v0.12 TSC2 Chirag Patel gene: TSC2 was added
gene: TSC2 was added to Kidney Cancer. Sources: Expert list,Expert Review
Mode of inheritance for gene: TSC2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: TSC2 were set to Renal carcinoma, MONDO:0005206; Tuberous sclerosis 2, MONDO:0013199; Tuberous sclerosis-2, MIM#613254
Review for gene: TSC2 was set to GREEN
Added comment: ClinGen definitive. Renal carcinoma reported in condition.
Sources: Expert list, Expert Review
Kidney Cancer v0.11 TSC1 Chirag Patel gene: TSC1 was added
gene: TSC1 was added to Kidney Cancer. Sources: Expert list,Expert Review
Mode of inheritance for gene: TSC1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: TSC1 were set to Renal carcinoma, MONDO:0005206; Tuberous sclerosis 1, MONDO:0008612; Tuberous sclerosis-1, MIM#191100
Review for gene: TSC1 was set to GREEN
Added comment: ClinGen definitive. Renal carcinoma reported in condition.
Sources: Expert list, Expert Review
Kidney Cancer v0.10 SDHD Chirag Patel Classified gene: SDHD as Green List (high evidence)
Kidney Cancer v0.10 SDHD Chirag Patel Gene: sdhd has been classified as Green List (High Evidence).
Kidney Cancer v0.9 SDHC Chirag Patel Classified gene: SDHC as Green List (high evidence)
Kidney Cancer v0.9 SDHC Chirag Patel Gene: sdhc has been classified as Green List (High Evidence).
Kidney Cancer v0.8 SDHB Chirag Patel Classified gene: SDHB as Green List (high evidence)
Kidney Cancer v0.8 SDHB Chirag Patel Gene: sdhb has been classified as Green List (High Evidence).
Kidney Cancer v0.7 SDHAF2 Chirag Patel Classified gene: SDHAF2 as Green List (high evidence)
Kidney Cancer v0.7 SDHAF2 Chirag Patel Gene: sdhaf2 has been classified as Green List (High Evidence).
Kidney Cancer v0.6 SDHA Chirag Patel Classified gene: SDHA as Green List (high evidence)
Kidney Cancer v0.6 SDHA Chirag Patel Gene: sdha has been classified as Green List (High Evidence).
Kidney Cancer v0.5 SDHA Chirag Patel gene: SDHA was added
gene: SDHA was added to Kidney Cancer. Sources: Expert list,Expert Review
Mode of inheritance for gene: SDHA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: SDHA were set to Renal carcinoma, MONDO:0005206; Hereditary pheochromocytoma-paraganglioma, MONDO:0017366; Pheochromocytoma/paraganglioma syndrome 5, MIM#614165
Review for gene: SDHA was set to GREEN
Added comment: ClinGen definitive. Renal carcinoma reported in condition.
Sources: Expert list, Expert Review
Kidney Cancer v0.4 SDHAF2 Chirag Patel gene: SDHAF2 was added
gene: SDHAF2 was added to Kidney Cancer. Sources: Expert list,Expert Review
Mode of inheritance for gene: SDHAF2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: SDHAF2 were set to Renal carcinoma, MONDO:0005206; Hereditary pheochromocytoma-paraganglioma, MONDO:0017366; Pheochromocytoma/paraganglioma syndrome 2, MIM#601650
Review for gene: SDHAF2 was set to GREEN
Added comment: ClinGen definitive. Renal carcinoma reported in condition.
Sources: Expert list, Expert Review
Kidney Cancer v0.3 SDHB Chirag Patel gene: SDHB was added
gene: SDHB was added to Kidney Cancer. Sources: Expert list,Expert Review
Mode of inheritance for gene: SDHB was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: SDHB were set to Renal carcinoma, MONDO:0005206; Hereditary pheochromocytoma-paraganglioma, MONDO:0017366; Pheochromocytoma/paraganglioma syndrome 4, MIM#115310
Review for gene: SDHB was set to GREEN
Added comment: ClinGen definitive. Renal carcinoma reported in condition.
Sources: Expert list, Expert Review
Kidney Cancer v0.2 SDHC Chirag Patel gene: SDHC was added
gene: SDHC was added to Kidney Cancer. Sources: Expert list,Expert Review
Mode of inheritance for gene: SDHC was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: SDHC were set to Renal carcinoma, MONDO:0005206; Hereditary pheochromocytoma-paraganglioma, MONDO:0017366; Pheochromocytoma/paraganglioma syndrome 3, MIM#605373
Review for gene: SDHC was set to GREEN
Added comment: ClinGen definitive. Renal carcinoma reported in condition.
Sources: Expert list, Expert Review
Kidney Cancer v0.1 SDHD Chirag Patel gene: SDHD was added
gene: SDHD was added to Kidney Cancer. Sources: Expert list,Expert Review
Mode of inheritance for gene: SDHD was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: SDHD were set to Renal carcinoma, MONDO:0005206; Hereditary pheochromocytoma-paraganglioma, MONDO:0017366; Pheochromocytoma/paraganglioma syndrome 1, MIM#168000
Review for gene: SDHD was set to GREEN
Added comment: ClinGen definitive. Renal carcinoma reported in condition.
Sources: Expert list, Expert Review
Thyroid Cancer v0.12 APC Chirag Patel Classified gene: APC as Green List (high evidence)
Thyroid Cancer v0.12 APC Chirag Patel Gene: apc has been classified as Green List (High Evidence).
Thyroid Cancer v0.11 CDKN1B Chirag Patel Classified gene: CDKN1B as Green List (high evidence)
Thyroid Cancer v0.11 CDKN1B Chirag Patel Gene: cdkn1b has been classified as Green List (High Evidence).
Thyroid Cancer v0.10 DICER1 Chirag Patel Classified gene: DICER1 as Green List (high evidence)
Thyroid Cancer v0.10 DICER1 Chirag Patel Gene: dicer1 has been classified as Green List (High Evidence).
Thyroid Cancer v0.9 PRKAR1A Chirag Patel Classified gene: PRKAR1A as Green List (high evidence)
Thyroid Cancer v0.9 PRKAR1A Chirag Patel Gene: prkar1a has been classified as Green List (High Evidence).
Thyroid Cancer v0.8 PTEN Chirag Patel Classified gene: PTEN as Green List (high evidence)
Thyroid Cancer v0.8 PTEN Chirag Patel Gene: pten has been classified as Green List (High Evidence).
Thyroid Cancer v0.7 RET Chirag Patel Classified gene: RET as Green List (high evidence)
Thyroid Cancer v0.7 RET Chirag Patel Gene: ret has been classified as Green List (High Evidence).
Thyroid Cancer v0.6 APC Chirag Patel gene: APC was added
gene: APC was added to Thyroid Neoplasm. Sources: Expert list,Expert Review
Mode of inheritance for gene: APC was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: APC were set to Thyroid cancer, MONDO:0002108; Thyroid gland papillary carcinoma, MONDO:0005075; Familial adenomatous polyposis 1, MONDO:0021056; Adenomatous polyposis coli, MIM#175100
Review for gene: APC was set to GREEN
Added comment: ClinGen definitive. Papillary thyroid cancer reported in condition.
Sources: Expert list, Expert Review
Thyroid Cancer v0.5 CDKN1B Chirag Patel gene: CDKN1B was added
gene: CDKN1B was added to Thyroid Neoplasm. Sources: Expert list,Expert Review
Mode of inheritance for gene: CDKN1B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: CDKN1B were set to Thyroid cancer, MONDO:0002108; Thyroid gland papillary carcinoma, MONDO:0005075; Multiple endocrine neoplasia type 4, MONDO:0012552; Multiple endocrine neoplasia, type 4, MIM#610755
Review for gene: CDKN1B was set to GREEN
Added comment: ClinGen definitive. Papillary thyroid cancer reported in condition.
Sources: Expert list, Expert Review
Thyroid Cancer v0.4 DICER1 Chirag Patel gene: DICER1 was added
gene: DICER1 was added to Thyroid Neoplasm. Sources: Expert list,Expert Review
Mode of inheritance for gene: DICER1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: DICER1 were set to Thyroid cancer, MONDO:0002108; Thyroid gland papillary carcinoma, MONDO:0005075; DICER1-related tumor predisposition, MONDO:0100216; DICER1 syndrome, MIM#601200
Review for gene: DICER1 was set to GREEN
Added comment: ClinGen definitive. Papillary thyroid cancer reported in condition.
Sources: Expert list, Expert Review
Thyroid Cancer v0.3 RET Chirag Patel changed review comment from: ClinGen definitive. GOF variants.
Sources: Expert list, Expert Review; to: ClinGen definitive. Medullary thyroid cancer reported in condition. GOF variants.
Sources: Expert list, Expert Review
Thyroid Cancer v0.3 PRKAR1A Chirag Patel gene: PRKAR1A was added
gene: PRKAR1A was added to Thyroid Neoplasm. Sources: Expert list,Expert Review
Mode of inheritance for gene: PRKAR1A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: PRKAR1A were set to Thyroid cancer, MONDO:0002108; Thyroid gland follicular carcinoma, MONDO:0005034; Carney complex type 1, MONDO:0008057; Carney complex, type 1, MIM#160980
Review for gene: PRKAR1A was set to GREEN
Added comment: ClinGen definitive. Follicular thyroid cancer reported in condition.
Sources: Expert list, Expert Review
Thyroid Cancer v0.2 PTEN Chirag Patel gene: PTEN was added
gene: PTEN was added to Thyroid Neoplasm. Sources: Expert list,Expert Review
Mode of inheritance for gene: PTEN was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: PTEN were set to Thyroid cancer, MONDO:0002108; Thyroid gland follicular carcinoma, MONDO:0005034; PTEN hamartoma tumor syndrome, MONDO:0017623; PTEN hamartoma tumour syndromes, MIM#158350
Review for gene: PTEN was set to GREEN
Added comment: ClinGen definitive. Follicular thyroid cancer reported in condition.
Sources: Expert list, Expert Review
Thyroid Cancer v0.1 RET Chirag Patel changed review comment from: ClinGen definitive. Thyroid cancer reported in condition. GOF variants.
Sources: Expert list, Expert Review; to: ClinGen definitive. GOF variants.
Sources: Expert list, Expert Review
Thyroid Cancer v0.1 RET Chirag Patel gene: RET was added
gene: RET was added to Thyroid Neoplasm. Sources: Expert list,Expert Review
Mode of inheritance for gene: RET was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: RET were set to Thyroid cancer, MONDO:0002108; Medullary thyroid gland carcinoma, MONDO:0015277; Multiple endocrine neoplasia type 2A, MONDO:0008234; Multiple endocrine neoplasia type 2B, MONDO:0008082; Multiple endocrine neoplasia, type 2A, MIM#171400; Multiple endocrine neoplasia, type 2B, MIM#162300; Pheochromocytoma, MIM#171300; Medullary thyroid carcinoma, MIM#155240; Pheochromocytoma, susceptibility to, MIM#171300
Mode of pathogenicity for gene: RET was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: RET was set to GREEN
Added comment: ClinGen definitive. Thyroid cancer reported in condition. GOF variants.
Sources: Expert list, Expert Review
Parathyroid Tumour v0.12 CASR Chirag Patel Classified gene: CASR as Green List (high evidence)
Parathyroid Tumour v0.12 CASR Chirag Patel Gene: casr has been classified as Green List (High Evidence).
Parathyroid Tumour v0.11 CDC73 Chirag Patel Classified gene: CDC73 as Green List (high evidence)
Parathyroid Tumour v0.11 CDC73 Chirag Patel Gene: cdc73 has been classified as Green List (High Evidence).
Parathyroid Tumour v0.10 CDKN1B Chirag Patel Classified gene: CDKN1B as Green List (high evidence)
Parathyroid Tumour v0.10 CDKN1B Chirag Patel Gene: cdkn1b has been classified as Green List (High Evidence).
Parathyroid Tumour v0.9 MEN1 Chirag Patel Classified gene: MEN1 as Green List (high evidence)
Parathyroid Tumour v0.9 MEN1 Chirag Patel Gene: men1 has been classified as Green List (High Evidence).
Parathyroid Tumour v0.8 RET Chirag Patel Classified gene: RET as Green List (high evidence)
Parathyroid Tumour v0.8 RET Chirag Patel Gene: ret has been classified as Green List (High Evidence).
Parathyroid Tumour v0.7 GCM2 Chirag Patel Classified gene: GCM2 as Green List (high evidence)
Parathyroid Tumour v0.7 GCM2 Chirag Patel Gene: gcm2 has been classified as Green List (High Evidence).
Parathyroid Tumour v0.6 CASR Chirag Patel gene: CASR was added
gene: CASR was added to Parathyroid Neoplasm. Sources: Expert list,Expert Review
Mode of inheritance for gene: CASR was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: CASR were set to Tumor of parathyroid gland, MONDO:0021360; Familial hypocalciuric hypercalcemia 1, MONDO:0007791; Hypocalciuric hypercalcemia, type I, MIM#145980; Hypocalcemia, autosomal dominant, MIM#601198
Review for gene: CASR was set to GREEN
Added comment: ClinGen definitive. Parathyroid neoplasm reported in condition.
Sources: Expert list, Expert Review
Parathyroid Tumour v0.5 CDC73 Chirag Patel gene: CDC73 was added
gene: CDC73 was added to Parathyroid Neoplasm. Sources: Expert list,Expert Review
Mode of inheritance for gene: CDC73 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: CDC73 were set to Tumor of parathyroid gland, MONDO:0021360; Hyperparathyroidism 2 with jaw tumors, MONDO:0007768; Hyperparathyroidism-jaw tumor syndrome, MIM#145001; Hyperparathyroidism, familial primary, MIM#145000
Review for gene: CDC73 was set to GREEN
Added comment: ClinGen definitive. Parathyroid neoplasm reported in condition.
Sources: Expert list, Expert Review
Parathyroid Tumour v0.4 GCM2 Chirag Patel changed review comment from: Established gene-disease association. Numerous families reported. GOF variants.
Sources: Expert list, Expert Review, Literature; to: Established gene-disease association. Numerous families reported.
Parathyroid neoplasm reported in condition.
GOF variants.
Sources: Expert list, Expert Review, Literature
Parathyroid Tumour v0.4 CDKN1B Chirag Patel gene: CDKN1B was added
gene: CDKN1B was added to Parathyroid Neoplasm. Sources: Expert list,Expert Review
Mode of inheritance for gene: CDKN1B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: CDKN1B were set to Tumor of parathyroid gland, MONDO:0021360; Multiple endocrine neoplasia type 4, MONDO:0012552; Multiple endocrine neoplasia, type 4, MIM#610755
Review for gene: CDKN1B was set to GREEN
Added comment: ClinGen definitive.
Sources: Expert list, Expert Review
Parathyroid Tumour v0.3 MEN1 Chirag Patel gene: MEN1 was added
gene: MEN1 was added to Parathyroid Neoplasm. Sources: Expert list,Expert Review
Mode of inheritance for gene: MEN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: MEN1 were set to Tumor of parathyroid gland, MONDO:0021360; Multiple endocrine neoplasia type 1, MONDO:0007540; Multiple endocrine neoplasia, type 1, MIM#131100
Review for gene: MEN1 was set to GREEN
Added comment: ClinGen definitive.
Sources: Expert list, Expert Review
Parathyroid Tumour v0.2 RET Chirag Patel gene: RET was added
gene: RET was added to Parathyroid Neoplasm. Sources: Expert list,Expert Review
Mode of inheritance for gene: RET was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: RET were set to Tumor of parathyroid gland, MONDO:0021360; Multiple endocrine neoplasia type 2A, MONDO:0008234; Multiple endocrine neoplasia type 2B, MONDO:0008082; Multiple endocrine neoplasia, type 2A, MIM#171400; Multiple endocrine neoplasia, type 2B, MIM#162300; Pheochromocytoma, MIM#171300; Medullary thyroid carcinoma, MIM#155240; Pheochromocytoma, susceptibility to, MIM#171300
Mode of pathogenicity for gene: RET was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: RET was set to GREEN
Added comment: ClinGen definitive. GOF variants.
Sources: Expert list, Expert Review
Parathyroid Tumour v0.1 GCM2 Chirag Patel gene: GCM2 was added
gene: GCM2 was added to Parathyroid Neoplasm. Sources: Expert list,Expert Review,Literature
Mode of inheritance for gene: GCM2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GCM2 were set to PMID: 27745835, 34967908, 33471711, 29108698
Phenotypes for gene: GCM2 were set to Tumor of parathyroid gland, MONDO:0021360; Hyperparathyroidism 4, MONDO:0024570; Hyperparathyroidism 4, MIM#617343
Mode of pathogenicity for gene: GCM2 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: GCM2 was set to GREEN
Added comment: Established gene-disease association. Numerous families reported. GOF variants.
Sources: Expert list, Expert Review, Literature
Melanoma v0.14 CDK4 Chirag Patel Mode of pathogenicity for gene: CDK4 was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Melanoma v0.13 POT1 Chirag Patel Classified gene: POT1 as Amber List (moderate evidence)
Melanoma v0.13 POT1 Chirag Patel Gene: pot1 has been classified as Amber List (Moderate Evidence).
Gastrointestinal Stromal Tumour v0.16 SDHD Chirag Patel Classified gene: SDHD as Green List (high evidence)
Gastrointestinal Stromal Tumour v0.16 SDHD Chirag Patel Gene: sdhd has been classified as Green List (High Evidence).
Gastrointestinal Stromal Tumour v0.15 SDHC Chirag Patel Classified gene: SDHC as Green List (high evidence)
Gastrointestinal Stromal Tumour v0.15 SDHC Chirag Patel Gene: sdhc has been classified as Green List (High Evidence).
Gastrointestinal Stromal Tumour v0.14 SDHB Chirag Patel Classified gene: SDHB as Green List (high evidence)
Gastrointestinal Stromal Tumour v0.14 SDHB Chirag Patel Gene: sdhb has been classified as Green List (High Evidence).
Gastrointestinal Stromal Tumour v0.13 SDHAF2 Chirag Patel Classified gene: SDHAF2 as Green List (high evidence)
Gastrointestinal Stromal Tumour v0.13 SDHAF2 Chirag Patel Gene: sdhaf2 has been classified as Green List (High Evidence).
Gastrointestinal Stromal Tumour v0.12 SDHA Chirag Patel Classified gene: SDHA as Green List (high evidence)
Gastrointestinal Stromal Tumour v0.12 SDHA Chirag Patel Gene: sdha has been classified as Green List (High Evidence).
Gastrointestinal Stromal Tumour v0.11 SDHD Chirag Patel gene: SDHD was added
gene: SDHD was added to Gastrointestinal Stromal Tumour. Sources: Expert list,Expert Review
Mode of inheritance for gene: SDHD was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: SDHD were set to Gastrointestinal stromal tumor, MONDO:0011719; Hereditary pheochromocytoma-paraganglioma, MONDO:0017366; Pheochromocytoma/paraganglioma syndrome 1, MIM#168000
Review for gene: SDHD was set to GREEN
Added comment: ClinGen definitive. GIST reported in condition.
Sources: Expert list, Expert Review
Gastrointestinal Stromal Tumour v0.10 SDHC Chirag Patel gene: SDHC was added
gene: SDHC was added to Gastrointestinal Stromal Tumour. Sources: Expert list,Expert Review
Mode of inheritance for gene: SDHC was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: SDHC were set to Gastrointestinal stromal tumor, MONDO:0011719; Hereditary pheochromocytoma-paraganglioma, MONDO:0017366; Pheochromocytoma/paraganglioma syndrome 3, MIM#605373
Review for gene: SDHC was set to GREEN
Added comment: ClinGen definitive. GIST reported in condition.
Sources: Expert list, Expert Review
Gastrointestinal Stromal Tumour v0.9 SDHB Chirag Patel gene: SDHB was added
gene: SDHB was added to Gastrointestinal Stromal Tumour. Sources: Expert list,Expert Review
Mode of inheritance for gene: SDHB was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: SDHB were set to Gastrointestinal stromal tumor, MONDO:0011719; Hereditary pheochromocytoma-paraganglioma, MONDO:0017366; Pheochromocytoma/paraganglioma syndrome 4, MIM#115310
Review for gene: SDHB was set to GREEN
Added comment: ClinGen definitive. GIST reported in condition.
Sources: Expert list, Expert Review
Gastrointestinal Stromal Tumour v0.8 SDHAF2 Chirag Patel gene: SDHAF2 was added
gene: SDHAF2 was added to Gastrointestinal Stromal Tumour. Sources: Expert list,Expert Review
Mode of inheritance for gene: SDHAF2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: SDHAF2 were set to Gastrointestinal stromal tumor, MONDO:0011719; Hereditary pheochromocytoma-paraganglioma, MONDO:0017366; Pheochromocytoma/paraganglioma syndrome 2, MIM#601650
Review for gene: SDHAF2 was set to GREEN
Added comment: ClinGen definitive. GIST reported in condition.
Sources: Expert list, Expert Review
Gastrointestinal Stromal Tumour v0.7 SDHA Chirag Patel gene: SDHA was added
gene: SDHA was added to Gastrointestinal Stromal Tumour. Sources: Expert list,Expert Review
Mode of inheritance for gene: SDHA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: SDHA were set to Gastrointestinal stromal tumor, MONDO:0011719; Hereditary pheochromocytoma-paraganglioma, MONDO:0017366; Pheochromocytoma/paraganglioma syndrome 5, MIM#614165
Review for gene: SDHA was set to GREEN
Added comment: ClinGen definitive. GIST reported in condition.
Sources: Expert list, Expert Review
Gastrointestinal Stromal Tumour v0.6 NF1 Chirag Patel Classified gene: NF1 as Green List (high evidence)
Gastrointestinal Stromal Tumour v0.6 NF1 Chirag Patel Gene: nf1 has been classified as Green List (High Evidence).
Gastrointestinal Stromal Tumour v0.5 PDGFRA Chirag Patel Classified gene: PDGFRA as Green List (high evidence)
Gastrointestinal Stromal Tumour v0.5 PDGFRA Chirag Patel Gene: pdgfra has been classified as Green List (High Evidence).
Gastrointestinal Stromal Tumour v0.4 KIT Chirag Patel Classified gene: KIT as Green List (high evidence)
Gastrointestinal Stromal Tumour v0.4 KIT Chirag Patel Gene: kit has been classified as Green List (High Evidence).
Gastrointestinal Stromal Tumour v0.3 NF1 Chirag Patel gene: NF1 was added
gene: NF1 was added to Gastrointestinal Stromal Tumour. Sources: Expert list,Expert Review
Mode of inheritance for gene: NF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: NF1 were set to Gastrointestinal stromal tumor, MONDO:0011719; Neurofibromatosis type 1, MONDO:0018975; Neurofibromatosis, type 1, MIM#162200
Review for gene: NF1 was set to GREEN
Added comment: ClinGen definitive. GIST reported in condition.
Single gene testing may be more appropriate if clinical features of NF1.
Sources: Expert list, Expert Review
Gastrointestinal Stromal Tumour v0.2 PDGFRA Chirag Patel gene: PDGFRA was added
gene: PDGFRA was added to Gastrointestinal Stromal Tumour. Sources: Expert list,Expert Review
Mode of inheritance for gene: PDGFRA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: PDGFRA were set to Gastrointestinal stromal tumor, MONDO:0011719; Gastrointestinal stromal tumor/GIST-plus syndrome, somatic or familial, MIM#175510
Mode of pathogenicity for gene: PDGFRA was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: PDGFRA was set to GREEN
Added comment: ClinGen definitive. GOF variants.
Sources: Expert list, Expert Review
Gastrointestinal Stromal Tumour v0.1 KIT Chirag Patel gene: KIT was added
gene: KIT was added to Gastrointestinal Stromal Tumour. Sources: Expert list,Expert Review
Mode of inheritance for gene: KIT was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: KIT were set to Gastrointestinal stromal tumor, MONDO:0011719; Gastrointestinal stromal tumor, familial, MIM#606764
Mode of pathogenicity for gene: KIT was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: KIT was set to GREEN
Added comment: ClinGen definitive. GOF variants.
Sources: Expert list, Expert Review
Diffuse Gastric Cancer v0.4 CDH1 Chirag Patel Classified gene: CDH1 as Green List (high evidence)
Diffuse Gastric Cancer v0.4 CDH1 Chirag Patel Gene: cdh1 has been classified as Green List (High Evidence).
Diffuse Gastric Cancer v0.3 CTNNA1 Chirag Patel Classified gene: CTNNA1 as Green List (high evidence)
Diffuse Gastric Cancer v0.3 CTNNA1 Chirag Patel Gene: ctnna1 has been classified as Green List (High Evidence).
Diffuse Gastric Cancer v0.2 CTNNA1 Chirag Patel gene: CTNNA1 was added
gene: CTNNA1 was added to Diffuse Gastric Cancer. Sources: Expert list,Expert Review
Mode of inheritance for gene: CTNNA1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: CTNNA1 were set to Diffuse gastric cancer, MONDO:0957519; CTNNA1-related diffuse gastric and lobular breast cancer syndrome, MONDO:0100256; no MIM#
Review for gene: CTNNA1 was set to GREEN
Added comment: ClinGen definitive.
Sources: Expert list, Expert Review
Diffuse Gastric Cancer v0.1 CDH1 Chirag Patel gene: CDH1 was added
gene: CDH1 was added to Diffuse Gastric Cancer. Sources: Expert list,Expert Review
Mode of inheritance for gene: CDH1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: CDH1 were set to Diffuse gastric cancer, MONDO:0957519; CDH1-related diffuse gastric and lobular breast cancer syndrome, MONDO:0100488; Diffuse gastric and lobular breast cancer syndrome with or without cleft lip and/or palate, MIM#137215
Review for gene: CDH1 was set to GREEN
Added comment: ClinGen definitive.
Sources: Expert list, Expert Review
Melanoma v0.12 POT1 Chirag Patel Classified gene: POT1 as Green List (high evidence)
Melanoma v0.12 POT1 Chirag Patel Gene: pot1 has been classified as Green List (High Evidence).
Melanoma v0.11 POT1 Chirag Patel gene: POT1 was added
gene: POT1 was added to Melanoma. Sources: Expert Review,Literature
Mode of inheritance for gene: POT1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: POT1 were set to PMID: 24686849, 30586141, 24686846, 38724174
Phenotypes for gene: POT1 were set to Melanoma, MONDO:0005105; Tumor predisposition syndrome 3, MONDO:0014368; Melanoma, cutaneous malignant, MIM#606478
Review for gene: POT1 was set to GREEN
Added comment: Tumor predisposition syndrome-3 (TPDS3) is characterised by an increased risk for the development of various types of benign and malignant neoplasms throughout life, with age-dependent penetrance (e.g. neoplasms involving epithelial, mesenchymal, and neuronal tissues, as well as clonal hematopoietic syndromes, including lymphoid and myeloid cancers).

Cutaneous melanoma is the most commonly reported malignancy in individuals with POT1-Tumor predisposition syndrome (increased risk for various benign and malignant neoplasms throughout life, with age-dependent penetrance - neoplasms involving epithelial, mesenchymal, and neuronal tissues, as well as clonal hematopoietic syndromes, including lymphoid and myeloid cancers). Multiple unrelated families reported with melanoma and POT1 variant.
Sources: Expert Review, Literature
Melanoma v0.9 CDKN2A Chirag Patel reviewed gene: CDKN2A: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Melanoma, MONDO:0005105, Melanoma cutaneous malignant susceptibility to 2, MONDO:0007964, Melanoma-pancreatic cancer syndrome, MONDO:0011713, Melanoma and neural system tumor syndrome, MONDO:0007967, Melanoma, cutaneous malignant, 2, MIM#155601, Melanoma-pancreatic cancer syndrome, MIM#606719, Melanoma and neural system tumor syndrome, MIM#155755; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Melanoma v0.9 CDK4 Chirag Patel Deleted their comment
Melanoma v0.9 CDK4 Chirag Patel commented on gene: CDK4: ClinGen definitive. GOF variants.
Melanoma v0.9 CDK4 Chirag Patel changed review comment from: ClinGen definitive.; to: ClinGen definitive. GOF variants.
Melanoma v0.9 CDK4 Chirag Patel reviewed gene: CDK4: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Melanoma, MONDO:0005105, CDK4 linked melanoma, MONDO:0022623, Melanoma cutaneous malignant susceptibility to 3, MONDO:0012183, Melanoma, cutaneous malignant, 3, MIM#609048; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Melanoma v0.9 BAP1 Chirag Patel reviewed gene: BAP1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Melanoma, MONDO:0005105, BAP1-related tumor predisposition syndrome, MONDO:0013692, BAP1-tumour predisposition syndrome, MIM#614327; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Melanoma v0.7 BAP1 Chirag Patel Deleted their review
Melanoma v0.6 BAP1 Chirag Patel reviewed gene: BAP1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Melanoma, MONDO:0005105, BAP1-related tumor predisposition syndrome, MONDO:0013692, BAP1-tumour predisposition syndrome, MIM#614327; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Melanoma v0.6 Chirag Patel Panel status changed from retired to public
Basal Cell Cancer v0.6 PTCH2 Chirag Patel gene: PTCH2 was added
gene: PTCH2 was added to Basal Cell Cancer. Sources: Literature,Expert Review
Mode of inheritance for gene: PTCH2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PTCH2 were set to PMID: 34170463, 18285427, 23479190, 30820324, 38354379
Phenotypes for gene: PTCH2 were set to Basal cell carcinoma, MONDO:0020804; Nevoid basal cell carcinoma syndrome, MONDO:0007187
Review for gene: PTCH2 was set to RED
Added comment: A number of case/family reports have proposed PTCH2 as a putative Gorlin Syndrome (GS) gene, but evidence to support this is lacking. PMID: 34170463 paper found no pathogenic or likely pathogenic PTCH2 variants in cohort of 21 PTCH1/SUFU negative GS families.
They assessed evidence from reported cases/families with PTCH2 variants, and determined that none of the previously published PTCH2 variants in GS families/cases could be considered pathogenic or likely pathogenic using current guidelines. There is also a high frequency of Loss-of-function (LoF) variants in the general population, including the presence of homozygous LoF variants without a clinical phenotype.
Sources: Literature, Expert Review
Schwannoma v0.12 SMARCB1 Chirag Patel changed review comment from: ClinGen definitive
Schwannomas reported in condition
Sources: Expert list, Expert Review; to: ClinGen definitive. Schwannomas reported in condition.
Sources: Expert list, Expert Review
Schwannoma v0.12 PRKAR1A Chirag Patel changed review comment from: ClinGen definitive
Schwannomas reported in condition
Sources: Expert list, Expert Review; to: ClinGen definitive. Schwannomas reported in condition.
Sources: Expert list, Expert Review
Schwannoma v0.12 NF2 Chirag Patel changed review comment from: ClinGen definitive
Schwannomas reported in condition
Sources: Expert list, Expert Review; to: ClinGen definitive. Schwannomas reported in condition.
Sources: Expert list, Expert Review
Schwannoma v0.12 NF1 Chirag Patel changed review comment from: ClinGen definitive
Schwannomas reported in condition
Sources: Expert list, Expert Review; to: ClinGen definitive. Schwannomas reported in condition.
Sources: Expert list, Expert Review
Meningioma v0.10 SUFU Chirag Patel changed review comment from: ClinGen definitive
Meningiomas reported in condition
Sources: Expert list, Expert Review; to: ClinGen definitive. Meningiomas reported in condition.
Sources: Expert list, Expert Review
Meningioma v0.10 SMARCB1 Chirag Patel changed review comment from: ClinGen definitive
Meningiomas reported in condition
Sources: Expert list, Expert Review; to: ClinGen definitive. Meningiomas reported in condition.
Sources: Expert list, Expert Review
Meningioma v0.10 NF2 Chirag Patel changed review comment from: ClinGen definitive
Meningiomas reported in condition
Sources: Expert list, Expert Review; to: ClinGen definitive. Meningiomas reported in condition.
Sources: Expert list, Expert Review
Meningioma v0.10 BAP1 Chirag Patel changed review comment from: ClinGen definitive
Meningiomas reported in condition
Sources: Expert list, Expert Review; to: ClinGen definitive. Meningiomas reported in condition.
Sources: Expert list, Expert Review
Basal Cell Cancer v0.5 SUFU Chirag Patel Classified gene: SUFU as Green List (high evidence)
Basal Cell Cancer v0.5 SUFU Chirag Patel Gene: sufu has been classified as Green List (High Evidence).
Basal Cell Cancer v0.4 SUFU Chirag Patel gene: SUFU was added
gene: SUFU was added to Basal Cell Cancer. Sources: Expert list,Expert Review
Mode of inheritance for gene: SUFU was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SUFU were set to PMID: 20301330
Phenotypes for gene: SUFU were set to Basal cell carcinoma, MONDO:0020804; Basal cell nevus syndrome 2, MONDO:0958189; Basal cell nevus syndrome 2, MIM#620343; Meningioma, familial, susceptibility to, MIM#607174; Medulloblastoma predisposition syndrome, MIM#155255
Review for gene: SUFU was set to GREEN
Added comment: Established gene-disease association with basal cell nevus syndrome (also known as Gorlin syndrome). Basal cell cancers reported in condition. ClinGen definitive for medulloblastoma.
Sources: Expert list, Expert Review
Basal Cell Cancer v0.3 PTCH1 Chirag Patel changed review comment from: ClinGen definitive
Basal cell cancers reported in condition
Sources: Expert list, Expert Review; to: ClinGen definitive. Basal cell cancers reported in condition
Sources: Expert list, Expert Review
Basal Cell Cancer v0.3 PTCH1 Chirag Patel Classified gene: PTCH1 as Green List (high evidence)
Basal Cell Cancer v0.3 PTCH1 Chirag Patel Gene: ptch1 has been classified as Green List (High Evidence).
Basal Cell Cancer v0.2 PTCH1 Chirag Patel Classified gene: PTCH1 as Green List (high evidence)
Basal Cell Cancer v0.2 PTCH1 Chirag Patel Gene: ptch1 has been classified as Green List (High Evidence).
Basal Cell Cancer v0.1 PTCH1 Chirag Patel gene: PTCH1 was added
gene: PTCH1 was added to Basal Cell Cancer. Sources: Expert list,Expert Review
Mode of inheritance for gene: PTCH1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: PTCH1 were set to Basal cell carcinoma, MONDO:0020804; Basal cell nevus syndrome 1, MONDO:0958174; Basal cell nevus syndrome 1, MIM#109400
Review for gene: PTCH1 was set to GREEN
Added comment: ClinGen definitive
Basal cell cancers reported in condition
Sources: Expert list, Expert Review
Schwannoma v0.12 SMARCA4 Chirag Patel gene: SMARCA4 was added
gene: SMARCA4 was added to Schwannoma. Sources: Expert Review,Literature
Mode of inheritance for gene: SMARCA4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SMARCA4 were set to PMID: 36786840
Phenotypes for gene: SMARCA4 were set to Schwannoma, MONDO:0002546; Rhabdoid tumor predisposition syndrome 2, MONDO:0013224; Rhabdoid tumor predisposition syndrome 2, MIM#613325
Review for gene: SMARCA4 was set to RED
Added comment: ClinGen definitive for RTPS2

1 family with 3 affected individuals with adult-onset schwannomas (2/3), glioblastoma (1/3), and malignant peripheral nerve sheath tumour (1/3). Whole-genome sequencing in proband identified a variant in SMARCA4 gene ([c.1752_1755del, p.(Lys585Argfs*27).

In the schwannomas, immunohistochemical (IHC) staining showed loss of BRG1 (SMARCA4) expression in 80–90% of cells and loss of INI1 (SMARCB1) in the complementary 10–20% of cells in all 5 schwannomas but complete retention of BRG1 and INI1 in the glioblastoma.

Whole exome sequencing (WES) of DNA from proband's blood, mother’s normal skin, all 5
schwannomas and the glioblastoma, confirmed the presence of the truncating SMARCA4 LPV in all samples. LOH was observed at the SMARCA4 locus, extending to 12–23 Mb of Chromosome 19p (Chr19p) in all schwannomas, but not in the glioblastoma. No LOH of Chr22q was detected in the schwannomas. The germline SMARCA4 variant was also detected in proband's maternal grandfather’s MPNST in a heterozygous state.
Sources: Expert Review, Literature
Neuroblastoma v0.6 SMARCA4 Chirag Patel changed review comment from: ClinGen definitive for RTPS2

11 patients with neuroblastoma (age of diagnosis from 2 months-26 years) with heterozygous germline variants in SMARCA4. Eight of the germline variants were expected to result in loss of function of SMARCA4 (large deletion, truncating and canonical splice variants), while the remaining four were missense variants. Loss of heterozygosity of the wild-type SMARCA4 allele was found in all eight cases where somatic testing was performed, supporting the notion that SMARCA4 functions as a classic tumour suppressor.
Sources: Expert Review, Literature; to: ClinGen definitive for RTPS2

11 patients with neuroblastoma (age of diagnosis from 2 months-26 years) with heterozygous germline variants in SMARCA4. Eight of the germline variants were expected to result in loss of function of SMARCA4 (large deletion, truncating and canonical splice variants), while the remaining four were missense variants. Loss of heterozygosity of the wild-type SMARCA4 allele was found in all eight cases where somatic testing was performed, supporting the notion that SMARCA4 functions as a classic tumour suppressor.
Sources: Expert Review, Literature
Neuroblastoma v0.6 SMARCA4 Chirag Patel Classified gene: SMARCA4 as Amber List (moderate evidence)
Neuroblastoma v0.6 SMARCA4 Chirag Patel Gene: smarca4 has been classified as Amber List (Moderate Evidence).
Neuroblastoma v0.5 SMARCA4 Chirag Patel gene: SMARCA4 was added
gene: SMARCA4 was added to Neuroblastoma. Sources: Expert Review,Literature
Mode of inheritance for gene: SMARCA4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: SMARCA4 were set to Neuroblastoma, MONDO:0005072; Rhabdoid tumor predisposition syndrome 2, MONDO:0013224; Rhabdoid tumor predisposition syndrome 2, MIM#613325
Review for gene: SMARCA4 was set to AMBER
Added comment: ClinGen definitive for RTPS2

11 patients with neuroblastoma (age of diagnosis from 2 months-26 years) with heterozygous germline variants in SMARCA4. Eight of the germline variants were expected to result in loss of function of SMARCA4 (large deletion, truncating and canonical splice variants), while the remaining four were missense variants. Loss of heterozygosity of the wild-type SMARCA4 allele was found in all eight cases where somatic testing was performed, supporting the notion that SMARCA4 functions as a classic tumour suppressor.
Sources: Expert Review, Literature
Neuroblastoma v0.4 PHOX2B Chirag Patel Classified gene: PHOX2B as Green List (high evidence)
Neuroblastoma v0.4 PHOX2B Chirag Patel Gene: phox2b has been classified as Green List (High Evidence).
Neuroblastoma v0.3 PHOX2B Chirag Patel gene: PHOX2B was added
gene: PHOX2B was added to Neuroblastoma. Sources: Expert list,Expert Review
Mode of inheritance for gene: PHOX2B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PHOX2B were set to PMID: 17637745
Phenotypes for gene: PHOX2B were set to Neuroblastoma, MONDO:0005072; Neuroblastoma susceptibility to 2, MONDO:0700041; Neuroblastoma, susceptibility to, 2, MIM#613013; Neuroblastoma with Hirschsprung disease, MIM #613013
Review for gene: PHOX2B was set to GREEN
Added comment: ClinGen definitive
Sources: Expert list, Expert Review
Neuroblastoma v0.2 ALK Chirag Patel Classified gene: ALK as Green List (high evidence)
Neuroblastoma v0.2 ALK Chirag Patel Gene: alk has been classified as Green List (High Evidence).
Neuroblastoma v0.1 ALK Chirag Patel gene: ALK was added
gene: ALK was added to Neuroblastoma. Sources: Expert list,Expert Review
Mode of inheritance for gene: ALK was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ALK were set to PMID: 18724359
Phenotypes for gene: ALK were set to Neuroblastoma, MONDO:0005072; Neuroblastoma susceptibility to 3, MONDO:0013083; Neuroblastoma, susceptibility to, 3, MIM#613014
Review for gene: ALK was set to GREEN
Added comment: ClinGen definitive
Sources: Expert list, Expert Review
Schwannoma v0.11 DGCR8 Chirag Patel gene: DGCR8 was added
gene: DGCR8 was added to Schwannoma. Sources: Literature,Expert Review
Mode of inheritance for gene: DGCR8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DGCR8 were set to PMID: 31805011
Phenotypes for gene: DGCR8 were set to Schwannoma, MONDO:0002546; Early-onset multinodular goiter and schwannomatosis, no MIM#
Review for gene: DGCR8 was set to RED
Added comment: 1 family with 6 affected individuals with early-onset MNG (6/6) and adult-onset schwannomatosis (5/6). Whole-exome sequencing identified a variant in DGCR8 gene (c.1552G>A; p.E518K) which segregated with disease.

Copy number loss of chromosome 22q, leading to loss of heterozygosity at the DGCR8 locus, was found in all 13 tissue samples from familial and nonfamilial DGCR8-E518K-positive tumours. miRNA profiling of PTCs, MNG, schwannomas, and Wilms tumours revealed a common profile among E518K hemizygous tumours. In vitro cleavage demonstrated improper processing of pre-miRNA by DGCR8-E518K. MicroRNA and RNA profiling show that this variant disrupts precursor microRNA production, impacting populations of canonical microRNAs and mirtrons.
Sources: Literature, Expert Review
Bone Marrow Failure v1.95 RBSN Zornitza Stark Marked gene: RBSN as ready
Bone Marrow Failure v1.95 RBSN Zornitza Stark Gene: rbsn has been classified as Red List (Low Evidence).
Bone Marrow Failure v1.95 RBSN Zornitza Stark gene: RBSN was added
gene: RBSN was added to Bone Marrow Failure. Sources: Literature
Mode of inheritance for gene: RBSN was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RBSN were set to 29784638
Phenotypes for gene: RBSN were set to Myelofibrosis, congenital, with anemia, neutropenia, developmental delay, and ocular abnormalities, MIM# 620939
Review for gene: RBSN was set to RED
Added comment: Single family reported, 3 affected sibs, homozygous splice site variant. However, also note biallelic variants in this gene have also been associated with a neurodevelopmental syndrome in the absence of bone marrow involvement, Kariminejad-Reversade neurodevelopmental syndrome, MIM#620937. Given the overall small number of families reported, it is currently unclear whether these are two distinct disorders or part of a spectrum.
Sources: Literature
Schwannoma v0.10 LZTR1 Chirag Patel Classified gene: LZTR1 as Green List (high evidence)
Schwannoma v0.10 LZTR1 Chirag Patel Gene: lztr1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.6207 RBSN Zornitza Stark Phenotypes for gene: RBSN were changed from intellectual disability, MONDO:0001071 to Kariminejad-Reversade neurodevelopmental syndrome, MIM# 620937
Intellectual disability syndromic and non-syndromic v0.6206 RBSN Zornitza Stark reviewed gene: RBSN: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Kariminejad-Reversade neurodevelopmental syndrome, MIM# 620937; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2013 RBSN Zornitza Stark Phenotypes for gene: RBSN were changed from intellectual disability, MONDO:0001071, RBSN-related to Kariminejad-Reversade neurodevelopmental syndrome, MIM# 620937
Schwannoma v0.9 LZTR1 Chirag Patel gene: LZTR1 was added
gene: LZTR1 was added to Schwannoma. Sources: Expert list,Expert Review
Mode of inheritance for gene: LZTR1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: LZTR1 were set to PMID: 24362817, 29517885
Phenotypes for gene: LZTR1 were set to Schwannoma, MONDO:0002546; Schwannomatosis 2, MONDO:0014299; Schwannomatosis, susceptibility to, 2, MIM#615670
Review for gene: LZTR1 was set to GREEN
gene: LZTR1 was marked as current diagnostic
Added comment: 15 different germline heterozygous mutations in the LZTR1 gene identified in 16/20 probands with schwannomatosis. There were 6 truncating mutations, 1 in-frame splice site mutation, 1 deletion affecting a splice site, and 7 missense mutations at highly conserved residues. Mutations segregated with disease in all available affected first-degree relatives, although four asymptomatic parents also carried an LZTR1 mutation.

All schwannomas studied also carried the heterozygous LZTR1 mutation, and all showed loss of heterozygosity (LOH) at chromosome 22q11, including the LZTR1, NF2, and SMARCB1 genes. In addition, all tumours carried a heterozygous somatic mutation in the NF2 gene. These findings were consistent with biallelic loss of function of both LZTR1 and NF2 in all tumours. Functional studies of the variants were not performed. Pathogenesis of tumour characterised as resulting from 3 mutational events: a germline LZTR1 mutation (E1), a deletion of 22q that includes the LZTR1 and NF2 genes (E2), and a somatic NF2 mutation (E3). Loss of LZTR1 function can predispose to the development of autosomal dominant multiple schwannomas, thus implicating LZTR1 as a tumor suppressor gene.
Sources: Expert list, Expert Review
Mendeliome v1.2012 RBSN Zornitza Stark edited their review of gene: RBSN: Changed phenotypes: Kariminejad-Reversade neurodevelopmental syndrome, MIM# 620937
Schwannoma v0.8 PRKAR1A Chirag Patel Classified gene: PRKAR1A as Green List (high evidence)
Schwannoma v0.8 PRKAR1A Chirag Patel Gene: prkar1a has been classified as Green List (High Evidence).
Schwannoma v0.7 NF1 Chirag Patel Classified gene: NF1 as Green List (high evidence)
Schwannoma v0.7 NF1 Chirag Patel Gene: nf1 has been classified as Green List (High Evidence).
Schwannoma v0.6 NF2 Chirag Patel Classified gene: NF2 as Green List (high evidence)
Schwannoma v0.6 NF2 Chirag Patel Gene: nf2 has been classified as Green List (High Evidence).
Schwannoma v0.5 PRKAR1A Chirag Patel gene: PRKAR1A was added
gene: PRKAR1A was added to Schwannoma. Sources: Expert list,Expert Review
Mode of inheritance for gene: PRKAR1A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: PRKAR1A were set to Schwannoma, MONDO:0002546; Carney complex type 1, MONDO:0008057; Carney complex, type 1, MIM#160980
Review for gene: PRKAR1A was set to GREEN
gene: PRKAR1A was marked as current diagnostic
Added comment: ClinGen definitive
Schwannomas reported in condition
Sources: Expert list, Expert Review
Schwannoma v0.4 SMARCB1 Chirag Patel Classified gene: SMARCB1 as Green List (high evidence)
Schwannoma v0.4 SMARCB1 Chirag Patel Gene: smarcb1 has been classified as Green List (High Evidence).
Schwannoma v0.3 SMARCB1 Chirag Patel gene: SMARCB1 was added
gene: SMARCB1 was added to Schwannoma. Sources: Expert list,Expert Review
Mode of inheritance for gene: SMARCB1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: SMARCB1 were set to Schwannoma, MONDO:0002546; Schwannomatosis 1, MONDO:0024517; Rhabdoid tumor predisposition syndrome 1, MONDO:0012252; Rhabdoid tumor predisposition syndrome 1, MIM#609322; Schwannomatosis, susceptibility to, 1, MIM#162091
Review for gene: SMARCB1 was set to GREEN
gene: SMARCB1 was marked as current diagnostic
Added comment: ClinGen definitive
Schwannomas reported in condition
Sources: Expert list, Expert Review
Schwannoma v0.2 NF2 Chirag Patel gene: NF2 was added
gene: NF2 was added to Schwannoma. Sources: Expert list,Expert Review
Mode of inheritance for gene: NF2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: NF2 were set to Schwannoma, MONDO:0002546; Neurofibromatosis type 2, MONDO:0007039; Neurofibromatosis, type 2, MIM#607174
Review for gene: NF2 was set to GREEN
gene: NF2 was marked as current diagnostic
Added comment: ClinGen definitive
Schwannomas reported in condition
Sources: Expert list, Expert Review
Schwannoma v0.1 NF1 Chirag Patel gene: NF1 was added
gene: NF1 was added to Schwannoma. Sources: Expert list,Expert Review
Mode of inheritance for gene: NF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: NF1 were set to Schwannoma, MONDO:0002546; Neurofibromatosis type 1, MONDO:0018975; Neurofibromatosis, type 1, MIM#162200
Review for gene: NF1 was set to GREEN
gene: NF1 was marked as current diagnostic
Added comment: ClinGen definitive
Schwannomas reported in condition
Sources: Expert list, Expert Review
Meningioma v0.10 SUFU Chirag Patel Classified gene: SUFU as Green List (high evidence)
Meningioma v0.10 SUFU Chirag Patel Gene: sufu has been classified as Green List (High Evidence).
Meningioma v0.9 SMARCE1 Chirag Patel Classified gene: SMARCE1 as Green List (high evidence)
Meningioma v0.9 SMARCE1 Chirag Patel Gene: smarce1 has been classified as Green List (High Evidence).
Meningioma v0.8 SMARCB1 Chirag Patel Classified gene: SMARCB1 as Green List (high evidence)
Meningioma v0.8 SMARCB1 Chirag Patel Gene: smarcb1 has been classified as Green List (High Evidence).
Meningioma v0.7 NF2 Chirag Patel Classified gene: NF2 as Green List (high evidence)
Meningioma v0.7 NF2 Chirag Patel Gene: nf2 has been classified as Green List (High Evidence).
Meningioma v0.6 BAP1 Chirag Patel Classified gene: BAP1 as Green List (high evidence)
Meningioma v0.6 BAP1 Chirag Patel Gene: bap1 has been classified as Green List (High Evidence).
Meningioma v0.5 SUFU Chirag Patel gene: SUFU was added
gene: SUFU was added to Meningioma. Sources: Expert list,Expert Review
Mode of inheritance for gene: SUFU was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: SUFU were set to Meningioma, MONDO:0016642; Basal cell nevus syndrome 2, MONDO:0958189; Basal cell nevus syndrome 2, MIM#620343; Meningioma, familial, susceptibility to, MIM#607174; Medulloblastoma predisposition syndrome, MIM#155255
Review for gene: SUFU was set to GREEN
gene: SUFU was marked as current diagnostic
Added comment: ClinGen definitive
Meningiomas reported in condition
Sources: Expert list, Expert Review
Meningioma v0.4 SMARCE1 Chirag Patel gene: SMARCE1 was added
gene: SMARCE1 was added to Meningioma. Sources: Expert list,Expert Review
Mode of inheritance for gene: SMARCE1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: SMARCE1 were set to Meningioma, MONDO:0016642; Meningioma, familial, susceptibility to, MIM#607174
Review for gene: SMARCE1 was set to GREEN
gene: SMARCE1 was marked as current diagnostic
Added comment: ClinGen definitive
Sources: Expert list, Expert Review
Meningioma v0.3 SMARCB1 Chirag Patel gene: SMARCB1 was added
gene: SMARCB1 was added to Meningioma. Sources: Expert list,Expert Review
Mode of inheritance for gene: SMARCB1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: SMARCB1 were set to Meningioma, MONDO:0016642; Rhabdoid tumor predisposition syndrome 1, MONDO:0012252; Rhabdoid tumor predisposition syndrome 1, MIM#609322; Schwannomatosis, susceptibility to, 1, MIM#162091
Review for gene: SMARCB1 was set to GREEN
gene: SMARCB1 was marked as current diagnostic
Added comment: ClinGen definitive
Meningiomas reported in condition
Sources: Expert list, Expert Review
Meningioma v0.2 NF2 Chirag Patel gene: NF2 was added
gene: NF2 was added to Meningioma. Sources: Expert list,Expert Review
Mode of inheritance for gene: NF2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: NF2 were set to Meningioma, MONDO:0016642; Neurofibromatosis type 2, MONDO:0007039; Neurofibromatosis, type 2, MIM#607174
Review for gene: NF2 was set to GREEN
gene: NF2 was marked as current diagnostic
Added comment: ClinGen definitive
Meningiomas reported in condition
Sources: Expert list, Expert Review
Meningioma v0.1 BAP1 Chirag Patel gene: BAP1 was added
gene: BAP1 was added to Meningioma. Sources: Expert list,Expert Review
Mode of inheritance for gene: BAP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: BAP1 were set to Meningioma, MONDO:0016642; BAP1-related tumor predisposition syndrome, MONDO:0013692; BAP1-tumour predisposition syndrome, MIM#614327
Review for gene: BAP1 was set to GREEN
gene: BAP1 was marked as current diagnostic
Added comment: ClinGen definitive
Meningiomas reported in condition
Sources: Expert list, Expert Review
Breast Cancer v0.0 Chirag Patel Added Panel Breast Cancer
Set panel types to: Cancer Germline
Ovarian Cancer v0.0 Chirag Patel Added Panel Ovarian Cancer
Set panel types to: Cancer Germline
Endometrial Cancer v0.0 Chirag Patel Added Panel Endometrial Cancer
Set panel types to: Cancer Germline
Prostate Cancer v0.0 Chirag Patel Added Panel Prostate Cancer
Set panel types to: Cancer Germline
Colorectal Cancer and Polyposis v0.0 Chirag Patel Added Panel Colorectal Cancer and Polyposis
Set panel types to: Cancer Germline
Pancreatic Cancer v0.0 Chirag Patel Added Panel Pancreatic Cancer
Set panel types to: Cancer Germline
Gastrointestinal Stromal Tumour v0.0 Chirag Patel Added Panel Gastrointestinal Stromal Tumour
Set panel types to: Cancer Germline
Diffuse Gastric Cancer v0.0 Chirag Patel Added Panel Diffuse Gastric Cancer
Set panel types to: Cancer Germline
Kidney Cancer v0.0 Chirag Patel Added Panel Kidney Cancer
Set panel types to: Cancer Germline
Wilms Tumour v0.0 Chirag Patel Added Panel Wilms Tumour
Set panel types to: Cancer Germline
Paraganglioma_phaeochromocytoma v0.0 Chirag Patel Added Panel Paraganglioma_phaeochromocytoma
Set panel types to: Cancer Germline
Pituitary Tumour v0.0 Chirag Patel Added Panel Pituitary Tumour
Set panel types to: Cancer Germline
Parathyroid Tumour v0.0 Chirag Patel Added Panel Parathyroid Neoplasm
Set panel types to: Cancer Germline
Thyroid Cancer v0.0 Chirag Patel Added Panel Thyroid Neoplasm
Set panel types to: Cancer Germline
Melanoma v0.5 Chirag Patel Panel status changed from public to retired
Neuroblastoma v0.0 Chirag Patel Added Panel Neuroblastoma
Set panel types to: Cancer Germline
Basal Cell Cancer v0.0 Chirag Patel Added Panel Basal Cell Cancer
Set panel types to: Cancer Germline
Medulloblastoma v0.11 Chirag Patel Panel status changed from public to retired
Sarcoma non-soft tissue v0.0 Chirag Patel Added Panel Sarcoma non-soft tissue
Set panel types to: Cancer Germline
Sarcoma soft tissue v0.0 Chirag Patel Added Panel Sarcoma soft tissue
Set panel types to: Cancer Germline
Schwannoma v0.0 Chirag Patel Added Panel Schwannoma
Set panel types to: Cancer Germline
Meningioma v0.0 Chirag Patel Added Panel Meningioma
Set panel types to: Cancer Germline
Mendeliome v1.2012 B2M Bryony Thompson Mode of inheritance for gene: B2M was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.2011 B2M Bryony Thompson reviewed gene: B2M: Rating: GREEN; Mode of pathogenicity: None; Publications: 22693999, 37223323, 24014031, 35575118, 32875920; Phenotypes: variant ABeta2M amyloidosis MONDO:0017810; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v1.56 RNU2-2P Zornitza Stark Marked gene: RNU2-2P as ready
Genetic Epilepsy v1.56 RNU2-2P Zornitza Stark Gene: rnu2-2p has been classified as Green List (High Evidence).
Mendeliome v1.2011 RNU2-2P Zornitza Stark Marked gene: RNU2-2P as ready
Mendeliome v1.2011 RNU2-2P Zornitza Stark Gene: rnu2-2p has been classified as Green List (High Evidence).
Mendeliome v1.2011 RNU2-2P Zornitza Stark Classified gene: RNU2-2P as Green List (high evidence)
Mendeliome v1.2011 RNU2-2P Zornitza Stark Gene: rnu2-2p has been classified as Green List (High Evidence).
Mendeliome v1.2010 RNU2-2P Zornitza Stark gene: RNU2-2P was added
gene: RNU2-2P was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RNU2-2P was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RNU2-2P were set to https://www.medrxiv.org/content/10.1101/2024.09.03.24312863v1
Phenotypes for gene: RNU2-2P were set to Neurodevelopmental disorder, MONDO:0700092, RNU2-2P-related
Review for gene: RNU2-2P was set to GREEN
Added comment: 15 individuals reported with de novo, recurrent variants in this gene at nucleotide positions 4 and 35. The disorder is characterized by intellectual disability, neurodevelopmental delay, autistic behavior, microcephaly, hypotonia, epilepsy and hyperventilation. All cases display a severe and complex seizure phenotype.
Sources: Literature
Genetic Epilepsy v1.56 RNU2-2P Zornitza Stark Classified gene: RNU2-2P as Green List (high evidence)
Genetic Epilepsy v1.56 RNU2-2P Zornitza Stark Gene: rnu2-2p has been classified as Green List (High Evidence).
Genetic Epilepsy v1.55 RNU2-2P Zornitza Stark Classified gene: RNU2-2P as Green List (high evidence)
Genetic Epilepsy v1.55 RNU2-2P Zornitza Stark Gene: rnu2-2p has been classified as Green List (High Evidence).
Genetic Epilepsy v1.54 RNU2-2P Zornitza Stark gene: RNU2-2P was added
gene: RNU2-2P was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: RNU2-2P was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RNU2-2P were set to https://www.medrxiv.org/content/10.1101/2024.09.03.24312863v1
Phenotypes for gene: RNU2-2P were set to Neurodevelopmental disorder, MONDO:0700092, RNU2-2P-related
Review for gene: RNU2-2P was set to GREEN
Added comment: 15 individuals reported with de novo, recurrent variants in this gene at nucleotide positions 4 and 35. The disorder is characterized by intellectual disability, neurodevelopmental delay, autistic behavior, microcephaly, hypotonia, epilepsy and hyperventilation. All cases display a severe and complex seizure phenotype.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.6206 RNU2-2P Zornitza Stark Marked gene: RNU2-2P as ready
Intellectual disability syndromic and non-syndromic v0.6206 RNU2-2P Zornitza Stark Gene: rnu2-2p has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.6206 RNU2-2P Zornitza Stark Classified gene: RNU2-2P as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.6206 RNU2-2P Zornitza Stark Gene: rnu2-2p has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.6205 RNU2-2P Zornitza Stark gene: RNU2-2P was added
gene: RNU2-2P was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: RNU2-2P was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RNU2-2P were set to https://www.medrxiv.org/content/10.1101/2024.09.03.24312863v1
Phenotypes for gene: RNU2-2P were set to Neurodevelopmental disorder, MONDO:0700092, RNU2-2P-related
Review for gene: RNU2-2P was set to GREEN
Added comment: 15 individuals reported with de novo, recurrent variants in this gene at nucleotide positions 4 and 35. The disorder is characterized by intellectual disability, neurodevelopmental delay, autistic behavior, microcephaly, hypotonia, epilepsy and hyperventilation. All cases display a severe and complex seizure phenotype.
Sources: Literature
Prepair 1000+ v1.287 NYX Andrew Coventry reviewed gene: NYX: Rating: GREEN; Mode of pathogenicity: None; Publications: 11062471 11062472 16670814 23714322 34064005 34165036 12506099 11062471 17004930; Phenotypes: Night blindness, congenital stationary (complete), 1A, X-linked MIM310500; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Prepair 1000+ v1.287 NPHS2 Andrew Coventry reviewed gene: NPHS2: Rating: GREEN; Mode of pathogenicity: None; Publications: 32467597 30260545 24509478 10742096 23242530 24509478 12464671; Phenotypes: Nephrotic syndrome, type 2 MIM#600995; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2009 PNKP Shakira Heerah reviewed gene: PNKP: Rating: GREEN; Mode of pathogenicity: None; Publications: 31436889, 31707899, 20118933, 23224214, 29243230, 2578773, 27066567; Phenotypes: Ataxia-oculomotor apraxia 4, Microcephaly, seizures, and developmental delay, Charcot-Marie-Tooth disease, type 2B2; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.287 NIPAL4 Andrew Coventry reviewed gene: NIPAL4: Rating: GREEN; Mode of pathogenicity: None; Publications: 15317751 17557927 10712205; Phenotypes: Ichthyosis, congenital, autosomal recessive 6 MIM#612281; Mode of inheritance: None
Prepair 1000+ v1.287 MPLKIP Andrew Coventry reviewed gene: MPLKIP: Rating: GREEN; Mode of pathogenicity: None; Publications: 15645389 16977596; Phenotypes: Trichothiodystrophy 4, nonphotosensitive MIM#234050; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.287 MGAT2 Andrew Coventry reviewed gene: MGAT2: Rating: GREEN; Mode of pathogenicity: None; Publications: 8808595 11228641 22105986 33044030 31420886; Phenotypes: Congenital disorder of glycosylation, type IIa MIM#212066; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.287 CTSF Cassandra Muller reviewed gene: CTSF: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Ceroid lipofuscinosis, neuronal, 13, Kufs type, 615362 (3); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.287 MCFD2 Andrew Coventry reviewed gene: MCFD2: Rating: AMBER; Mode of pathogenicity: None; Publications: 12717434 17610559 18391077 15886209; Phenotypes: Factor V and factor VIII, combined deficiency of MIM#613625; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2009 NFU1 Zornitza Stark Phenotypes for gene: NFU1 were changed from Multiple mitochondrial dysfunctions syndrome 1, MIM# 605711 to Multiple mitochondrial dysfunctions syndrome 1, MIM# 605711; Spastic paraplegia 93, autosomal recessive, MIM# 620938
Mendeliome v1.2008 NFU1 Zornitza Stark edited their review of gene: NFU1: Changed phenotypes: Multiple mitochondrial dysfunctions syndrome 1, MIM# 605711, Spastic paraplegia 93, autosomal recessive, MIM# 620938
Hereditary Spastic Paraplegia - paediatric v1.84 NFU1 Zornitza Stark Phenotypes for gene: NFU1 were changed from Multiple mitochondrial dysfunctions syndrome 1 (MIM#605711) to Multiple mitochondrial dysfunctions syndrome 1 (MIM#605711); Spastic paraplegia 93, autosomal recessive, MIM# 620938
Hereditary Spastic Paraplegia - paediatric v1.83 NFU1 Zornitza Stark reviewed gene: NFU1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Spastic paraplegia 93, autosomal recessive, MIM# 620938; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.287 LRP5 Andrew Coventry reviewed gene: LRP5: Rating: GREEN; Mode of pathogenicity: None; Publications: 9056564 9831343 11719191 15346351 18602879; Phenotypes: Exudative vitreoretinopathy 4 MIM#601813, Osteoporosis-pseudoglioma syndrome MIM#259770; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Amyloidosis v0.27 Bryony Thompson Panel name changed from Renal Amyloidosis to Amyloidosis
HPO terms changed from Renal amyloidosis, HP:0001917 to Renal amyloidosis, HP:0001917; Amyloidosis, HP:0011034
List of related panels changed from Renal amyloidosis; HP:0001917 to Renal amyloidosis; HP:0001917; Amyloidosis; HP:0011034
Panel types changed to Victorian Clinical Genetics Services; KidGen; Royal Melbourne Hospital
Lysosomal Storage Disorder v1.13 SGMS1 Bryony Thompson Marked gene: SGMS1 as ready
Lysosomal Storage Disorder v1.13 SGMS1 Bryony Thompson Gene: sgms1 has been classified as Amber List (Moderate Evidence).
Lysosomal Storage Disorder v1.13 SGMS1 Bryony Thompson Classified gene: SGMS1 as Amber List (moderate evidence)
Lysosomal Storage Disorder v1.13 SGMS1 Bryony Thompson Gene: sgms1 has been classified as Amber List (Moderate Evidence).
Lysosomal Storage Disorder v1.12 SGMS1 Bryony Thompson Classified gene: SGMS1 as Amber List (moderate evidence)
Lysosomal Storage Disorder v1.12 SGMS1 Bryony Thompson Gene: sgms1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2008 SGMS1 Bryony Thompson Marked gene: SGMS1 as ready
Mendeliome v1.2008 SGMS1 Bryony Thompson Gene: sgms1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2008 SGMS1 Bryony Thompson Classified gene: SGMS1 as Amber List (moderate evidence)
Mendeliome v1.2008 SGMS1 Bryony Thompson Gene: sgms1 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.6204 REPS2 Bryony Thompson Marked gene: REPS2 as ready
Intellectual disability syndromic and non-syndromic v0.6204 REPS2 Bryony Thompson Gene: reps2 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.6204 REPS2 Bryony Thompson Classified gene: REPS2 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.6204 REPS2 Bryony Thompson Gene: reps2 has been classified as Amber List (Moderate Evidence).
Cerebral Palsy v1.368 REPS2 Bryony Thompson Marked gene: REPS2 as ready
Cerebral Palsy v1.368 REPS2 Bryony Thompson Gene: reps2 has been classified as Amber List (Moderate Evidence).
Cerebral Palsy v1.368 REPS2 Bryony Thompson Classified gene: REPS2 as Amber List (moderate evidence)
Cerebral Palsy v1.368 REPS2 Bryony Thompson Gene: reps2 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.6203 TTL Bryony Thompson Marked gene: TTL as ready
Intellectual disability syndromic and non-syndromic v0.6203 TTL Bryony Thompson Gene: ttl has been classified as Amber List (Moderate Evidence).
Cerebral Palsy v1.368 REPS2 Bryony Thompson Classified gene: REPS2 as Amber List (moderate evidence)
Cerebral Palsy v1.368 REPS2 Bryony Thompson Gene: reps2 has been classified as Amber List (Moderate Evidence).
Tubulinopathies v1.2 TTL Bryony Thompson Marked gene: TTL as ready
Tubulinopathies v1.2 TTL Bryony Thompson Gene: ttl has been classified as Amber List (Moderate Evidence).
Tubulinopathies v1.2 TTL Bryony Thompson Classified gene: TTL as Amber List (moderate evidence)
Tubulinopathies v1.2 TTL Bryony Thompson Gene: ttl has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.6203 TTL Bryony Thompson Classified gene: TTL as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.6203 TTL Bryony Thompson Gene: ttl has been classified as Amber List (Moderate Evidence).
Tubulinopathies v1.2 TTL Bryony Thompson Classified gene: TTL as Amber List (moderate evidence)
Tubulinopathies v1.2 TTL Bryony Thompson Gene: ttl has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2007 REPS2 Bryony Thompson Marked gene: REPS2 as ready
Mendeliome v1.2007 REPS2 Bryony Thompson Gene: reps2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2007 TTL Bryony Thompson Marked gene: TTL as ready
Mendeliome v1.2007 TTL Bryony Thompson Gene: ttl has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2007 REPS2 Bryony Thompson Classified gene: REPS2 as Amber List (moderate evidence)
Mendeliome v1.2007 REPS2 Bryony Thompson Gene: reps2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2006 TTL Bryony Thompson Classified gene: TTL as Amber List (moderate evidence)
Mendeliome v1.2006 TTL Bryony Thompson Gene: ttl has been classified as Amber List (Moderate Evidence).
Mitochondrial disease v0.930 MRPL42 Bryony Thompson Marked gene: MRPL42 as ready
Mitochondrial disease v0.930 MRPL42 Bryony Thompson Gene: mrpl42 has been classified as Red List (Low Evidence).
Mitochondrial disease v0.930 MRPL42 Bryony Thompson Classified gene: MRPL42 as Red List (low evidence)
Mitochondrial disease v0.930 MRPL42 Bryony Thompson Gene: mrpl42 has been classified as Red List (Low Evidence).
Mendeliome v1.2005 MRPL42 Bryony Thompson Marked gene: MRPL42 as ready
Mendeliome v1.2005 MRPL42 Bryony Thompson Gene: mrpl42 has been classified as Red List (Low Evidence).
Mendeliome v1.2005 MRPL42 Bryony Thompson Classified gene: MRPL42 as Red List (low evidence)
Mendeliome v1.2005 MRPL42 Bryony Thompson Gene: mrpl42 has been classified as Red List (Low Evidence).
Mendeliome v1.2004 MED16 Bryony Thompson Marked gene: MED16 as ready
Mendeliome v1.2004 MED16 Bryony Thompson Gene: med16 has been classified as Green List (High Evidence).
Mendeliome v1.2004 MED16 Bryony Thompson Classified gene: MED16 as Green List (high evidence)
Mendeliome v1.2004 MED16 Bryony Thompson Gene: med16 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.6202 GPN2 Bryony Thompson Marked gene: GPN2 as ready
Intellectual disability syndromic and non-syndromic v0.6202 GPN2 Bryony Thompson Gene: gpn2 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.6202 GPN2 Bryony Thompson Classified gene: GPN2 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.6202 GPN2 Bryony Thompson Gene: gpn2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2003 GPN2 Bryony Thompson Marked gene: GPN2 as ready
Mendeliome v1.2003 GPN2 Bryony Thompson Gene: gpn2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2003 GPN2 Bryony Thompson Classified gene: GPN2 as Amber List (moderate evidence)
Mendeliome v1.2003 GPN2 Bryony Thompson Gene: gpn2 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.6201 FKBP4 Bryony Thompson Marked gene: FKBP4 as ready
Intellectual disability syndromic and non-syndromic v0.6201 FKBP4 Bryony Thompson Gene: fkbp4 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.6201 FKBP4 Bryony Thompson Classified gene: FKBP4 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.6201 FKBP4 Bryony Thompson Gene: fkbp4 has been classified as Amber List (Moderate Evidence).
Differences of Sex Development v0.294 FKBP4 Bryony Thompson Marked gene: FKBP4 as ready
Differences of Sex Development v0.294 FKBP4 Bryony Thompson Gene: fkbp4 has been classified as Amber List (Moderate Evidence).
Differences of Sex Development v0.294 FKBP4 Bryony Thompson Classified gene: FKBP4 as Amber List (moderate evidence)
Differences of Sex Development v0.294 FKBP4 Bryony Thompson Gene: fkbp4 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2002 FKBP4 Bryony Thompson Marked gene: FKBP4 as ready
Mendeliome v1.2002 FKBP4 Bryony Thompson Gene: fkbp4 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2002 FKBP4 Bryony Thompson Classified gene: FKBP4 as Amber List (moderate evidence)
Mendeliome v1.2002 FKBP4 Bryony Thompson Gene: fkbp4 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.6200 EIF3I Bryony Thompson Marked gene: EIF3I as ready
Intellectual disability syndromic and non-syndromic v0.6200 EIF3I Bryony Thompson Gene: eif3i has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.6200 EIF3I Bryony Thompson Classified gene: EIF3I as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.6200 EIF3I Bryony Thompson Gene: eif3i has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.6199 EIF3I Bryony Thompson Classified gene: EIF3I as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.6199 EIF3I Bryony Thompson Gene: eif3i has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2001 EIF3I Bryony Thompson Marked gene: EIF3I as ready
Mendeliome v1.2001 EIF3I Bryony Thompson Gene: eif3i has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2001 EIF3I Bryony Thompson Classified gene: EIF3I as Amber List (moderate evidence)
Mendeliome v1.2001 EIF3I Bryony Thompson Gene: eif3i has been classified as Amber List (Moderate Evidence).
Ciliary Dyskinesia v1.40 DNAH17 Bryony Thompson Marked gene: DNAH17 as ready
Ciliary Dyskinesia v1.40 DNAH17 Bryony Thompson Gene: dnah17 has been classified as Green List (High Evidence).
Ciliary Dyskinesia v1.40 DNAH17 Bryony Thompson Classified gene: DNAH17 as Green List (high evidence)
Ciliary Dyskinesia v1.40 DNAH17 Bryony Thompson Gene: dnah17 has been classified as Green List (High Evidence).
Mendeliome v1.2000 DNAH17 Bryony Thompson Marked gene: DNAH17 as ready
Mendeliome v1.2000 DNAH17 Bryony Thompson Gene: dnah17 has been classified as Green List (High Evidence).
Mendeliome v1.2000 DNAH17 Bryony Thompson Classified gene: DNAH17 as Green List (high evidence)
Mendeliome v1.2000 DNAH17 Bryony Thompson Gene: dnah17 has been classified as Green List (High Evidence).
Joubert syndrome and other neurological ciliopathies v1.28 CEP76 Bryony Thompson Marked gene: CEP76 as ready
Joubert syndrome and other neurological ciliopathies v1.28 CEP76 Bryony Thompson Gene: cep76 has been classified as Amber List (Moderate Evidence).
Joubert syndrome and other neurological ciliopathies v1.28 CEP76 Bryony Thompson Classified gene: CEP76 as Amber List (moderate evidence)
Joubert syndrome and other neurological ciliopathies v1.28 CEP76 Bryony Thompson Gene: cep76 has been classified as Amber List (Moderate Evidence).
Syndromic Retinopathy v0.214 CEP76 Bryony Thompson Marked gene: CEP76 as ready
Syndromic Retinopathy v0.214 CEP76 Bryony Thompson Gene: cep76 has been classified as Green List (High Evidence).
Syndromic Retinopathy v0.214 CEP76 Bryony Thompson Classified gene: CEP76 as Green List (high evidence)
Syndromic Retinopathy v0.214 CEP76 Bryony Thompson Gene: cep76 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.6198 CEP76 Bryony Thompson Marked gene: CEP76 as ready
Intellectual disability syndromic and non-syndromic v0.6198 CEP76 Bryony Thompson Gene: cep76 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.6198 CEP76 Bryony Thompson Classified gene: CEP76 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.6198 CEP76 Bryony Thompson Gene: cep76 has been classified as Green List (High Evidence).
Ciliopathies v1.60 CEP76 Bryony Thompson Marked gene: CEP76 as ready
Ciliopathies v1.60 CEP76 Bryony Thompson Gene: cep76 has been classified as Green List (High Evidence).
Ciliopathies v1.60 CEP76 Bryony Thompson Classified gene: CEP76 as Green List (high evidence)
Ciliopathies v1.60 CEP76 Bryony Thompson Gene: cep76 has been classified as Green List (High Evidence).
Mendeliome v1.1999 CEP76 Bryony Thompson Marked gene: CEP76 as ready
Mendeliome v1.1999 CEP76 Bryony Thompson Gene: cep76 has been classified as Green List (High Evidence).
Mendeliome v1.1999 CEP76 Bryony Thompson Classified gene: CEP76 as Green List (high evidence)
Mendeliome v1.1999 CEP76 Bryony Thompson Gene: cep76 has been classified as Green List (High Evidence).
Amyloidosis v0.26 B2M Bryony Thompson Classified gene: B2M as Green List (high evidence)
Amyloidosis v0.26 B2M Bryony Thompson Gene: b2m has been classified as Green List (High Evidence).
Amyloidosis v0.25 B2M Bryony Thompson gene: B2M was added
gene: B2M was added to Renal Amyloidosis. Sources: Literature
Mode of inheritance for gene: B2M was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: B2M were set to 22693999; 37223323; 24014031; 35575118; 32875920
Phenotypes for gene: B2M were set to variant ABeta2M amyloidosis MONDO:0017810
Review for gene: B2M was set to GREEN
Added comment: 4 probands/families with amyloidosis and supporting in vitro functional studies.
Sources: Literature
Amyloidosis v0.24 TTR Bryony Thompson Marked gene: TTR as ready
Amyloidosis v0.24 TTR Bryony Thompson Gene: ttr has been classified as Green List (High Evidence).
Amyloidosis v0.24 TTR Bryony Thompson Classified gene: TTR as Green List (high evidence)
Amyloidosis v0.24 TTR Bryony Thompson Gene: ttr has been classified as Green List (High Evidence).
Amyloidosis v0.23 TTR Bryony Thompson gene: TTR was added
gene: TTR was added to Renal Amyloidosis. Sources: Literature
Mode of inheritance for gene: TTR was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TTR were set to 20301373; 38484868
Phenotypes for gene: TTR were set to hereditary ATTR amyloidosis MONDO:0017132
Review for gene: TTR was set to GREEN
gene: TTR was marked as current diagnostic
Added comment: The kidney is one of the main organs affected by transthyretin amyloidosis.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.6197 MRAS Krithika Murali Mode of inheritance for gene: MRAS was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.6197 MRAS Krithika Murali Classified gene: MRAS as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.6197 MRAS Krithika Murali Gene: mras has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.6196 MRAS Krithika Murali Marked gene: MRAS as ready
Intellectual disability syndromic and non-syndromic v0.6196 MRAS Krithika Murali Gene: mras has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.6196 MRAS Krithika Murali gene: MRAS was added
gene: MRAS was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: MRAS was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: MRAS were set to Noonan syndrome 11 - MIM#618499
Review for gene: MRAS was set to GREEN
Added comment: Developmental delay is a phenotypic feature
Sources: Literature
Spontaneous coronary artery dissection v0.53 FLNA Kunal Verma reviewed gene: FLNA: Rating: AMBER; Mode of pathogenicity: None; Publications: 34863227; Phenotypes: Spontaneous coronary artery dissection; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Renal Tubulopathies and related disorders v1.15 SLC36A2 Bryony Thompson Classified gene: SLC36A2 as Amber List (moderate evidence)
Renal Tubulopathies and related disorders v1.15 SLC36A2 Bryony Thompson Added comment: Comment on list classification: Biochemical phenotypes without adverse clinical consequences
Renal Tubulopathies and related disorders v1.15 SLC36A2 Bryony Thompson Gene: slc36a2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1998 CEP76 Mark Cleghorn gene: CEP76 was added
gene: CEP76 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: CEP76 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: CEP76 were set to complex neurodevelopmental disorder MONDO:0100038; Joubert syndrome; Bardet-Biedl syndrome; retinitis pigmentosa
Penetrance for gene: CEP76 were set to unknown
Review for gene: CEP76 was set to GREEN
Added comment: Erica Davis, Stanley Manne Children’s research institute, Chicago
ESHG presentation 4/6/24, unpublished

CEP76 associated with syndromic ciliopathy

CEP76 localizes to centrioles and basal body primary cilia
Role in normal centriolar duplication

Index case
Bardet Biedl syndrome
Compound heterozygous pLoF variants in CEP76

Via Gene matcher
7 cases in 7 families- biallelic CEP76 and various clinical features within ciliopathy spectrum:
Obesity
Ocular phenotype
Structural brain anomalies
Renal?

3/7 families clinical Dx Joubert syndrome
1/7 BBS
1/7 GDD/ID NOS
2/7 retinitis pigmentosa (1 of these with learning difficulties)

Mixture of biallelic pLOF and missense variant

CEP76 knockout zebrafish model shows retinal phenotype w photoreceptor loss, similar to homozygous known BBS4 pathogenic variant

Cell based fx studies with missense variants above, consistent with centriolar duplication dysfunction
Sources: Other
Intellectual disability syndromic and non-syndromic v0.6195 CEP76 Mark Cleghorn gene: CEP76 was added
gene: CEP76 was added to Intellectual disability syndromic and non-syndromic. Sources: Other
Mode of inheritance for gene: CEP76 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: CEP76 were set to complex neurodevelopmental disorder MONDO:0100038; Joubert syndrome; Bardet-Biedl syndrome; retinitis pigmentosa
Penetrance for gene: CEP76 were set to unknown
Review for gene: CEP76 was set to GREEN
Added comment: Erica Davis, Stanley Manne Children’s research institute, Chicago
ESHG presentation 4/6/24, unpublished

CEP76 associated with syndromic ciliopathy

CEP76 localizes to centrioles and basal body primary cilia
Role in normal centriolar duplication

Index case
Bardet Biedl syndrome
Compound heterozygous pLoF variants in CEP76

Via Gene matcher
7 cases in 7 families- biallelic CEP76 and various clinical features within ciliopathy spectrum:
Obesity
Ocular phenotype
Structural brain anomalies
Renal?

3/7 families clinical Dx Joubert syndrome
1/7 BBS
1/7 GDD/ID NOS
2/7 retinitis pigmentosa (1 of these with learning difficulties)

Mixture of biallelic pLOF and missense variant

CEP76 knockout zebrafish model shows retinal phenotype w photoreceptor loss, similar to homozygous known BBS4 pathogenic variant

Cell based fx studies with missense variants above, consistent with centriolar duplication dysfunction
Sources: Other
Syndromic Retinopathy v0.213 CEP76 Mark Cleghorn gene: CEP76 was added
gene: CEP76 was added to Syndromic Retinopathy. Sources: Other
Mode of inheritance for gene: CEP76 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: CEP76 were set to complex neurodevelopmental disorder MONDO:0100038; Joubert syndrome; Bardet-Biedl syndrome; retinitis pigmentosa
Penetrance for gene: CEP76 were set to unknown
Review for gene: CEP76 was set to GREEN
Added comment: Erica Davis, Stanley Manne Children’s research institute, Chicago
ESHG presentation 4/6/24, unpublished

CEP76 associated with syndromic ciliopathy

CEP76 localizes to centrioles and basal body primary cilia
Role in normal centriolar duplication

Index case
Bardet Biedl syndrome
Compound heterozygous pLoF variants in CEP76

Via Gene matcher
7 cases in 7 families- biallelic CEP76 and various clinical features within ciliopathy spectrum:
Obesity
Ocular phenotype
Structural brain anomalies
Renal?

3/7 families clinical Dx Joubert syndrome
1/7 BBS
1/7 GDD/ID NOS
2/7 retinitis pigmentosa (1 of these with learning difficulties)

Mixture of biallelic pLOF and missense variant

CEP76 knockout zebrafish model shows retinal phenotype w photoreceptor loss, similar to homozygous known BBS4 pathogenic variant

Cell based fx studies with missense variants above, consistent with centriolar duplication dysfunction
Sources: Other
Ciliopathies v1.59 CEP76 Mark Cleghorn gene: CEP76 was added
gene: CEP76 was added to Ciliopathies. Sources: Other
Mode of inheritance for gene: CEP76 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: CEP76 were set to complex neurodevelopmental disorder MONDO:0100038; Joubert syndrome; Bardet-Biedl syndrome; retinitis pigmentosa
Penetrance for gene: CEP76 were set to unknown
Review for gene: CEP76 was set to GREEN
Added comment: Erica Davis, Stanley Manne Children’s research institute, Chicago
ESHG presentation 4/6/24, unpublished

CEP76 associated with syndromic ciliopathy

CEP76 localizes to centrioles and basal body primary cilia
Role in normal centriolar duplication

Index case
Bardet Biedl syndrome
Compound heterozygous pLoF variants in CEP76

Via Gene matcher
7 cases in 7 families- biallelic CEP76 and various clinical features within ciliopathy spectrum:
Obesity
Ocular phenotype
Structural brain anomalies
Renal?

3/7 families clinical Dx Joubert syndrome
1/7 BBS
1/7 GDD/ID NOS
2/7 retinitis pigmentosa (1 of these with learning difficulties)

Mixture of biallelic pLOF and missense variant

CEP76 knockout zebrafish model shows retinal phenotype w photoreceptor loss, similar to homozygous known BBS4 pathogenic variant

Cell based fx studies with missense variants above, consistent with centriolar duplication dysfunction
Sources: Other
Joubert syndrome and other neurological ciliopathies v1.27 CEP76 Mark Cleghorn gene: CEP76 was added
gene: CEP76 was added to Joubert syndrome and other neurological ciliopathies. Sources: Other
Mode of inheritance for gene: CEP76 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: CEP76 were set to complex neurodevelopmental disorder MONDO:0100038; Joubert syndrome; Bardet-Biedl syndrome; retinitis pigmentosa
Penetrance for gene: CEP76 were set to unknown
Review for gene: CEP76 was set to GREEN
Added comment: Erica Davis, Stanley Manne Children’s research institute, Chicago
ESHG presentation 4/6/24, unpublished

CEP76 associated with syndromic ciliopathy

CEP76 localizes to centrioles and basal body primary cilia
Role in normal centriolar duplication

Index case
Bardet Biedl syndrome
Compound heterozygous pLoF variants in CEP76

Via Gene matcher
7 cases in 7 families- biallelic CEP76 and various clinical features within ciliopathy spectrum:
Obesity
Ocular phenotype
Structural brain anomalies
Renal?

3/7 families clinical Dx Joubert syndrome
1/7 BBS
1/7 GDD/ID NOS
2/7 retinitis pigmentosa (1 of these with learning difficulties)

Mixture of biallelic pLOF and missense variants

CEP76 knockout zebrafish model shows retinal phenotype w photoreceptor loss, similar to homozygous known BBS4 pathogenic variant

Cell based fx studies with missense variants above, consistent with centriolar duplication dysfunction
Sources: Other
Mendeliome v1.1998 EIF3I Mark Cleghorn gene: EIF3I was added
gene: EIF3I was added to Mendeliome. Sources: Other
Mode of inheritance for gene: EIF3I was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: EIF3I were set to complex neurodevelopmental disorder MONDO:0100038
Penetrance for gene: EIF3I were set to unknown
Review for gene: EIF3I was set to AMBER
Added comment: Marcello Scala, Genoa
ESHG presentation 4/6/24, unpublished

De novo EIF3I missense variants as a cause for novel NDD syndrome

EIF3 complex involved in regulating initiation of mRNA translation
Negative regulator of the TGF beta pathway

8 individuals from 8 families
Mod/severe GDD or ID
Short stature
Midline brain anomalies (hypoplasia/agenesis of corpus callosum and pituitary hypoplasia)
Frontal bossing, hypertelorism, long philtrum
All w rare de novo missense variants in EIF3I, clustering within highly conserved WD repeats

Functional studies
Transfected HEK293 cell studies suggested EIF3I protein from variant alleles (from patients above) had disrupted interaction with other EIF subunits, and cells had reduced protein synthesis overall
No animal models
Sources: Other
Intellectual disability syndromic and non-syndromic v0.6195 EIF3I Mark Cleghorn gene: EIF3I was added
gene: EIF3I was added to Intellectual disability syndromic and non-syndromic. Sources: Other
Mode of inheritance for gene: EIF3I was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: EIF3I were set to complex neurodevelopmental disorder MONDO:0100038
Penetrance for gene: EIF3I were set to unknown
Review for gene: EIF3I was set to AMBER
Added comment: Marcello Scala, Genoa
ESHG presentation 4/6/24, unpublished

De novo EIF3I missense variants as a cause for novel NDD syndrome

EIF3 complex involved in regulating initiation of mRNA translation
Negative regulator of the TGF beta pathway

8 individuals from 8 families
Mod/severe GDD or ID
Short stature
Midline brain anomalies (hypoplasia/agenesis of corpus callosum and pituitary hypoplasia)
Frontal bossing, hypertelorism, long philtrum
All w rare de novo missense variants om EIF3I, clustering within highly conserved WD repeats

Functional studies
Transfected HEK293 cell studies suggested EIF3I protein from variant alleles (from patients above) had disrupted interaction with other EIF subunits, and cells had reduced protein synthesis overall
No animal models
Sources: Other
Intellectual disability syndromic and non-syndromic v0.6195 DDHD2 Bryony Thompson Phenotypes for gene: DDHD2 were changed from hereditary spastic paraplegia 54 MONDO:0014018 to hereditary spastic paraplegia 54 MONDO:0014018
Intellectual disability syndromic and non-syndromic v0.6194 DDHD2 Bryony Thompson Marked gene: DDHD2 as ready
Intellectual disability syndromic and non-syndromic v0.6194 DDHD2 Bryony Thompson Gene: ddhd2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.6194 DDHD2 Bryony Thompson Phenotypes for gene: DDHD2 were changed from to hereditary spastic paraplegia 54 MONDO:0014018
Intellectual disability syndromic and non-syndromic v0.6193 DDHD2 Bryony Thompson Publications for gene: DDHD2 were set to
Intellectual disability syndromic and non-syndromic v0.6192 DDHD2 Bryony Thompson Mode of inheritance for gene: DDHD2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.6191 DDHD2 Bryony Thompson reviewed gene: DDHD2: Rating: GREEN; Mode of pathogenicity: None; Publications: 23486545, 23176823, 36090575, 26113134, 25417924; Phenotypes: hereditary spastic paraplegia 54 MONDO:0014018; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability syndromic and non-syndromic v0.6191 DDC Bryony Thompson Marked gene: DDC as ready
Intellectual disability syndromic and non-syndromic v0.6191 DDC Bryony Thompson Gene: ddc has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.6191 DDC Bryony Thompson Publications for gene: DDC were set to
Intellectual disability syndromic and non-syndromic v0.6190 DDC Bryony Thompson Mode of inheritance for gene: DDC was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.6189 DDC Bryony Thompson reviewed gene: DDC: Rating: GREEN; Mode of pathogenicity: None; Publications: 37824694; Phenotypes: Aromatic L-amino acid decarboxylase deficiency MONDO:0012084; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v1.1998 MRPL42 Mark Cleghorn gene: MRPL42 was added
gene: MRPL42 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: MRPL42 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: MRPL42 were set to complex neurodevelopmental disorder MONDO:0100038
Penetrance for gene: MRPL42 were set to unknown
Review for gene: MRPL42 was set to RED
Added comment: Bjorn Fischer-Zirnsak, Charite Berlin
ESHG presentation 4/6/24, unpublished

++ supportive functional data (on patient-derived cells) presented, but only 1 case

Biallelic MRPL42 LoF with lethal mitochondrial disease

Index case, born to consanguineous parents
Small
Hypotonia
Seizures
Conductive hearing impairment
CV: hypertrophic RV, small VSD
Hepatomegaly
Lactic acidosis

Homozygous MRPL42: c.219+6T>A (spliceAI 0.83 donor loss)
RNASeq and RT-PCR supportive of aberrant splicing resulting in out of frame exon 4 skipping
Sources: Other
Mitochondrial disease v0.929 MRPL42 Mark Cleghorn gene: MRPL42 was added
gene: MRPL42 was added to Mitochondrial disease. Sources: Other
Mode of inheritance for gene: MRPL42 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: MRPL42 were set to complex neurodevelopmental disorder MONDO:0100038
Penetrance for gene: MRPL42 were set to unknown
Review for gene: MRPL42 was set to RED
Added comment: Bjorn Fischer-Zirnsak, Charite Berlin
ESHG presentation 4/6/24, unpublished

++ supportive functional data (on patient-derived cells) presented, but only 1 case

Biallelic MRPL42 LoF with lethal mitochondrial disease

Index case, born to consanguineous parents
Small
Hypotonia
Seizures
Conductive hearing impairment
CV: hypertrophic RV, small VSD
Hepatomegaly
Lactic acidosis

Homozygous MRPL42: c.219+6T>A (spliceAI 0.83 donor loss)
RNASeq and RT-PCR supportive of aberrant splicing resulting in out of frame exon 4 skipping
Sources: Other
Mendeliome v1.1998 MED16 Mark Cleghorn gene: MED16 was added
gene: MED16 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: MED16 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: MED16 were set to complex neurodevelopmental disorder MONDO:0100038
Review for gene: MED16 was set to GREEN
Added comment: Charlotte Guillouet, Imagine institute Paris
ESHG presentation 4/6/24, unpublished

MED16 is part of tail of ‘mediator complex’
Plays a role in enhancer/promotor regions

Disruptive variants in other genes encoding proteins within this mediator complex (MED11/12/12/17/20, CDK8) are assoc w neurodevelopmental/neurodegenerative disorders

Cases
index family
Sibs (M/F) to consanguineous parents w NDD/mod ID, tetralogy of Fallot or VSD, bilat deafness, micrognathia, malar hypoplasia, dental AbN, pre auricular tags, hypoplastic nails, brachydactly
WES: biallelic MED16 p.Asp217Asn

Via genematcher
16 families total, 22 individuals, homozygous or compound het rare MED16 variants
Mixture of pLoF and missense variants

Motor delay in 16/17
DD or ID in 17/17
Speech delay in 15/15
6/19 ToF
7/19 other septal/aortic defects
6/18 deafness
11/18 microretrognathia
6/17 cleft palate
8/19 preauricular tags
9/20 puffy eyelids
12/20 nasal dysplasia (most commonly short columella w bulbous nasal tip)
7/20 corpus callosum anomalies

Not clear that functional work recapitulated phenotype as yet?
Immunofluroescence on HeLa cells transfected with variants observed ?conclusion
MED16 knockout mouse > growth delay, pre weaning lethality
MED16 knockout zebrafish > reduced body length, early death, no obvious craniofacial phenotype
Sources: Other
Mendeliome v1.1998 GPN2 Mark Cleghorn gene: GPN2 was added
gene: GPN2 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: GPN2 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: GPN2 were set to complex neurodevelopmental disorder MONDO:0100038; Perrault syndrome
Penetrance for gene: GPN2 were set to unknown
Review for gene: GPN2 was set to AMBER
Added comment: GPN2
ESHG talk 2/6/24, unpublished
Thomas Smith, University of Manchester

Biallelic GPN2 proposed to cause Perrault syndrome (SNHL, ovarian dysfunction, NDD)
RNA polymerase assembly factor

4 families (14 affected individuals) w biallalic GPN2 rare missense variants
Segregated w phenotype
Fam 2 and 3 may be distantly related (leaving 3 distinct kindreds)

Clinical features
13/14 SNHL
3/4 families all females of adolescent age or older had primary ovarian insufficiency
4/4 GDD, ataxia (no data on family w 10 affected indiv.)

Some functional work, not conclusive
Sources: Other
Mendeliome v1.1998 FKBP4 Mark Cleghorn gene: FKBP4 was added
gene: FKBP4 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: FKBP4 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: FKBP4 were set to complex neurodevelopmental disorder MONDO:0100038
Penetrance for gene: FKBP4 were set to unknown
Review for gene: FKBP4 was set to AMBER
Added comment: Rebecca Yarwood, University of Manchester
ESHG presentation 4/6/24, unpublished

Bilalleic FKBP4 w NDD + DSD
Protein has functions in hormone receptor trafficking
FKPB4 highly expressed in stem cell and progenitor cells in gonad and neuronal degeneration

Index case
Severe GDD
abN external genitalia
CV AbN
FBBP4 p.E196*

Via GeneMatcher
7 families (12 individuals)

12/12 severe GDD/ID
9/10 microcephaly
11/12 external genital abnormalities (details not provided)

All w homozygous pLoF variants (mixture of canonical splice, frameshift, nonsense)
Sources: Other
Intellectual disability syndromic and non-syndromic v0.6189 FKBP4 Mark Cleghorn gene: FKBP4 was added
gene: FKBP4 was added to Intellectual disability syndromic and non-syndromic. Sources: Other
Mode of inheritance for gene: FKBP4 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: FKBP4 were set to complex neurodevelopmental disorder MONDO:0100038
Penetrance for gene: FKBP4 were set to unknown
Review for gene: FKBP4 was set to AMBER
Added comment: Rebecca Yarwood, University of Manchester
ESHG presentation 4/6/24, unpublished

Bilalleic FKBP4 w NDD + DSD
Protein has functions in hormone receptor trafficking
FKPB4 highly expressed in stem cell and progenitor cells in gonad and neuronal degeneration

Index case
Severe GDD
abN external genitalia
CV AbN
FBBP4 p.E196*

Via GeneMatcher
7 families (12 individuals)

12/12 severe GDD/ID
9/10 microcephaly
11/12 external genital abnormalities (details not provided)

All w homozygous pLoF variants (mixture of canonical splice, frameshift, nonsense)
Sources: Other
Differences of Sex Development v0.293 FKBP4 Mark Cleghorn gene: FKBP4 was added
gene: FKBP4 was added to Differences of Sex Development. Sources: Other
Mode of inheritance for gene: FKBP4 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: FKBP4 were set to complex neurodevelopmental disorder MONDO:0100038
Penetrance for gene: FKBP4 were set to unknown
Review for gene: FKBP4 was set to AMBER
Added comment: Rebecca Yarwood, University of Manchester
ESHG presentation 4/6/24, unpublished

Bilalleic FKBP4 w NDD + DSD
Protein has functions in hormone receptor trafficking
FKPB4 highly expressed in stem cell and progenitor cells in gonad and neuronal degeneration

Index case
Severe GDD
abN external genitalia
CV AbN
FBBP4 p.E196*

Via GeneMatcher
7 families (12 individuals)

12/12 severe GDD/ID
9/10 microcephaly
11/12 external genital abnormalities (details not provided)

All w homozygous pLoF variants (mixture of canonical splice, frameshift, nonsense)
Sources: Other
Mendeliome v1.1998 SGMS1 Mark Cleghorn gene: SGMS1 was added
gene: SGMS1 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: SGMS1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: SGMS1 were set to complex neurodevelopmental disorder MONDO:0100038
Review for gene: SGMS1 was set to AMBER
Added comment: SGMS1
Johannes Kopp, Charite Berlin
ESHG presentation 4/6/24, unpublished

Biallelic SGMS1 with novel metabolic disorder

Only 2 families (3 cases) reported
NDD, AbN cerebral myelination, SNHL, ichthyosis

Homozygous or compound het SGMS1 missense

Functional work to support role of SGMS1 in sphingolipid metabolism
Sources: Other
Prepair 1000+ v1.287 ADGRV1 Lauren Thomas reviewed gene: ADGRV1: Rating: GREEN; Mode of pathogenicity: None; Publications: 19357117; Phenotypes: Usher syndrome, type 2C, MIM# 605472 (3); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.6189 MED16 Bryony Thompson Classified gene: MED16 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.6189 MED16 Bryony Thompson Gene: med16 has been classified as Green List (High Evidence).
Prepair 1000+ v1.287 ADGRG1 Lauren Thomas reviewed gene: ADGRG1: Rating: GREEN; Mode of pathogenicity: None; Publications: 16240336, 33299078; Phenotypes: Polymicrogyria, bilateral frontoparietal, MIM#606854; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Lysosomal Storage Disorder v1.11 SGMS1 Mark Cleghorn gene: SGMS1 was added
gene: SGMS1 was added to Lysosomal Storage Disorder. Sources: Other
Mode of inheritance for gene: SGMS1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: SGMS1 were set to complex neurodevelopmental disorder MONDO:0100038
Penetrance for gene: SGMS1 were set to unknown
Review for gene: SGMS1 was set to AMBER
Added comment: SGMS1
Johannes Kopp, Charite Berlin
ESHG presentation 4/6/24, unpublished

Biallelic SGMS1 with novel metabolic disorder

Only 2 families (3 cases) reported
NDD, AbN cerebral myelination, SNHL, ichthyosis

Homozygous or compound het SGMS1 missense

Functional work to support role of SGMS1 in sphingolipid metabolism
Sources: Other
Intellectual disability syndromic and non-syndromic v0.6188 MED16 Mark Cleghorn gene: MED16 was added
gene: MED16 was added to Intellectual disability syndromic and non-syndromic. Sources: Other
Mode of inheritance for gene: MED16 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: MED16 were set to complex neurodevelopmental disorder MONDO:0100038
Penetrance for gene: MED16 were set to unknown
Review for gene: MED16 was set to GREEN
Added comment: MED16
Charlotte Guillouet, Imagine institute Paris
ESHG presentation 4/6/24, unpublished

MED16 is part of tail of ‘mediator complex’
Plays a role in enhancer/promotor regions

Disruptive variants in other genes encoding proteins within this mediator complex (MED11/12/12/17/20, CDK8) are assoc w neurodevelopmental/neurodegenerative disorders

Cases
index family
Sibs (M/F) to consanguineous parents w NDD/mod ID, tetralogy of Fallot or VSD, bilat deafness, micrognathia, malar hypoplasia, dental AbN, pre auricular tags, hypoplastic nails, brachydactly
WES: biallelic MED16 p.Asp217Asn

Via genematcher
16 families total, 22 individuals, homozygous or compound het rare MED16 variants
Mixture of pLoF and missense variants

Motor delay in 16/17
DD or ID in 17/17
Speech delay in 15/15
6/19 ToF
7/19 other septal/aortic defects
6/18 deafness
11/18 microretognathia
6/17 cleft palate
8/19 preauricular tags
9/20 puffy eyelids
12/20 nasal dysplasia (most commonly short columella w bulbous nasal tip)
7/20 corpus callosum anomalies

Not clear that functional work recapitulated phenotype as yet?
Immunofluroescence on HeLa cells transfected with variants observed ?conclusion
MED16 knockout mouse > growth delay, pre weaning lethality
MED16 knockout zebrafish > reduced body length, early death, no obvious craniofacial phenotype
Sources: Other
Prepair 1000+ v1.287 ADA2 Lauren Thomas reviewed gene: ADA2: Rating: GREEN; Mode of pathogenicity: None; Publications: 24552284, 24552285, 33791889; Phenotypes: Vasculitis, autoinflammation, immunodeficiency, and hematologic defects syndrome, MIM# 615688; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.287 ABCC6 Lauren Thomas reviewed gene: ABCC6: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Pseudoxanthoma elasticum MIM#264800, Arterial calcification, generalized, of infancy, 2 MIM#614473; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.287 COL2A1 Zornitza Stark Marked gene: COL2A1 as ready
Prepair 1000+ v1.287 COL2A1 Zornitza Stark Gene: col2a1 has been classified as Red List (Low Evidence).
Prepair 1000+ v1.287 COL2A1 Zornitza Stark Classified gene: COL2A1 as Red List (low evidence)
Prepair 1000+ v1.287 COL2A1 Zornitza Stark Gene: col2a1 has been classified as Red List (Low Evidence).
Prepair 1000+ v1.286 COL2A1 Zornitza Stark reviewed gene: COL2A1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Spondyloperipheral dysplasia, MIM #271700; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Prepair 1000+ v1.286 GNAT2 Zornitza Stark Marked gene: GNAT2 as ready
Prepair 1000+ v1.286 GNAT2 Zornitza Stark Gene: gnat2 has been classified as Green List (High Evidence).
Prepair 1000+ v1.286 GNAT2 Zornitza Stark Phenotypes for gene: GNAT2 were changed from Achromatopsia-4, 613856 (3) to Achromatopsia 4 MIM#613856
Prepair 1000+ v1.285 GNAT2 Zornitza Stark Publications for gene: GNAT2 were set to
Prepair 1000+ v1.284 DLL3 Zornitza Stark Marked gene: DLL3 as ready
Prepair 1000+ v1.284 DLL3 Zornitza Stark Gene: dll3 has been classified as Green List (High Evidence).
Prepair 1000+ v1.284 DLL3 Zornitza Stark Phenotypes for gene: DLL3 were changed from Spondylocostal dysostosis 1, autosomal recessive, 277300 (3) to Spondylocostal dysostosis 1, autosomal recessive, MIM# 277300; MONDO:0020692
Prepair 1000+ v1.283 DLL3 Zornitza Stark Publications for gene: DLL3 were set to
Intellectual disability syndromic and non-syndromic v0.6188 LARS2 Chirag Patel reviewed gene: LARS2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 29205794, 32423379, 30737337, 26537577, 23541342; Phenotypes: Perrault syndrome 4, MIM# 615300, Hydrops, lactic acidosis, and sideroblastic anemia, MIM# 617021; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability syndromic and non-syndromic v0.6188 LARGE1 Chirag Patel reviewed gene: LARGE1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 12966029, 19067344, 17436019, 21248746, 19299310; Phenotypes: Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 6, MIM# 613154, Muscular dystrophy-dystroglycanopathy (congenital with mental retardation), type B, 6, MIM# 608840; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability syndromic and non-syndromic v0.6188 LAMP2 Chirag Patel reviewed gene: LAMP2: Rating: GREEN; Mode of pathogenicity: None; Publications: PubMed: 10972294; Phenotypes: Danon disease, MIM# 300257, MONDO:0010281; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males); Current diagnostic: yes
Intellectual disability syndromic and non-syndromic v0.6188 PARN Chirag Patel reviewed gene: PARN: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 25893599, 26342108; Phenotypes: Dyskeratosis congenita, autosomal recessive 6, MIM# 616353; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Regression v0.559 PAX6 Chirag Patel Classified gene: PAX6 as Red List (low evidence)
Regression v0.559 PAX6 Chirag Patel Gene: pax6 has been classified as Red List (Low Evidence).
Ataxia - paediatric v1.27 PAX6 Chirag Patel Classified gene: PAX6 as Red List (low evidence)
Ataxia - paediatric v1.27 PAX6 Chirag Patel Gene: pax6 has been classified as Red List (Low Evidence).
Ataxia - paediatric v1.26 PAX6 Chirag Patel reviewed gene: PAX6: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Regression v0.558 PAX6 Chirag Patel Classified gene: PAX6 as Red List (low evidence)
Regression v0.558 PAX6 Chirag Patel Gene: pax6 has been classified as Red List (Low Evidence).
Regression v0.558 PAX6 Chirag Patel Classified gene: PAX6 as Red List (low evidence)
Regression v0.558 PAX6 Chirag Patel Gene: pax6 has been classified as Red List (Low Evidence).
Regression v0.557 PAX6 Chirag Patel reviewed gene: PAX6: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability syndromic and non-syndromic v0.6188 PAX6 Chirag Patel reviewed gene: PAX6: Rating: GREEN; Mode of pathogenicity: None; Publications: PubMed: 26130484, 31700164; Phenotypes: Microphthalmia/coloboma 12, OMIM #120200; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital hypothyroidism v0.43 PAX8 Chirag Patel reviewed gene: PAX8: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33272083, 9590296 11232006 15356023 15718293; Phenotypes: Hypothyroidism, congenital, due to thyroid dysgenesis or hypoplasia, MIM# 218700; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability syndromic and non-syndromic v0.6188 PAX8 Chirag Patel reviewed gene: PAX8: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33272083, 9590296 11232006 15356023 15718293; Phenotypes: Hypothyroidism, congenital, due to thyroid dysgenesis or hypoplasia, MIM# 218700; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability syndromic and non-syndromic v0.6188 PC Chirag Patel reviewed gene: PC: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 9585612, 12112657; Phenotypes: Pyruvate carboxylase deficiency - MIM#266150; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
BabyScreen+ newborn screening v1.114 AHCY Carolyn Bursle reviewed gene: AHCY: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Prepair 1000+ v1.282 CSTB Lilian Downie Marked gene: CSTB as ready
Prepair 1000+ v1.282 CSTB Lilian Downie Added comment: Comment when marking as ready: downgrade to amber when updating, common variant not detected with WES
Prepair 1000+ v1.282 CSTB Lilian Downie Gene: cstb has been classified as Green List (High Evidence).
Prepair 1000+ v1.282 EIF2B4 Lilian Downie Marked gene: EIF2B4 as ready
Prepair 1000+ v1.282 EIF2B4 Lilian Downie Gene: eif2b4 has been classified as Green List (High Evidence).
Prepair 1000+ v1.282 EIF2B4 Lilian Downie Publications for gene: EIF2B4 were set to
Prepair 1000+ v1.281 ERBB3 Lilian Downie Marked gene: ERBB3 as ready
Prepair 1000+ v1.281 ERBB3 Lilian Downie Added comment: Comment when marking as ready: Upgrade to green
Prepair 1000+ v1.281 ERBB3 Lilian Downie Gene: erbb3 has been classified as Amber List (Moderate Evidence).
Prepair 1000+ v1.281 ERBB3 Lilian Downie Tag for review tag was added to gene: ERBB3.
Prepair 1000+ v1.281 ERBB3 Lilian Downie Phenotypes for gene: ERBB3 were changed from Lethal congenital contractural syndrome 2, 607598 (3) to Visceral neuropathy, familial, 1, autosomal recessive MIM#243180
Prepair 1000+ v1.280 ERBB3 Lilian Downie Publications for gene: ERBB3 were set to
Intellectual disability syndromic and non-syndromic v0.6188 SLC6A3 Zornitza Stark Marked gene: SLC6A3 as ready
Intellectual disability syndromic and non-syndromic v0.6188 SLC6A3 Zornitza Stark Gene: slc6a3 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.6188 SLC6A3 Zornitza Stark Phenotypes for gene: SLC6A3 were changed from to Parkinsonism-dystonia, infantile, 1, MIM# 613135
Intellectual disability syndromic and non-syndromic v0.6187 SLC6A3 Zornitza Stark Publications for gene: SLC6A3 were set to
Intellectual disability syndromic and non-syndromic v0.6186 SLC6A3 Zornitza Stark Mode of inheritance for gene: SLC6A3 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.6185 SLC6A3 Zornitza Stark reviewed gene: SLC6A3: Rating: GREEN; Mode of pathogenicity: None; Publications: 21112253; Phenotypes: Parkinsonism-dystonia, infantile, 1, MIM# 613135; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.6185 SRD5A3 Zornitza Stark Marked gene: SRD5A3 as ready
Intellectual disability syndromic and non-syndromic v0.6185 SRD5A3 Zornitza Stark Gene: srd5a3 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.6185 SRD5A3 Zornitza Stark Phenotypes for gene: SRD5A3 were changed from to Congenital disorder of glycosylation, type Iq, MIM#612379; Kahrizi syndrome, MIM# 612713
Intellectual disability syndromic and non-syndromic v0.6184 SRD5A3 Zornitza Stark Publications for gene: SRD5A3 were set to
Intellectual disability syndromic and non-syndromic v0.6183 SRD5A3 Zornitza Stark Mode of inheritance for gene: SRD5A3 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.6182 SRD5A3 Zornitza Stark reviewed gene: SRD5A3: Rating: GREEN; Mode of pathogenicity: None; Publications: 32424323; Phenotypes: Congenital disorder of glycosylation, type Iq, MIM#612379, Kahrizi syndrome, MIM# 612713; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.6182 SLC6A8 Zornitza Stark Marked gene: SLC6A8 as ready
Intellectual disability syndromic and non-syndromic v0.6182 SLC6A8 Zornitza Stark Gene: slc6a8 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.6182 SLC6A8 Zornitza Stark Phenotypes for gene: SLC6A8 were changed from to Cerebral creatine deficiency syndrome 1, MIM# 300352
Intellectual disability syndromic and non-syndromic v0.6181 SLC6A8 Zornitza Stark Publications for gene: SLC6A8 were set to
Intellectual disability syndromic and non-syndromic v0.6180 SLC6A8 Zornitza Stark Mode of inheritance for gene: SLC6A8 was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability syndromic and non-syndromic v0.6179 SLC6A8 Zornitza Stark reviewed gene: SLC6A8: Rating: GREEN; Mode of pathogenicity: None; Publications: 27604308, 16738945; Phenotypes: Cerebral creatine deficiency syndrome 1, MIM# 300352; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Prepair 1000+ v1.279 B3GALNT2 Lilian Downie Marked gene: B3GALNT2 as ready
Prepair 1000+ v1.279 B3GALNT2 Lilian Downie Added comment: Comment when marking as ready: Congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A) is an autosomal recessive disorder with congenital muscular dystrophy resulting in muscle weakness early in life and brain and eye anomalies. It is usually associated with delayed psychomotor development and shortened life expectancy. The phenotype includes the alternative clinical designations Walker-Warburg syndrome (WWS) and muscle-eye-brain disease (MEB). The disorder represents the most severe end of a phenotypic spectrum of similar disorders resulting from defective glycosylation of alpha-dystroglycan (DAG1; 128239), collectively known as 'dystroglycanopathies'
Prepair 1000+ v1.279 B3GALNT2 Lilian Downie Gene: b3galnt2 has been classified as Green List (High Evidence).
Prepair 1000+ v1.279 B3GALNT2 Lilian Downie Publications for gene: B3GALNT2 were set to
Prepair 1000+ v1.278 EVC2 Lilian Downie Marked gene: EVC2 as ready
Prepair 1000+ v1.278 EVC2 Lilian Downie Gene: evc2 has been classified as Green List (High Evidence).
Prepair 1000+ v1.278 EVC2 Lilian Downie Publications for gene: EVC2 were set to
Prepair 1000+ v1.277 FAT4 Lilian Downie Marked gene: FAT4 as ready
Prepair 1000+ v1.277 FAT4 Lilian Downie Gene: fat4 has been classified as Green List (High Evidence).
Prepair 1000+ v1.277 FAT4 Lilian Downie Phenotypes for gene: FAT4 were changed from Hennekam lymphangiectasia-lymphedema syndrome 2, 616006 (3) to Hennekam lymphangiectasia-lymphedema syndrome 2 MIM#616006; Van Maldergem syndrome 2 MIM#615546
Prepair 1000+ v1.276 FAT4 Lilian Downie Publications for gene: FAT4 were set to
Prepair 1000+ v1.275 FKTN Lilian Downie Marked gene: FKTN as ready
Prepair 1000+ v1.275 FKTN Lilian Downie Gene: fktn has been classified as Green List (High Evidence).
Prepair 1000+ v1.275 FKTN Lilian Downie Phenotypes for gene: FKTN were changed from Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4, 253800 (3) to Cardiomyopathy, dilated, 1X MIM#611615; Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4MIM#253800; Muscular dystrophy-dystroglycanopathy (congenital without impaired intellectual development), type B, 4 MIM#613152; Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 4 MIM# 611588
Prepair 1000+ v1.274 FKTN Lilian Downie Publications for gene: FKTN were set to
Prepair 1000+ v1.273 GDF5 Lilian Downie Marked gene: GDF5 as ready
Prepair 1000+ v1.273 GDF5 Lilian Downie Gene: gdf5 has been classified as Green List (High Evidence).
Prepair 1000+ v1.273 GDF5 Lilian Downie Publications for gene: GDF5 were set to
Intellectual disability syndromic and non-syndromic v0.6179 SPTBN2 Zornitza Stark Mode of inheritance for gene: SPTBN2 was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.6178 SPTBN2 Zornitza Stark reviewed gene: SPTBN2: Rating: GREEN; Mode of pathogenicity: None; Publications: 23236289, 23838597, 22781464, 31617442, 31066025; Phenotypes: Spinocerebellar ataxia, autosomal recessive 14, MIM# 615386, Spinocerebellar ataxia 5, MIM# 600224; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hypercalcaemia v1.2 AP2S1 Chirag Patel reviewed gene: AP2S1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 29325022; Phenotypes: Hypocalciuric hypercalcaemia, type III, MIM# 600740, MONDO:0010926; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.6178 ST3GAL3 Zornitza Stark Marked gene: ST3GAL3 as ready
Intellectual disability syndromic and non-syndromic v0.6178 ST3GAL3 Zornitza Stark Gene: st3gal3 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.6178 ST3GAL3 Zornitza Stark Phenotypes for gene: ST3GAL3 were changed from to Intellectual disability, autosomal recessive 12 MIM# 611090
Intellectual disability syndromic and non-syndromic v0.6177 ST3GAL3 Zornitza Stark Publications for gene: ST3GAL3 were set to
Prepair 1000+ v1.272 FANCC Lilian Downie Marked gene: FANCC as ready
Prepair 1000+ v1.272 FANCC Lilian Downie Added comment: Comment when marking as ready: Characteristic clinical features include developmental abnormalities in major organ systems, early-onset bone marrow failure, and a high predisposition to cancer. The cellular hallmark of FA is hypersensitivity to DNA crosslinking agents and high frequency of chromosomal aberrations pointing to a defect in DNA repair
Prepair 1000+ v1.272 FANCC Lilian Downie Gene: fancc has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.6176 ST3GAL3 Zornitza Stark Mode of inheritance for gene: ST3GAL3 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.272 FANCC Lilian Downie Publications for gene: FANCC were set to
Intellectual disability syndromic and non-syndromic v0.6175 ST3GAL3 Zornitza Stark reviewed gene: ST3GAL3: Rating: GREEN; Mode of pathogenicity: None; Publications: 23252400, 21907012, 31584066, 37938134; Phenotypes: Intellectual disability, autosomal recessive 12 MIM# 611090; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital Disorders of Glycosylation v1.45 ST3GAL3 Zornitza Stark Phenotypes for gene: ST3GAL3 were changed from Mental retardation, autosomal recessive 12 MIM# 611090 to Intellectual disability, autosomal recessive 12 MIM# 611090
Prepair 1000+ v1.271 KCNJ11 Lilian Downie Marked gene: KCNJ11 as ready
Prepair 1000+ v1.271 KCNJ11 Lilian Downie Added comment: Comment when marking as ready: Permanent neonatal diabetes mellitus-2 (PNDM2) is characterized by onset of insulin-requiring hyperglycemia within the first months of life that requires insulin therapy throughout life. Some patients additionally have marked developmental delay, muscle weakness, and epilepsy
Prepair 1000+ v1.271 KCNJ11 Lilian Downie Gene: kcnj11 has been classified as Green List (High Evidence).
Prepair 1000+ v1.271 KCNJ11 Lilian Downie Publications for gene: KCNJ11 were set to
Congenital Disorders of Glycosylation v1.44 ST3GAL3 Zornitza Stark edited their review of gene: ST3GAL3: Changed phenotypes: Intellectual disability, autosomal recessive 12 MIM# 611090
Prepair 1000+ v1.270 COL4A4 Lilian Downie Marked gene: COL4A4 as ready
Prepair 1000+ v1.270 COL4A4 Lilian Downie Gene: col4a4 has been classified as Green List (High Evidence).
Prepair 1000+ v1.270 COL4A4 Lilian Downie Publications for gene: COL4A4 were set to
Intellectual disability syndromic and non-syndromic v0.6175 SUCLG1 Zornitza Stark Marked gene: SUCLG1 as ready
Intellectual disability syndromic and non-syndromic v0.6175 SUCLG1 Zornitza Stark Gene: suclg1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.6175 SUCLG1 Zornitza Stark Phenotypes for gene: SUCLG1 were changed from Mitochondrial DNA depletion syndrome 9 (encephalomyopathic type with methylmalonic aciduria) MIM#245400 to Mitochondrial DNA depletion syndrome 9 (encephalomyopathic type with methylmalonic aciduria) MIM#245400
Intellectual disability syndromic and non-syndromic v0.6174 SUCLG1 Zornitza Stark Phenotypes for gene: SUCLG1 were changed from to Mitochondrial DNA depletion syndrome 9 (encephalomyopathic type with methylmalonic aciduria) MIM#245400
Prepair 1000+ v1.269 ICOS Lilian Downie Marked gene: ICOS as ready
Prepair 1000+ v1.269 ICOS Lilian Downie Gene: icos has been classified as Green List (High Evidence).
Prepair 1000+ v1.269 ICOS Lilian Downie Publications for gene: ICOS were set to
Intellectual disability syndromic and non-syndromic v0.6173 SUCLG1 Zornitza Stark Publications for gene: SUCLG1 were set to
Prepair 1000+ v1.268 ICOS Lilian Downie Tag SV/CNV tag was added to gene: ICOS.
Intellectual disability syndromic and non-syndromic v0.6172 SUCLG1 Zornitza Stark Mode of inheritance for gene: SUCLG1 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.268 ITGB2 Lilian Downie Marked gene: ITGB2 as ready
Prepair 1000+ v1.268 ITGB2 Lilian Downie Gene: itgb2 has been classified as Green List (High Evidence).
Prepair 1000+ v1.268 ITGB2 Lilian Downie Publications for gene: ITGB2 were set to
Intellectual disability syndromic and non-syndromic v0.6171 SUCLG1 Zornitza Stark Mode of inheritance for gene: SUCLG1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.6170 SUCLG1 Zornitza Stark reviewed gene: SUCLG1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33230783, 28358460; Phenotypes: Mitochondrial DNA depletion syndrome 9 (encephalomyopathic type with methylmalonic aciduria) MIM#245400; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.267 JAK3 Lilian Downie Marked gene: JAK3 as ready
Prepair 1000+ v1.267 JAK3 Lilian Downie Gene: jak3 has been classified as Green List (High Evidence).
Prepair 1000+ v1.267 JAK3 Lilian Downie Publications for gene: JAK3 were set to
Intellectual disability syndromic and non-syndromic v0.6170 SURF1 Zornitza Stark Marked gene: SURF1 as ready
Intellectual disability syndromic and non-syndromic v0.6170 SURF1 Zornitza Stark Gene: surf1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.6170 SURF1 Zornitza Stark Phenotypes for gene: SURF1 were changed from to Mitochondrial complex IV deficiency, nuclear type 1, MIM# 220110
Prepair 1000+ v1.266 LAMB1 Lilian Downie Marked gene: LAMB1 as ready
Prepair 1000+ v1.266 LAMB1 Lilian Downie Gene: lamb1 has been classified as Green List (High Evidence).
Prepair 1000+ v1.266 LAMB1 Lilian Downie Publications for gene: LAMB1 were set to
Intellectual disability syndromic and non-syndromic v0.6169 SURF1 Zornitza Stark Publications for gene: SURF1 were set to
Intellectual disability syndromic and non-syndromic v0.6168 SURF1 Zornitza Stark Mode of inheritance for gene: SURF1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.265 LGI4 Lilian Downie Marked gene: LGI4 as ready
Prepair 1000+ v1.265 LGI4 Lilian Downie Gene: lgi4 has been classified as Green List (High Evidence).
Prepair 1000+ v1.265 LGI4 Lilian Downie Publications for gene: LGI4 were set to
Intellectual disability syndromic and non-syndromic v0.6167 SURF1 Zornitza Stark reviewed gene: SURF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 9843204, 9837813; Phenotypes: Mitochondrial complex IV deficiency, nuclear type 1, MIM# 220110; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.264 CPT1A Lilian Downie Marked gene: CPT1A as ready
Prepair 1000+ v1.264 CPT1A Lilian Downie Gene: cpt1a has been classified as Green List (High Evidence).
Prepair 1000+ v1.264 CPT1A Lilian Downie Publications for gene: CPT1A were set to
Prepair 1000+ v1.263 CSTB Lilian Downie Tag for review tag was added to gene: CSTB.
Prepair 1000+ v1.263 CSTB Lilian Downie Publications for gene: CSTB were set to
Prepair 1000+ v1.262 CFH Lilian Downie Marked gene: CFH as ready
Prepair 1000+ v1.262 CFH Lilian Downie Added comment: Comment when marking as ready: This deficiency, with biallelic form can cause atypical hemolytic uremic syndrome (HUS), type II or III membranoproliferative glomerulonephritis (MPGN) and increased susceptibility to meningicoccal infection. Can be early onset and severe requiring renal transplant. Variable expression

Gene also known as HF1
Prepair 1000+ v1.262 CFH Lilian Downie Gene: cfh has been classified as Green List (High Evidence).
Limb-Girdle Muscular Dystrophy and Distal Myopathy v1.37 CAPN3 Sangavi Sivagnanasundram reviewed gene: CAPN3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: muscular dystrophy, limb-girdle, autosomal dominant MONDO:0015151, autosomal recessive limb-girdle muscular dystrophy MONDO:0015152; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1998 CAPN3 Sangavi Sivagnanasundram reviewed gene: CAPN3: Rating: GREEN; Mode of pathogenicity: Other; Publications: ; Phenotypes: muscular dystrophy, limb-girdle, autosomal dominant MONDO:0015151, autosomal recessive limb-girdle muscular dystrophy MONDO:0015152; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Limb-Girdle Muscular Dystrophy and Distal Myopathy v1.37 BVES Sangavi Sivagnanasundram reviewed gene: BVES: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: autosomal recessive limb-girdle muscular dystrophy MONDO:0015152; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1998 BVES Sangavi Sivagnanasundram reviewed gene: BVES: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: autosomal recessive limb-girdle muscular dystrophy MONDO:0015152; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary angioedema v1.5 F12 Sangavi Sivagnanasundram changed review comment from: Update to ClinGen ClinGen Hemostasis Thrombosis VCEP - classified as DEFINITIVE for this gene-disease association on 04/09/2024 - https://search.clinicalgenome.org/CCID:004793; to: Update to ClinGen Hemostasis Thrombosis VCEP - classified as DEFINITIVE for this gene-disease association on 04/09/2024 - https://search.clinicalgenome.org/CCID:004793
Hereditary angioedema v1.5 F12 Sangavi Sivagnanasundram reviewed gene: F12: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: hereditary angioedema type 3 MONDO:0012526; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Bleeding and Platelet Disorders v1.52 EPHB2 Sangavi Sivagnanasundram reviewed gene: EPHB2: Rating: AMBER; Mode of pathogenicity: None; Publications: 30213874; Phenotypes: bleeding disorder, platelet-type, 22 MONDO:0032765; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.6167 TMEM5 Zornitza Stark Tag new gene name tag was added to gene: TMEM5.
Intellectual disability syndromic and non-syndromic v0.6167 TMEM5 Zornitza Stark Marked gene: TMEM5 as ready
Intellectual disability syndromic and non-syndromic v0.6167 TMEM5 Zornitza Stark Gene: tmem5 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.6167 TMEM5 Zornitza Stark Phenotypes for gene: TMEM5 were changed from to Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 10, MIM# 615041
Intellectual disability syndromic and non-syndromic v0.6166 TMEM5 Zornitza Stark Publications for gene: TMEM5 were set to 23217329; 23519211
Intellectual disability syndromic and non-syndromic v0.6165 TMEM5 Zornitza Stark Publications for gene: TMEM5 were set to
Intellectual disability syndromic and non-syndromic v0.6164 TMEM5 Zornitza Stark Mode of inheritance for gene: TMEM5 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.6163 TMEM5 Zornitza Stark reviewed gene: TMEM5: Rating: GREEN; Mode of pathogenicity: None; Publications: 23217329, 23519211; Phenotypes: Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 10, MIM# 615041; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Renal Macrocystic Disease v0.70 ALG8 Chirag Patel edited their review of gene: ALG8: Added comment: 2023 Paper:
236 individuals identified with ALG8 protein-truncating variants. Patients were significantly at increased risk of having any kidney/liver cyst diagnosis (Odds Ratio 2.42), cystic kidney disease (OR 3.03), and nephrolithiasis (OR 1.89). ALG8 PTV heterozygotes were significantly more likely to have cystic kidney disease, defined as four or more kidney cysts (57.7% vs. 7.7%), or bilateral kidney cysts (69.2% vs. 15.4%), but not one or more liver cyst (11.5% vs. 7.7%).

ALG8 PTVs were not associated with chronic kidney disease or kidney failure in the MyCode study or the UK Biobank data. Thus, PTVs in ALG8 result in increased risk of a mild cystic kidney disease phenotype.; Changed publications: PMID: 36574950
Autoinflammatory Disorders v1.51 PTCRA Zornitza Stark Phenotypes for gene: PTCRA were changed from Autoinflammatory syndrome, MONDO:0019751, PTCRA-related to Immunodeficiency 126, MIM# 620931
Autoinflammatory Disorders v1.50 PTCRA Zornitza Stark edited their review of gene: PTCRA: Changed phenotypes: Immunodeficiency 126, MIM# 620931
Mendeliome v1.1998 PTCRA Zornitza Stark Phenotypes for gene: PTCRA were changed from Autoinflammatory syndrome, MONDO:0019751, PTCRA-related to Immunodeficiency 126, MIM# 620931
Mendeliome v1.1997 PTCRA Zornitza Stark edited their review of gene: PTCRA: Changed phenotypes: Immunodeficiency 126, MIM# 620931
Intellectual disability syndromic and non-syndromic v0.6163 TSEN2 Zornitza Stark Marked gene: TSEN2 as ready
Intellectual disability syndromic and non-syndromic v0.6163 TSEN2 Zornitza Stark Gene: tsen2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.6163 TSEN2 Zornitza Stark Phenotypes for gene: TSEN2 were changed from to Pontocerebellar hypoplasia type 2B, MIM# 612389
Intellectual disability syndromic and non-syndromic v0.6162 TSEN2 Zornitza Stark Publications for gene: TSEN2 were set to 23562994; 20952379
Intellectual disability syndromic and non-syndromic v0.6161 TSEN2 Zornitza Stark Publications for gene: TSEN2 were set to
Intellectual disability syndromic and non-syndromic v0.6160 TSEN2 Zornitza Stark Mode of inheritance for gene: TSEN2 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.6159 TSEN2 Zornitza Stark Mode of inheritance for gene: TSEN2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.6158 TSEN2 Zornitza Stark reviewed gene: TSEN2: Rating: GREEN; Mode of pathogenicity: None; Publications: 23562994, 20952379; Phenotypes: Pontocerebellar hypoplasia type 2B, MIM# 612389; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.6158 TTC19 Zornitza Stark Marked gene: TTC19 as ready
Intellectual disability syndromic and non-syndromic v0.6158 TTC19 Zornitza Stark Gene: ttc19 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.6158 TTC19 Zornitza Stark Phenotypes for gene: TTC19 were changed from to Mitochondrial complex III deficiency, nuclear type 2, MIM#615157
Intellectual disability syndromic and non-syndromic v0.6157 TTC19 Zornitza Stark Publications for gene: TTC19 were set to
Intellectual disability syndromic and non-syndromic v0.6156 TTC19 Zornitza Stark Mode of inheritance for gene: TTC19 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.6155 TTC19 Zornitza Stark changed review comment from: Mitochondrial complex III deficiency nuclear type 2 is an autosomal recessive severe neurodegenerative disorder that usually presents in childhood, but may show later onset, even in adulthood. Affected individuals have motor disability, with ataxia, apraxia, dystonia, and dysarthria, associated with necrotic lesions throughout the brain. Most patients also have cognitive impairment and axonal neuropathy and become severely disabled later in life. The disorder may present clinically as spinocerebellar ataxia or Leigh syndrome, or with psychiatric disturbances.

At least 4 unrelated families reported.; to: Mitochondrial complex III deficiency nuclear type 2 is an autosomal recessive severe neurodegenerative disorder that usually presents in childhood, but may show later onset, even in adulthood. Affected individuals have motor disability, with ataxia, apraxia, dystonia, and dysarthria, associated with necrotic lesions throughout the brain. Most patients also have cognitive impairment and axonal neuropathy and become severely disabled later in life. The disorder may present clinically as spinocerebellar ataxia or Leigh syndrome, or with psychiatric disturbances.

Included due to phenotypic overlap.

At least 4 unrelated families reported.
Intellectual disability syndromic and non-syndromic v0.6155 TTC19 Zornitza Stark reviewed gene: TTC19: Rating: GREEN; Mode of pathogenicity: None; Publications: 21278747, 23532514, 24368687, 24397319; Phenotypes: Mitochondrial complex III deficiency, nuclear type 2, MIM#615157; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.6155 TUBA1A Zornitza Stark Marked gene: TUBA1A as ready
Intellectual disability syndromic and non-syndromic v0.6155 TUBA1A Zornitza Stark Gene: tuba1a has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.6155 TUBA1A Zornitza Stark Phenotypes for gene: TUBA1A were changed from to Lissencephaly 3, MIM# 611603
Intellectual disability syndromic and non-syndromic v0.6154 TUBA1A Zornitza Stark Mode of inheritance for gene: TUBA1A was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.6153 TUBA1A Zornitza Stark reviewed gene: TUBA1A: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Lissencephaly 3, MIM# 611603; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Microcephaly v1.278 ZNRF3 Bryony Thompson Marked gene: ZNRF3 as ready
Microcephaly v1.278 ZNRF3 Bryony Thompson Gene: znrf3 has been classified as Amber List (Moderate Evidence).
Microcephaly v1.278 ZNRF3 Bryony Thompson Classified gene: ZNRF3 as Amber List (moderate evidence)
Microcephaly v1.278 ZNRF3 Bryony Thompson Gene: znrf3 has been classified as Amber List (Moderate Evidence).
Congenital Heart Defect v0.420 ZNRF3 Bryony Thompson Marked gene: ZNRF3 as ready
Congenital Heart Defect v0.420 ZNRF3 Bryony Thompson Gene: znrf3 has been classified as Amber List (Moderate Evidence).
Microcephaly v1.277 ZNRF3 Bryony Thompson gene: ZNRF3 was added
gene: ZNRF3 was added to Microcephaly. Sources: Literature
Mode of inheritance for gene: ZNRF3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ZNRF3 were set to 39168120
Phenotypes for gene: ZNRF3 were set to complex neurodevelopmental disorder MONDO:0100038
Review for gene: ZNRF3 was set to AMBER
Added comment: 12 individuals with ZNRF3 variants and various phenotypes. 8 individuals with de novo missense and neurodevelopment disorders (NDD), including cluster of variants in the RING ligase domain with macrocephalic NDD. Plus 4 individuals from 3 families with de novo truncating or de novo/inherited large in-frame deletion variants with non-NDD phenotypes, including heart, adrenal, or nephrotic problems. Overall, 4 individuals had congenital heart defects and 2 had microcephaly. Also, supporting in vitro functional assays.
Sources: Literature
Macrocephaly_Megalencephaly v0.145 ZNRF3 Bryony Thompson Marked gene: ZNRF3 as ready
Macrocephaly_Megalencephaly v0.145 ZNRF3 Bryony Thompson Gene: znrf3 has been classified as Green List (High Evidence).
Macrocephaly_Megalencephaly v0.145 ZNRF3 Bryony Thompson Classified gene: ZNRF3 as Green List (high evidence)
Macrocephaly_Megalencephaly v0.145 ZNRF3 Bryony Thompson Gene: znrf3 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.420 ZNRF3 Bryony Thompson Classified gene: ZNRF3 as Amber List (moderate evidence)
Congenital Heart Defect v0.420 ZNRF3 Bryony Thompson Gene: znrf3 has been classified as Amber List (Moderate Evidence).
Macrocephaly_Megalencephaly v0.144 ZNRF3 Bryony Thompson Classified gene: ZNRF3 as Green List (high evidence)
Macrocephaly_Megalencephaly v0.144 ZNRF3 Bryony Thompson Gene: znrf3 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.419 ZNRF3 Bryony Thompson gene: ZNRF3 was added
gene: ZNRF3 was added to Congenital Heart Defect. Sources: Literature
Mode of inheritance for gene: ZNRF3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ZNRF3 were set to 39168120
Phenotypes for gene: ZNRF3 were set to complex neurodevelopmental disorder MONDO:0100038
Review for gene: ZNRF3 was set to AMBER
Added comment: 12 individuals with ZNRF3 variants and various phenotypes. 8 individuals with de novo missense and neurodevelopment disorders (NDD), including cluster of variants in the RING ligase domain with macrocephalic NDD. Plus 4 individuals from 3 families with de novo truncating or de novo/inherited large in-frame deletion variants with non-NDD phenotypes, including heart, adrenal, or nephrotic problems. Overall, 4 individuals had congenital heart defects and 2 had microcephaly. Also, supporting in vitro functional assays.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.6153 ZNRF3 Bryony Thompson Marked gene: ZNRF3 as ready
Intellectual disability syndromic and non-syndromic v0.6153 ZNRF3 Bryony Thompson Gene: znrf3 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.6153 ZNRF3 Bryony Thompson Classified gene: ZNRF3 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.6153 ZNRF3 Bryony Thompson Gene: znrf3 has been classified as Green List (High Evidence).
Macrocephaly_Megalencephaly v0.143 ZNRF3 Bryony Thompson gene: ZNRF3 was added
gene: ZNRF3 was added to Macrocephaly_Megalencephaly. Sources: Literature
Mode of inheritance for gene: ZNRF3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ZNRF3 were set to 39168120
Phenotypes for gene: ZNRF3 were set to complex neurodevelopmental disorder MONDO:0100038
Review for gene: ZNRF3 was set to GREEN
Added comment: 12 individuals with ZNRF3 variants and various phenotypes. 8 individuals with de novo missense and neurodevelopment disorders (NDD), including cluster of variants in the RING ligase domain with macrocephalic NDD. Plus 4 individuals from 3 families with de novo truncating or de novo/inherited large in-frame deletion variants with non-NDD phenotypes, including heart, adrenal, or nephrotic problems. Overall, 4 individuals had congenital heart defects and 2 had microcephaly. Also, supporting in vitro functional assays.
Sources: Literature
Mendeliome v1.1997 ZNRF3 Bryony Thompson Marked gene: ZNRF3 as ready
Mendeliome v1.1997 ZNRF3 Bryony Thompson Gene: znrf3 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.6152 ZNRF3 Bryony Thompson gene: ZNRF3 was added
gene: ZNRF3 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: ZNRF3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ZNRF3 were set to 39168120
Phenotypes for gene: ZNRF3 were set to Complex neurodevelopmental disorder MONDO:0100038
Review for gene: ZNRF3 was set to GREEN
Added comment: 12 individuals with ZNRF3 variants and various phenotypes. 8 individuals with de novo missense and neurodevelopment disorders (NDD), including cluster of variants in the RING ligase domain with macrocephalic NDD. Plus 4 individuals from 3 families with de novo truncating or de novo/inherited large in-frame deletion variants with non-NDD phenotypes, including heart, adrenal, or nephrotic problems. Overall, 4 individuals had congenital heart defects and 2 had microcephaly. Also, supporting in vitro functional assays.
Sources: Literature
Mendeliome v1.1997 ZNRF3 Bryony Thompson Classified gene: ZNRF3 as Green List (high evidence)
Mendeliome v1.1997 ZNRF3 Bryony Thompson Gene: znrf3 has been classified as Green List (High Evidence).
Mendeliome v1.1996 ZNRF3 Bryony Thompson gene: ZNRF3 was added
gene: ZNRF3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ZNRF3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ZNRF3 were set to 39168120
Phenotypes for gene: ZNRF3 were set to complex neurodevelopmental disorder MONDO:0100038
Review for gene: ZNRF3 was set to GREEN
Added comment: 12 individuals with ZNRF3 variants and various phenotypes. 8 individuals with de novo missense and neurodevelopment disorders (NDD), including cluster of variants in the RING ligase domain with macrocephalic NDD. Plus 4 individuals from 3 families with de novo truncating or de novo/inherited large in-frame deletion variants with non-NDD phenotypes, including heart, adrenal, or nephrotic problems. Overall, 4 individuals had congenital heart defects and 2 had microcephaly. Also, supporting in vitro functional assays.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.6151 NFIA Zornitza Stark Marked gene: NFIA as ready
Intellectual disability syndromic and non-syndromic v0.6151 NFIA Zornitza Stark Gene: nfia has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.6151 DHTKD1 Zornitza Stark Marked gene: DHTKD1 as ready
Intellectual disability syndromic and non-syndromic v0.6151 DHTKD1 Zornitza Stark Gene: dhtkd1 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.6151 DHTKD1 Zornitza Stark Phenotypes for gene: DHTKD1 were changed from to 2-aminoadipic 2-oxoadipic aciduria MIM#204750; Disorders of histidine, tryptophan or lysine metabolism
Intellectual disability syndromic and non-syndromic v0.6150 DHTKD1 Zornitza Stark Publications for gene: DHTKD1 were set to
Intellectual disability syndromic and non-syndromic v0.6149 DHTKD1 Zornitza Stark Mode of inheritance for gene: DHTKD1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.6148 DHTKD1 Zornitza Stark Classified gene: DHTKD1 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.6148 DHTKD1 Zornitza Stark Gene: dhtkd1 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.6147 DCX Zornitza Stark Marked gene: DCX as ready
Intellectual disability syndromic and non-syndromic v0.6147 DCX Zornitza Stark Gene: dcx has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.6147 DCX Zornitza Stark Phenotypes for gene: DCX were changed from to Lissencephaly, X-linked, MIM# 300067; Subcortical laminal heterotopia, X-linked 300067
Intellectual disability syndromic and non-syndromic v0.6146 DCX Zornitza Stark Publications for gene: DCX were set to 26743950; 11468322; 20726879; 20301364; 12552055; 9489699
Intellectual disability syndromic and non-syndromic v0.6145 DCX Zornitza Stark Publications for gene: DCX were set to
Intellectual disability syndromic and non-syndromic v0.6144 DCX Zornitza Stark Mode of inheritance for gene: DCX was changed from Unknown to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Intellectual disability syndromic and non-syndromic v0.6143 DARS2 Zornitza Stark Marked gene: DARS2 as ready
Intellectual disability syndromic and non-syndromic v0.6143 DARS2 Zornitza Stark Gene: dars2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.6143 DARS2 Zornitza Stark Phenotypes for gene: DARS2 were changed from to Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation, MIM# 611105
Intellectual disability syndromic and non-syndromic v0.6142 DARS2 Zornitza Stark Publications for gene: DARS2 were set to
Intellectual disability syndromic and non-syndromic v0.6141 DARS2 Zornitza Stark Mode of inheritance for gene: DARS2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.6140 D2HGDH Zornitza Stark Marked gene: D2HGDH as ready
Intellectual disability syndromic and non-syndromic v0.6140 D2HGDH Zornitza Stark Gene: d2hgdh has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.6140 D2HGDH Zornitza Stark Phenotypes for gene: D2HGDH were changed from to D-2-hydroxyglutaric aciduria MIM#600721
Intellectual disability syndromic and non-syndromic v0.6139 D2HGDH Zornitza Stark Publications for gene: D2HGDH were set to
Prepair 1000+ v1.262 CFH Cassandra Muller reviewed gene: CFH: Rating: AMBER; Mode of pathogenicity: None; Publications: 7742208, 9312129, 10803850, 14978182; Phenotypes: Complement factor H deficiency, 609814 (3); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.6138 D2HGDH Zornitza Stark Mode of inheritance for gene: D2HGDH was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.6137 D2HGDH Zornitza Stark Mode of inheritance for gene: D2HGDH was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.6136 COX15 Zornitza Stark Phenotypes for gene: COX15 were changed from Mitochondrial complex IV deficiency, nuclear type 6, MIM# 615119 to Mitochondrial complex IV deficiency, nuclear type 6, MIM# 615119
Intellectual disability syndromic and non-syndromic v0.6136 COX15 Zornitza Stark Marked gene: COX15 as ready
Intellectual disability syndromic and non-syndromic v0.6136 COX15 Zornitza Stark Gene: cox15 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.6136 COX15 Zornitza Stark Phenotypes for gene: COX15 were changed from Mitochondrial complex IV deficiency, nuclear type 6, MIM# 615119 to Mitochondrial complex IV deficiency, nuclear type 6, MIM# 615119
Intellectual disability syndromic and non-syndromic v0.6135 COX15 Zornitza Stark Phenotypes for gene: COX15 were changed from to Mitochondrial complex IV deficiency, nuclear type 6, MIM# 615119
Prepair 1000+ v1.262 CSTB Cassandra Muller reviewed gene: CSTB: Rating: AMBER; Mode of pathogenicity: None; Publications: 9012407; Phenotypes: Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg), 254800 (3); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1995 RFC4 Chirag Patel Classified gene: RFC4 as Green List (high evidence)
Mendeliome v1.1995 RFC4 Chirag Patel Gene: rfc4 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.6134 GPN2 Mark Cleghorn gene: GPN2 was added
gene: GPN2 was added to Intellectual disability syndromic and non-syndromic. Sources: Other
Mode of inheritance for gene: GPN2 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: GPN2 were set to complex neurodevelopmental disorder MONDO:0100038; Perrault syndrome
Review for gene: GPN2 was set to AMBER
Added comment: GPN2
ESHG talk 2/6/24, unpublished
Thomas Smith, University of Manchester

Biallelic GPN2 proposed to cause Perrault syndrome (SNHL, ovarian dysfunction, NDD)
RNA polymerase assembly factor

4 families (14 affected individuals) w biallalic GPN2 rare missense variants
Segregated w phenotype
Fam 2 and 3 may be distantly related (leaving 3 distinct kindreds)

Clinical features
13/14 SNHL
3/4 families all females of adolescent age or older had primary ovarian insufficiency
4/4 GDD, ataxia (no data on family w 10 affected indiv.)

Some functional work, not conclusive
Sources: Other
Mendeliome v1.1994 ATP6V1C1 Zornitza Stark Marked gene: ATP6V1C1 as ready
Mendeliome v1.1994 ATP6V1C1 Zornitza Stark Gene: atp6v1c1 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.6134 ATP6V1C1 Zornitza Stark Marked gene: ATP6V1C1 as ready
Intellectual disability syndromic and non-syndromic v0.6134 ATP6V1C1 Zornitza Stark Gene: atp6v1c1 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.6134 ATP6V1C1 Zornitza Stark gene: ATP6V1C1 was added
gene: ATP6V1C1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: ATP6V1C1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ATP6V1C1 were set to 39210597
Phenotypes for gene: ATP6V1C1 were set to neurodevelopmental disorder MONDO:0700092, ATP6V1C1-related
Review for gene: ATP6V1C1 was set to RED
Added comment: 1x de novo missense p.Glu289Lys (absent in v4 gnomad). Manual inspection of IGV found the dad was mosaic 7% VAF and he shared some of the clinical features (minor digit anomalies). Some functional studies using patient fibroblasts were performed, demonstrating similar effects as known pathogenic variants in ATP6V1B2. - lysosomal morphology - autophagic flux dysregulation - increased acidification of lysosome borderline red/amber
Sources: Literature
Mendeliome v1.1994 ATP6V1C1 Zornitza Stark Phenotypes for gene: ATP6V1C1 were changed from to neurodevelopmental disorder MONDO:0700092, ATP6V1C1-related
Intellectual disability syndromic and non-syndromic v0.6133 C12orf66 Zornitza Stark Marked gene: C12orf66 as ready
Intellectual disability syndromic and non-syndromic v0.6133 C12orf66 Zornitza Stark Gene: c12orf66 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.6133 C12orf66 Zornitza Stark Classified gene: C12orf66 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.6133 C12orf66 Zornitza Stark Gene: c12orf66 has been classified as Green List (High Evidence).
Mendeliome v1.1993 C12orf66 Zornitza Stark Marked gene: C12orf66 as ready
Mendeliome v1.1993 C12orf66 Zornitza Stark Gene: c12orf66 has been classified as Green List (High Evidence).
Mendeliome v1.1993 C12orf66 Zornitza Stark Classified gene: C12orf66 as Green List (high evidence)
Mendeliome v1.1993 C12orf66 Zornitza Stark Gene: c12orf66 has been classified as Green List (High Evidence).
Mendeliome v1.1992 RFC4 Chirag Patel gene: RFC4 was added
gene: RFC4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RFC4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RFC4 were set to PMID: 39106866
Phenotypes for gene: RFC4 were set to RFC4-related multisystem disorder
Review for gene: RFC4 was set to GREEN
gene: RFC4 was marked as current diagnostic
Added comment: 9 affected individuals (aged birth to 47yrs) from 8 unrelated families with a multisystem disorder. Clinical features included: muscle weakness/myopathy (9/9), motor incoordination/gait disturbance (8/8), delayed gross motor development (6/9), dysarthria (5/5), peripheral neuropathy (3/3 adults), bilateral sensorineural hearing impairment (6/9), decreased body weight (8/9), short stature (5/9), microcephaly (4/9), respiratory issues/insufficiency (6/9), cerebellar atrophy (4/9), pituitary hypoplasia (3/9).

WES or WGS identified biallelic loss-of-function variants in RFC4 (3 frameshift, 2 splice site, 1 single AA duplication, 2 single AA deletions, 2 missense), and almost all are likely to disrupt the C-terminal domain indispensable for Replication factor C (RFC) complex formation. All variants segregated with the disease.

The RFC complex (with 5 subunits) is central to process of regulation of DNA replication, and it loads proliferating cell nuclear antigen onto DNA to facilitate the recruitment of replication and repair proteins and enhance DNA polymerase processivity. RFC1 is associated with CANVAS but the contributions of RFC2-5 subunits on human Mendelian disorders is unknown.

Analysis of a previously determined cryo-EM structure of RFC bound to proliferating cell nuclear antigen suggested that the variants disrupt interactions within RFC4 and/or destabilize the RFC complex. Cellular studies using RFC4-deficient HeLa cells and primary fibroblasts demonstrated decreased RFC4 protein, compromised stability of the other RFC complex subunits, and perturbed RFC complex formation. Additionally, functional studies of the RFC4 variants affirmed diminished RFC complex formation, and cell cycle studies suggested perturbation of DNA replication and cell cycle progression.
Sources: Literature
Mendeliome v1.1991 COQ8B Zornitza Stark Phenotypes for gene: COQ8B were changed from Nephrotic syndrome, type 9 MIM#615573 to Nephrotic syndrome, type 9 MIM#615573; Retinitis pigmentosa MONDO:0019200
Mendeliome v1.1990 COQ8B Zornitza Stark Publications for gene: COQ8B were set to 24270420
Mendeliome v1.1989 SF3B1 Zornitza Stark Classified gene: SF3B1 as Green List (high evidence)
Mendeliome v1.1989 SF3B1 Zornitza Stark Gene: sf3b1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.6132 SF3B1 Zornitza Stark Marked gene: SF3B1 as ready
Intellectual disability syndromic and non-syndromic v0.6132 SF3B1 Zornitza Stark Gene: sf3b1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.6132 SF3B1 Zornitza Stark Classified gene: SF3B1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.6132 SF3B1 Zornitza Stark Gene: sf3b1 has been classified as Green List (High Evidence).
Mendeliome v1.1988 SF3B1 Zornitza Stark Marked gene: SF3B1 as ready
Mendeliome v1.1988 SF3B1 Zornitza Stark Gene: sf3b1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1988 SF3B1 Zornitza Stark Classified gene: SF3B1 as Amber List (moderate evidence)
Mendeliome v1.1988 SF3B1 Zornitza Stark Gene: sf3b1 has been classified as Amber List (Moderate Evidence).
Muscular dystrophy and myopathy_Paediatric v1.70 JPH1 Zornitza Stark Classified gene: JPH1 as Green List (high evidence)
Muscular dystrophy and myopathy_Paediatric v1.70 JPH1 Zornitza Stark Gene: jph1 has been classified as Green List (High Evidence).
Muscular dystrophy and myopathy_Paediatric v1.70 JPH1 Zornitza Stark Classified gene: JPH1 as Green List (high evidence)
Muscular dystrophy and myopathy_Paediatric v1.70 JPH1 Zornitza Stark Gene: jph1 has been classified as Green List (High Evidence).
Mendeliome v1.1987 JPH1 Zornitza Stark Marked gene: JPH1 as ready
Mendeliome v1.1987 JPH1 Zornitza Stark Gene: jph1 has been classified as Green List (High Evidence).
Mendeliome v1.1987 JPH1 Zornitza Stark Classified gene: JPH1 as Green List (high evidence)
Mendeliome v1.1987 JPH1 Zornitza Stark Gene: jph1 has been classified as Green List (High Evidence).
Muscular dystrophy and myopathy_Paediatric v1.70 RFC4 Chirag Patel Classified gene: RFC4 as Green List (high evidence)
Muscular dystrophy and myopathy_Paediatric v1.70 RFC4 Chirag Patel Gene: rfc4 has been classified as Green List (High Evidence).
Muscular dystrophy and myopathy_Paediatric v1.70 JPH1 Zornitza Stark Marked gene: JPH1 as ready
Muscular dystrophy and myopathy_Paediatric v1.70 JPH1 Zornitza Stark Gene: jph1 has been classified as Green List (High Evidence).
Muscular dystrophy and myopathy_Paediatric v1.70 JPH1 Zornitza Stark Classified gene: JPH1 as Green List (high evidence)
Muscular dystrophy and myopathy_Paediatric v1.70 JPH1 Zornitza Stark Gene: jph1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.6131 RFC4 Chirag Patel Classified gene: RFC4 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.6131 RFC4 Chirag Patel Gene: rfc4 has been classified as Green List (High Evidence).
Deafness_IsolatedAndComplex v1.198 RFC4 Chirag Patel Classified gene: RFC4 as Green List (high evidence)
Deafness_IsolatedAndComplex v1.198 RFC4 Chirag Patel Gene: rfc4 has been classified as Green List (High Evidence).
Muscular dystrophy and myopathy_Paediatric v1.69 RFC4 Chirag Patel Classified gene: RFC4 as Green List (high evidence)
Muscular dystrophy and myopathy_Paediatric v1.69 RFC4 Chirag Patel Gene: rfc4 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.6131 RFC4 Chirag Patel Classified gene: RFC4 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.6131 RFC4 Chirag Patel Gene: rfc4 has been classified as Green List (High Evidence).
Deafness_IsolatedAndComplex v1.198 RFC4 Chirag Patel Classified gene: RFC4 as Green List (high evidence)
Deafness_IsolatedAndComplex v1.198 RFC4 Chirag Patel Gene: rfc4 has been classified as Green List (High Evidence).
Muscular dystrophy and myopathy_Paediatric v1.69 RFC4 Chirag Patel Classified gene: RFC4 as Green List (high evidence)
Muscular dystrophy and myopathy_Paediatric v1.69 RFC4 Chirag Patel Gene: rfc4 has been classified as Green List (High Evidence).
Congenital diaphragmatic hernia v1.16 MED12 Zornitza Stark Marked gene: MED12 as ready
Congenital diaphragmatic hernia v1.16 MED12 Zornitza Stark Gene: med12 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.6130 MED22 Zornitza Stark Marked gene: MED22 as ready
Intellectual disability syndromic and non-syndromic v0.6130 MED22 Zornitza Stark Gene: med22 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.6130 MED22 Zornitza Stark Classified gene: MED22 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.6130 MED22 Zornitza Stark Gene: med22 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1986 MED22 Zornitza Stark Marked gene: MED22 as ready
Mendeliome v1.1986 MED22 Zornitza Stark Gene: med22 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1986 MED22 Zornitza Stark Classified gene: MED22 as Amber List (moderate evidence)
Mendeliome v1.1986 MED22 Zornitza Stark Gene: med22 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.6129 LARP1 Zornitza Stark Marked gene: LARP1 as ready
Intellectual disability syndromic and non-syndromic v0.6129 LARP1 Zornitza Stark Gene: larp1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.6129 LARP1 Zornitza Stark Classified gene: LARP1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.6129 LARP1 Zornitza Stark Gene: larp1 has been classified as Green List (High Evidence).
Mendeliome v1.1985 LARP1 Zornitza Stark Marked gene: LARP1 as ready
Mendeliome v1.1985 LARP1 Zornitza Stark Gene: larp1 has been classified as Green List (High Evidence).
Mendeliome v1.1985 LARP1 Zornitza Stark Classified gene: LARP1 as Green List (high evidence)
Mendeliome v1.1985 LARP1 Zornitza Stark Gene: larp1 has been classified as Green List (High Evidence).
Autism v0.199 LARP1 Zornitza Stark Marked gene: LARP1 as ready
Autism v0.199 LARP1 Zornitza Stark Gene: larp1 has been classified as Green List (High Evidence).
Autism v0.199 LARP1 Zornitza Stark Classified gene: LARP1 as Green List (high evidence)
Autism v0.199 LARP1 Zornitza Stark Gene: larp1 has been classified as Green List (High Evidence).
Hereditary Spastic Paraplegia - paediatric v1.83 PNPLA8 Zornitza Stark Marked gene: PNPLA8 as ready
Hereditary Spastic Paraplegia - paediatric v1.83 PNPLA8 Zornitza Stark Gene: pnpla8 has been classified as Green List (High Evidence).
Hereditary Spastic Paraplegia - paediatric v1.83 PNPLA8 Zornitza Stark Phenotypes for gene: PNPLA8 were changed from PNPLA8-related neurological diseases to Complex neurodevelopmental disorder, MONDO:0100038, PNPLA8-related
Intellectual disability syndromic and non-syndromic v0.6128 PNPLA8 Zornitza Stark Marked gene: PNPLA8 as ready
Intellectual disability syndromic and non-syndromic v0.6128 PNPLA8 Zornitza Stark Gene: pnpla8 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.6128 PNPLA8 Zornitza Stark Phenotypes for gene: PNPLA8 were changed from PNPLA8-related neurological diseases to Complex neurodevelopmental disorder, MONDO:0100038, PNPLA8-related
Mitochondrial disease v0.929 PNPLA8 Zornitza Stark Phenotypes for gene: PNPLA8 were changed from Complex neurodevelopmental disorder, MONDO:0100038, PNPLA8-related; Mitochondrial myopathy with lactic acidosis (MIM#251950), AR to Complex neurodevelopmental disorder, MONDO:0100038, PNPLA8-related; Mitochondrial myopathy with lactic acidosis (MIM#251950), AR
Mitochondrial disease v0.928 PNPLA8 Zornitza Stark Phenotypes for gene: PNPLA8 were changed from Mitochondrial myopathy with lactic acidosis (MIM#251950), AR to Complex neurodevelopmental disorder, MONDO:0100038, PNPLA8-related; Mitochondrial myopathy with lactic acidosis (MIM#251950), AR
Genetic Epilepsy v1.53 PNPLA8 Zornitza Stark Marked gene: PNPLA8 as ready
Genetic Epilepsy v1.53 PNPLA8 Zornitza Stark Gene: pnpla8 has been classified as Green List (High Evidence).
Genetic Epilepsy v1.53 PNPLA8 Zornitza Stark Phenotypes for gene: PNPLA8 were changed from Complex neurodevelopmental disorder, MONDO:0100038, PNPLA8-related to Complex neurodevelopmental disorder, MONDO:0100038, PNPLA8-related
Genetic Epilepsy v1.52 PNPLA8 Zornitza Stark Phenotypes for gene: PNPLA8 were changed from PNPLA8-related neurological diseases to Complex neurodevelopmental disorder, MONDO:0100038, PNPLA8-related
Cerebellar and Pontocerebellar Hypoplasia v1.70 RFC4 Chirag Patel Classified gene: RFC4 as Green List (high evidence)
Cerebellar and Pontocerebellar Hypoplasia v1.70 RFC4 Chirag Patel Gene: rfc4 has been classified as Green List (High Evidence).
Microcephaly v1.276 PNPLA8 Zornitza Stark Marked gene: PNPLA8 as ready
Microcephaly v1.276 PNPLA8 Zornitza Stark Gene: pnpla8 has been classified as Green List (High Evidence).
Microcephaly v1.276 PNPLA8 Zornitza Stark Phenotypes for gene: PNPLA8 were changed from PNPLA8-related neurological diseases to Complex neurodevelopmental disorder, MONDO:0100038, PNPLA8-related
Mendeliome v1.1984 PNPLA8 Zornitza Stark Phenotypes for gene: PNPLA8 were changed from Mitochondrial myopathy with lactic acidosis (MIM#251950), AR to Complex neurodevelopmental disorder, MONDO:0100038, PNPLA8-related; Mitochondrial myopathy with lactic acidosis (MIM#251950), AR
Cerebellar and Pontocerebellar Hypoplasia v1.69 PNPLA8 Zornitza Stark Marked gene: PNPLA8 as ready
Cerebellar and Pontocerebellar Hypoplasia v1.69 PNPLA8 Zornitza Stark Gene: pnpla8 has been classified as Green List (High Evidence).
Cerebellar and Pontocerebellar Hypoplasia v1.69 PNPLA8 Zornitza Stark Phenotypes for gene: PNPLA8 were changed from Complex neurodevelopmental disorder, MONDO:0100038, PNPLA8-related to Complex neurodevelopmental disorder, MONDO:0100038, PNPLA8-related
Cerebellar and Pontocerebellar Hypoplasia v1.69 PNPLA8 Zornitza Stark Phenotypes for gene: PNPLA8 were changed from PNPLA8-related neurological diseases to Complex neurodevelopmental disorder, MONDO:0100038, PNPLA8-related
Dystonia - complex v0.238 PNPLA8 Zornitza Stark Marked gene: PNPLA8 as ready
Dystonia - complex v0.238 PNPLA8 Zornitza Stark Gene: pnpla8 has been classified as Green List (High Evidence).
Dystonia - complex v0.238 PNPLA8 Zornitza Stark Phenotypes for gene: PNPLA8 were changed from PNPLA8-related neurological diseases to Complex neurodevelopmental disorder, MONDO:0100038, PNPLA8-related
Cerebellar and Pontocerebellar Hypoplasia v1.68 RFC4 Chirag Patel gene: RFC4 was added
gene: RFC4 was added to Cerebellar and Pontocerebellar Hypoplasia. Sources: Literature
Mode of inheritance for gene: RFC4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RFC4 were set to PMID: 39106866
Phenotypes for gene: RFC4 were set to RFC4-related multisystem disorder
Review for gene: RFC4 was set to GREEN
gene: RFC4 was marked as current diagnostic
Added comment: 9 affected individuals (aged birth to 47yrs) from 8 unrelated families with a multisystem disorder. Clinical features included: muscle weakness/myopathy (9/9), motor incoordination/gait disturbance (8/8), delayed gross motor development (6/9), dysarthria (5/5), peripheral neuropathy (3/3 adults), bilateral sensorineural hearing impairment (6/9), decreased body weight (8/9), short stature (5/9), microcephaly (4/9), respiratory issues/insufficiency (6/9), cerebellar atrophy (4/9), pituitary hypoplasia (3/9).

WES or WGS identified biallelic loss-of-function variants in RFC4 (3 frameshift, 2 splice site, 1 single AA duplication, 2 single AA deletions, 2 missense), and almost all are likely to disrupt the C-terminal domain indispensable for Replication factor C (RFC) complex formation. All variants segregated with the disease.

The RFC complex (with 5 subunits) is central to process of regulation of DNA replication, and it loads proliferating cell nuclear antigen onto DNA to facilitate the recruitment of replication and repair proteins and enhance DNA polymerase processivity. RFC1 is associated with CANVAS but the contributions of RFC2-5 subunits on human Mendelian disorders is unknown.

Analysis of a previously determined cryo-EM structure of RFC bound to proliferating cell nuclear antigen suggested that the variants disrupt interactions within RFC4 and/or destabilize the RFC complex. Cellular studies using RFC4-deficient HeLa cells and primary fibroblasts demonstrated decreased RFC4 protein, compromised stability of the other RFC complex subunits, and perturbed RFC complex formation. Additionally, functional studies of the RFC4 variants affirmed diminished RFC complex formation, and cell cycle studies suggested perturbation of DNA replication and cell cycle progression.
Sources: Literature
Deafness_IsolatedAndComplex v1.197 RFC4 Chirag Patel gene: RFC4 was added
gene: RFC4 was added to Deafness_IsolatedAndComplex. Sources: Literature
Mode of inheritance for gene: RFC4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RFC4 were set to PMID: 39106866
Phenotypes for gene: RFC4 were set to RFC4-related multisystem disorder
Review for gene: RFC4 was set to GREEN
gene: RFC4 was marked as current diagnostic
Added comment: 9 affected individuals (aged birth to 47yrs) from 8 unrelated families with a multisystem disorder. Clinical features included: muscle weakness/myopathy (9/9), motor incoordination/gait disturbance (8/8), delayed gross motor development (6/9), dysarthria (5/5), peripheral neuropathy (3/3 adults), bilateral sensorineural hearing impairment (6/9), decreased body weight (8/9), short stature (5/9), microcephaly (4/9), respiratory issues/insufficiency (6/9), cerebellar atrophy (4/9), pituitary hypoplasia (3/9).

WES or WGS identified biallelic loss-of-function variants in RFC4 (3 frameshift, 2 splice site, 1 single AA duplication, 2 single AA deletions, 2 missense), and almost all are likely to disrupt the C-terminal domain indispensable for Replication factor C (RFC) complex formation. All variants segregated with the disease.

The RFC complex (with 5 subunits) is central to process of regulation of DNA replication, and it loads proliferating cell nuclear antigen onto DNA to facilitate the recruitment of replication and repair proteins and enhance DNA polymerase processivity. RFC1 is associated with CANVAS but the contributions of RFC2-5 subunits on human Mendelian disorders is unknown.

Analysis of a previously determined cryo-EM structure of RFC bound to proliferating cell nuclear antigen suggested that the variants disrupt interactions within RFC4 and/or destabilize the RFC complex. Cellular studies using RFC4-deficient HeLa cells and primary fibroblasts demonstrated decreased RFC4 protein, compromised stability of the other RFC complex subunits, and perturbed RFC complex formation. Additionally, functional studies of the RFC4 variants affirmed diminished RFC complex formation, and cell cycle studies suggested perturbation of DNA replication and cell cycle progression.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.6127 RFC4 Chirag Patel gene: RFC4 was added
gene: RFC4 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: RFC4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RFC4 were set to PMID: 39106866
Phenotypes for gene: RFC4 were set to RFC4-related multisystem disorder
Review for gene: RFC4 was set to GREEN
gene: RFC4 was marked as current diagnostic
Added comment: 9 affected individuals (aged birth to 47yrs) from 8 unrelated families with a multisystem disorder. Clinical features included: muscle weakness/myopathy (9/9), motor incoordination/gait disturbance (8/8), delayed gross motor development (6/9), dysarthria (5/5), peripheral neuropathy (3/3 adults), bilateral sensorineural hearing impairment (6/9), decreased body weight (8/9), short stature (5/9), microcephaly (4/9), respiratory issues/insufficiency (6/9), cerebellar atrophy (4/9), pituitary hypoplasia (3/9).

WES or WGS identified biallelic loss-of-function variants in RFC4 (3 frameshift, 2 splice site, 1 single AA duplication, 2 single AA deletions, 2 missense), and almost all are likely to disrupt the C-terminal domain indispensable for Replication factor C (RFC) complex formation. All variants segregated with the disease.

The RFC complex (with 5 subunits) is central to process of regulation of DNA replication, and it loads proliferating cell nuclear antigen onto DNA to facilitate the recruitment of replication and repair proteins and enhance DNA polymerase processivity. RFC1 is associated with CANVAS but the contributions of RFC2-5 subunits on human Mendelian disorders is unknown.

Analysis of a previously determined cryo-EM structure of RFC bound to proliferating cell nuclear antigen suggested that the variants disrupt interactions within RFC4 and/or destabilize the RFC complex. Cellular studies using RFC4-deficient HeLa cells and primary fibroblasts demonstrated decreased RFC4 protein, compromised stability of the other RFC complex subunits, and perturbed RFC complex formation. Additionally, functional studies of the RFC4 variants affirmed diminished RFC complex formation, and cell cycle studies suggested perturbation of DNA replication and cell cycle progression.
Sources: Literature
Muscular dystrophy and myopathy_Paediatric v1.68 RFC4 Chirag Patel gene: RFC4 was added
gene: RFC4 was added to Muscular dystrophy and myopathy_Paediatric. Sources: Literature
Mode of inheritance for gene: RFC4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RFC4 were set to PMID: 39106866
Phenotypes for gene: RFC4 were set to RFC4-related multisystem disorder
Review for gene: RFC4 was set to GREEN
gene: RFC4 was marked as current diagnostic
Added comment: 9 affected individuals (aged birth to 47yrs) from 8 unrelated families with a multisystem disorder. Clinical features included: muscle weakness/myopathy (9/9), motor incoordination/gait disturbance (8/8), delayed gross motor development (6/9), dysarthria (5/5), peripheral neuropathy (3/3 adults), bilateral sensorineural hearing impairment (6/9), decreased body weight (8/9), short stature (5/9), microcephaly (4/9), respiratory issues/insufficiency (6/9), cerebellar atrophy (4/9), pituitary hypoplasia (3/9).

WES or WGS identified biallelic loss-of-function variants in RFC4 (3 frameshift, 2 splice site, 1 single AA duplication, 2 single AA deletions, 2 missense), and almost all are likely to disrupt the C-terminal domain indispensable for Replication factor C (RFC) complex formation. All variants segregated with the disease.

The RFC complex (with 5 subunits) is central to process of regulation of DNA replication, and it loads proliferating cell nuclear antigen onto DNA to facilitate the recruitment of replication and repair proteins and enhance DNA polymerase processivity. RFC1 is associated with CANVAS but the contributions of RFC2-5 subunits on human Mendelian disorders is unknown.

Analysis of a previously determined cryo-EM structure of RFC bound to proliferating cell nuclear antigen suggested that the variants disrupt interactions within RFC4 and/or destabilize the RFC complex. Cellular studies using RFC4-deficient HeLa cells and primary fibroblasts demonstrated decreased RFC4 protein, compromised stability of the other RFC complex subunits, and perturbed RFC complex formation. Additionally, functional studies of the RFC4 variants affirmed diminished RFC complex formation, and cell cycle studies suggested perturbation of DNA replication and cell cycle progression.
Sources: Literature
Mendeliome v1.1983 SPARCL1 Zornitza Stark Marked gene: SPARCL1 as ready
Mendeliome v1.1983 SPARCL1 Zornitza Stark Gene: sparcl1 has been classified as Red List (Low Evidence).
Mendeliome v1.1983 SPARCL1 Zornitza Stark gene: SPARCL1 was added
gene: SPARCL1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SPARCL1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SPARCL1 were set to 39169229
Phenotypes for gene: SPARCL1 were set to Corneal dystrophy, MONDO:0018102
Review for gene: SPARCL1 was set to RED
Added comment: 8 affected individuals with corneal dystrophy from 1 family (3 generations). Affected individuals had diffuse central stromal opacity, with reduced visual acuity in older family members. Histopathology of affected cornea tissue revealed mild stromal textural alterations with alcianophilic deposits.

WGS from 4 affected individuals in family identified a novel heterozygous missense variant in exon 4 of SPARCL1 (c.334G > A; p.(Glu112Lys)) which segregated with disease.

SPARC-like protein 1 (SPARCL1) is a secreted matricellular protein involved in cell migration, cell adhesion, tissue repair, and remodelling. SPARCL1 has been shown to regulate decorin. Heterozygous variants in DCN, encoding decorin, cause autosomal dominant congenital stromal corneal dystrophy, suggesting a common pathogenic pathway. Immunohistochemistry showed the level of decorin was significantly decreased in the corneal stroma of the affected tissue, and SPARCL1 appeared to be retained in the epithelium.
Sources: Literature
Corneal Dystrophy v1.11 SPARCL1 Zornitza Stark Marked gene: SPARCL1 as ready
Corneal Dystrophy v1.11 SPARCL1 Zornitza Stark Gene: sparcl1 has been classified as Red List (Low Evidence).
Optic Atrophy v1.37 NDUFA7 Zornitza Stark Classified gene: NDUFA7 as Red List (low evidence)
Optic Atrophy v1.37 NDUFA7 Zornitza Stark Gene: ndufa7 has been classified as Red List (Low Evidence).
Mendeliome v1.1982 NDUFA7 Zornitza Stark Phenotypes for gene: NDUFA7 were changed from to Optic atrophy, MONDO:0003608, NDUFA7-related
Optic Atrophy v1.36 NDUFA7 Zornitza Stark Classified gene: NDUFA7 as Red List (low evidence)
Optic Atrophy v1.36 NDUFA7 Zornitza Stark Gene: ndufa7 has been classified as Red List (Low Evidence).
Prepair 1000+ v1.262 CPT1A Cassandra Muller reviewed gene: CPT1A: Rating: GREEN; Mode of pathogenicity: None; Publications: 12189492, 25778941, 23430932; Phenotypes: CPT deficiency, hepatic, type IA, 255120 (3); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1981 NDUFA7 Zornitza Stark Mode of inheritance for gene: NDUFA7 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Optic Atrophy v1.35 NDUFA7 Zornitza Stark reviewed gene: NDUFA7: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Optic atrophy, MONDO:0003608, NDUFA7-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1980 NDUFA7 Zornitza Stark edited their review of gene: NDUFA7: Changed rating: RED
Mendeliome v1.1980 NDUFA7 Zornitza Stark reviewed gene: NDUFA7: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Optic atrophy, MONDO:0003608, NDUFA7-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Optic Atrophy v1.35 NDUFA7 Zornitza Stark Marked gene: NDUFA7 as ready
Optic Atrophy v1.35 NDUFA7 Zornitza Stark Gene: ndufa7 has been classified as Amber List (Moderate Evidence).
Optic Atrophy v1.35 NDUFA7 Zornitza Stark Phenotypes for gene: NDUFA7 were changed from Leber Hereditary Optic Neuropathy, MIM#619382 to Optic atrophy, MONDO:0003608, NDUFA7-related
Optic Atrophy v1.34 NDUFA7 Zornitza Stark Classified gene: NDUFA7 as Amber List (moderate evidence)
Optic Atrophy v1.34 NDUFA7 Zornitza Stark Gene: ndufa7 has been classified as Amber List (Moderate Evidence).
Optic Atrophy v1.33 NDUFA7 Zornitza Stark Classified gene: NDUFA7 as Amber List (moderate evidence)
Optic Atrophy v1.33 NDUFA7 Zornitza Stark Gene: ndufa7 has been classified as Amber List (Moderate Evidence).
Hyperinsulinism v1.30 MAGEL2 Zornitza Stark Marked gene: MAGEL2 as ready
Hyperinsulinism v1.30 MAGEL2 Zornitza Stark Gene: magel2 has been classified as Green List (High Evidence).
Hyperinsulinism v1.30 MAGEL2 Zornitza Stark Classified gene: MAGEL2 as Green List (high evidence)
Hyperinsulinism v1.30 MAGEL2 Zornitza Stark Gene: magel2 has been classified as Green List (High Evidence).
Hyperinsulinism v1.29 MAGEL2 Zornitza Stark gene: MAGEL2 was added
gene: MAGEL2 was added to Hyperinsulinism. Sources: Expert list
Mode of inheritance for gene: MAGEL2 was set to MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed)
Publications for gene: MAGEL2 were set to 25473036; 29599419; 31397880
Phenotypes for gene: MAGEL2 were set to Schaaf-Yang syndrome, MIM# 615547
Review for gene: MAGEL2 was set to GREEN
Added comment: MAGEL2 is a maternally imprinted gene, paternally expressed, located on chromosome 15q11, within the critical region of Prader Willi syndrome. Congenital hyperinsulinism due to pathogenic variants on the paternal allele of MAGEL2 have been reported in 3 patients from 2 families with a diagnosis of persistent congenital hyperinsulinism and extra pancreatic features (ptosis, exotropia, high palate, smooth philtrum, inverted nipples, skeletal anomalies, hypotonia, low muscle mass and increased central distribution of body fat) (Soden et al Sci Transl Med 2014 PMID:25473036). Hypoglycaemia has been reported in a further 13 cases (Jobling et al J Med Genet 2018 PMID: 29599419, Patak et al 2019, Clin Genet PMID: 31397880).
Sources: Expert list
Hyperinsulinism v1.28 CACNA1C Zornitza Stark Marked gene: CACNA1C as ready
Hyperinsulinism v1.28 CACNA1C Zornitza Stark Gene: cacna1c has been classified as Amber List (Moderate Evidence).
Hyperinsulinism v1.28 CACNA1C Zornitza Stark Classified gene: CACNA1C as Amber List (moderate evidence)
Hyperinsulinism v1.28 CACNA1C Zornitza Stark Gene: cacna1c has been classified as Amber List (Moderate Evidence).
Hyperinsulinism v1.27 CACNA1C Zornitza Stark gene: CACNA1C was added
gene: CACNA1C was added to Hyperinsulinism. Sources: Expert list
Mode of inheritance for gene: CACNA1C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CACNA1C were set to 35897673
Phenotypes for gene: CACNA1C were set to Hyperinsulinism, MONDO:0002177, CACNA1C-related; Timothy syndrome, MIM# 601005
Review for gene: CACNA1C was set to AMBER
Added comment: PMID: 35897673 reports novel heterozygous CACNA1C variant in a patient with congenital hyperinsulinism (CHI), which appears to have gain-of-function and loss-of-function effects at the electrophysiological level, explaining the hyperinsulinism and resulting hypoglycemia in the patient reported. It appeared that c.1679T>C, p.L566P (NM_000719.6) reported in this patient has a minor effects on the cardiac action potential in an in silico model, in contrast to c.1216G>T, p.G406R (NM_000719.6) which is associated with the Long QT in Timothy syndrome (OMIM:601005). Therefore the authors conclude that this represents a novel congeital non-syndromic hyperinsulinism.
Hypoglycemia is also seen in Timothy syndrome patients with c.1216G>T, p.G406R (Table S3, PMID: 35897673).
Sources: Expert list
Hyperinsulinism v1.26 GPC3 Zornitza Stark Marked gene: GPC3 as ready
Hyperinsulinism v1.26 GPC3 Zornitza Stark Gene: gpc3 has been classified as Red List (Low Evidence).
Hyperinsulinism v1.26 AKT2 Zornitza Stark Marked gene: AKT2 as ready
Hyperinsulinism v1.26 AKT2 Zornitza Stark Gene: akt2 has been classified as Red List (Low Evidence).
Hyperinsulinism v1.26 PGM1 Zornitza Stark Marked gene: PGM1 as ready
Hyperinsulinism v1.26 PGM1 Zornitza Stark Gene: pgm1 has been classified as Green List (High Evidence).
Hyperinsulinism v1.26 PGM1 Zornitza Stark Publications for gene: PGM1 were set to PMID: 24499211, 27206562
Hyperinsulinism v1.25 MAFA Zornitza Stark Marked gene: MAFA as ready
Hyperinsulinism v1.25 MAFA Zornitza Stark Gene: mafa has been classified as Green List (High Evidence).
Hyperinsulinism v1.25 EP300 Zornitza Stark Marked gene: EP300 as ready
Hyperinsulinism v1.25 EP300 Zornitza Stark Gene: ep300 has been classified as Green List (High Evidence).
Hyperinsulinism v1.25 EP300 Zornitza Stark Publications for gene: EP300 were set to PMID: 31137009, 33442921, 2240025, 31414570, 33043588
Hyperinsulinism v1.24 CREBBP Zornitza Stark Marked gene: CREBBP as ready
Hyperinsulinism v1.24 CREBBP Zornitza Stark Gene: crebbp has been classified as Green List (High Evidence).
Hyperinsulinism v1.24 CREBBP Zornitza Stark Publications for gene: CREBBP were set to PMID: 31137009, 33442921, 2240025, 31414570, 33043588
Genetic Epilepsy v1.51 KMT2C Zornitza Stark Marked gene: KMT2C as ready
Genetic Epilepsy v1.51 KMT2C Zornitza Stark Gene: kmt2c has been classified as Green List (High Evidence).
Genetic Epilepsy v1.51 KMT2C Zornitza Stark Classified gene: KMT2C as Green List (high evidence)
Genetic Epilepsy v1.51 KMT2C Zornitza Stark Gene: kmt2c has been classified as Green List (High Evidence).
Genetic Epilepsy v1.50 KMT2C Zornitza Stark Classified gene: KMT2C as Green List (high evidence)
Genetic Epilepsy v1.50 KMT2C Zornitza Stark Gene: kmt2c has been classified as Green List (High Evidence).
Genetic Epilepsy v1.49 KMT2C Zornitza Stark gene: KMT2C was added
gene: KMT2C was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: KMT2C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KMT2C were set to 39013459
Phenotypes for gene: KMT2C were set to Kleefstra syndrome 2, MIM# 617768
Review for gene: KMT2C was set to GREEN
Added comment: Large cohort of 98 individuals reported. Seizures are part of the phenotype.
Sources: Literature
Mendeliome v1.1980 ABL1 Sangavi Sivagnanasundram reviewed gene: ABL1: Rating: AMBER; Mode of pathogenicity: None; Publications: 39155385, 38743093; Phenotypes: Human ABL1 Deficiency Syndrome (HADS); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1980 GMPPB Sangavi Sivagnanasundram reviewed gene: GMPPB: Rating: GREEN; Mode of pathogenicity: None; Publications: 27147698; Phenotypes: myopathy caused by variation in GMPPB MONDO:0700084; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.262 LMNA Zornitza Stark Phenotypes for gene: LMNA were changed from Restrictive dermopathy, lethal, 275210 (3) to Mandibuloacral dysplasia, MIM# 248370
Prepair 1000+ v1.261 LMNA Zornitza Stark edited their review of gene: LMNA: Changed phenotypes: Mandibuloacral dysplasia, MIM# 248370
Prepair 1000+ v1.261 GNE Zornitza Stark Marked gene: GNE as ready
Prepair 1000+ v1.261 GNE Zornitza Stark Gene: gne has been classified as Green List (High Evidence).
Prepair 1000+ v1.261 GNE Zornitza Stark Phenotypes for gene: GNE were changed from Inclusion body myopathy, autosomal recessive, 600737 (3) to Nonaka myopathy MIM#605820; Thrombocytopenia 12 with or without myopathy MIM#620757
Prepair 1000+ v1.260 GNE Zornitza Stark Publications for gene: GNE were set to
Prepair 1000+ v1.259 GNE Zornitza Stark Tag for review tag was added to gene: GNE.
Prepair 1000+ v1.259 GNE Zornitza Stark reviewed gene: GNE: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Nonaka myopathy MIM#605820, Thrombocytopenia 12 with or without myopathy MIM#620757; Mode of inheritance: None
Prepair 1000+ v1.259 B9D1 Lilian Downie Marked gene: B9D1 as ready
Prepair 1000+ v1.259 B9D1 Lilian Downie Added comment: Comment when marking as ready: Promote to green when final list confirmed
Prepair 1000+ v1.259 B9D1 Lilian Downie Gene: b9d1 has been classified as Amber List (Moderate Evidence).
Prepair 1000+ v1.259 B9D1 Lilian Downie Publications for gene: B9D1 were set to 21493627; 24886560; 25920555
Prepair 1000+ v1.258 B9D1 Lilian Downie reviewed gene: B9D1: Rating: AMBER; Mode of pathogenicity: None; Publications: 21493627, 24886560, 25920555, 32622957; Phenotypes: Joubert syndrome 27, MIM# 617120, Meckel syndrome 9, MIM# 614209; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Optic Atrophy v1.32 NDUFA7 Mark Cleghorn gene: NDUFA7 was added
gene: NDUFA7 was added to Optic Atrophy. Sources: Other
Mode of inheritance for gene: NDUFA7 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: NDUFA7 were set to Leber Hereditary Optic Neuropathy, MIM#619382
Penetrance for gene: NDUFA7 were set to unknown
Review for gene: NDUFA7 was set to AMBER
Added comment: NDUFA7
ESHG talk 2/6/24, unpublished
Christine Michaela Neuhofer, Technische Universitat Munchen

Biallelic LoF with Leber Hereditary optic neuropathy (LHON)

Only 1 case, with LHON and homozygous NDUFA7:c.51+1dup
NDUFA7 protein interacts w DNAJC30 – known nuclear LHON gene

Analysis on patient fibroblasts supports disruption to complex I activity via DNAJC30
Sources: Other
Corneal Dystrophy v1.11 SPARCL1 Chirag Patel gene: SPARCL1 was added
gene: SPARCL1 was added to Corneal Dystrophy. Sources: Literature
Mode of inheritance for gene: SPARCL1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SPARCL1 were set to PMID: 39169229
Phenotypes for gene: SPARCL1 were set to Corneal dystrophy, MONDO:0018102
Review for gene: SPARCL1 was set to RED
Added comment: 8 affected individuals with corneal dystrophy from 1 family (3 generations). Affected individuals had diffuse central stromal opacity, with reduced visual acuity in older family members. Histopathology of affected cornea tissue revealed mild stromal textural alterations with alcianophilic deposits.

WGS from 4 affected individuals in family identified a novel heterozygous missense variant in exon 4 of SPARCL1 (c.334G > A; p.(Glu112Lys)) which segregated with disease.

SPARC-like protein 1 (SPARCL1) is a secreted matricellular protein involved in cell migration, cell adhesion, tissue repair, and remodelling. SPARCL1 has been shown to regulate decorin. Heterozygous variants in DCN, encoding decorin, cause autosomal dominant congenital stromal corneal dystrophy, suggesting a common pathogenic pathway. Immunohistochemistry showed the level of decorin was significantly decreased in the corneal stroma of the affected tissue, and SPARCL1 appeared to be retained in the epithelium.
Sources: Literature
Dystonia - complex v0.237 PNPLA8 Chirag Patel Classified gene: PNPLA8 as Green List (high evidence)
Dystonia - complex v0.237 PNPLA8 Chirag Patel Gene: pnpla8 has been classified as Green List (High Evidence).
Dystonia - complex v0.236 PNPLA8 Chirag Patel gene: PNPLA8 was added
gene: PNPLA8 was added to Dystonia - complex. Sources: Literature
Mode of inheritance for gene: PNPLA8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PNPLA8 were set to PMID: 39082157
Phenotypes for gene: PNPLA8 were set to PNPLA8-related neurological diseases
Review for gene: PNPLA8 was set to GREEN
gene: PNPLA8 was marked as current diagnostic
Added comment: Cohort analysis of clinical features of new and previously reported individuals with biallelic PNPLA8 variants (25 affected individuals across 20 families). They showed that PNPLA8-related neurological diseases manifest as a continuum ranging from variable developmental and/or degenerative epileptic-dyskinetic encephalopathy to childhood-onset neurodegeneration. Complete loss of PNPLA8 was associated with the more profound end of the spectrum. 11/15 individuals (info available) had dystonia (onset in childhood).

Using cerebral organoids generated from human induced pluripotent stem cells, they found that loss of PNPLA8 led to developmental defects by reducing the number of basal radial glial cells and upper-layer neurons. Neural progenitor cells lacking PNPLA8 showed a reduced amount of lysophosphatidic acid, lysophosphatidylethanolamine and phosphatidic acid. They show that PNPLA8 is crucial to meet phospholipid synthetic needs and to produce abundant basal radial glial cells in human brain development.
Sources: Literature
Hereditary Spastic Paraplegia - paediatric v1.82 PNPLA8 Chirag Patel Classified gene: PNPLA8 as Green List (high evidence)
Hereditary Spastic Paraplegia - paediatric v1.82 PNPLA8 Chirag Patel Gene: pnpla8 has been classified as Green List (High Evidence).
Cerebellar and Pontocerebellar Hypoplasia v1.67 PNPLA8 Chirag Patel Classified gene: PNPLA8 as Green List (high evidence)
Cerebellar and Pontocerebellar Hypoplasia v1.67 PNPLA8 Chirag Patel Gene: pnpla8 has been classified as Green List (High Evidence).
Hereditary Spastic Paraplegia - paediatric v1.81 PNPLA8 Chirag Patel gene: PNPLA8 was added
gene: PNPLA8 was added to Hereditary Spastic Paraplegia - paediatric. Sources: Literature
Mode of inheritance for gene: PNPLA8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PNPLA8 were set to PMID: 39082157
Phenotypes for gene: PNPLA8 were set to PNPLA8-related neurological diseases
Review for gene: PNPLA8 was set to GREEN
gene: PNPLA8 was marked as current diagnostic
Added comment: Cohort analysis of clinical features of new and previously reported individuals with biallelic PNPLA8 variants (25 affected individuals across 20 families). They showed that PNPLA8-related neurological diseases manifest as a continuum ranging from variable developmental and/or degenerative epileptic-dyskinetic encephalopathy to childhood-onset neurodegeneration. Complete loss of PNPLA8 was associated with the more profound end of the spectrum. 15/23 individuals (info available) had spasticity (onset in early childhood).

Using cerebral organoids generated from human induced pluripotent stem cells, they found that loss of PNPLA8 led to developmental defects by reducing the number of basal radial glial cells and upper-layer neurons. Neural progenitor cells lacking PNPLA8 showed a reduced amount of lysophosphatidic acid, lysophosphatidylethanolamine and phosphatidic acid. They show that PNPLA8 is crucial to meet phospholipid synthetic needs and to produce abundant basal radial glial cells in human brain development.
Sources: Literature
Cerebellar and Pontocerebellar Hypoplasia v1.66 PNPLA8 Chirag Patel gene: PNPLA8 was added
gene: PNPLA8 was added to Cerebellar and Pontocerebellar Hypoplasia. Sources: Literature
Mode of inheritance for gene: PNPLA8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PNPLA8 were set to PMID: 39082157
Phenotypes for gene: PNPLA8 were set to PNPLA8-related neurological diseases
Review for gene: PNPLA8 was set to GREEN
gene: PNPLA8 was marked as current diagnostic
Added comment: Cohort analysis of clinical features of new and previously reported individuals with biallelic PNPLA8 variants (25 affected individuals across 20 families). They showed that PNPLA8-related neurological diseases manifest as a continuum ranging from variable developmental and/or degenerative epileptic-dyskinetic encephalopathy to childhood-onset neurodegeneration. Complete loss of PNPLA8 was associated with the more profound end of the spectrum. 20/21 individuals (info available) had cerebellar atrophy with/without pontocerebellar hypoplasia.

Using cerebral organoids generated from human induced pluripotent stem cells, they found that loss of PNPLA8 led to developmental defects by reducing the number of basal radial glial cells and upper-layer neurons. Neural progenitor cells lacking PNPLA8 showed a reduced amount of lysophosphatidic acid, lysophosphatidylethanolamine and phosphatidic acid. They show that PNPLA8 is crucial to meet phospholipid synthetic needs and to produce abundant basal radial glial cells in human brain development.
Sources: Literature
Genetic Epilepsy v1.48 PNPLA8 Chirag Patel Classified gene: PNPLA8 as Green List (high evidence)
Genetic Epilepsy v1.48 PNPLA8 Chirag Patel Gene: pnpla8 has been classified as Green List (High Evidence).
Autism v0.198 LARP1 Sangavi Sivagnanasundram gene: LARP1 was added
gene: LARP1 was added to Autism. Sources: Other
Mode of inheritance for gene: LARP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: LARP1 were set to 39182167
Phenotypes for gene: LARP1 were set to Neurodevelopmental disorder; MONDO:0700092
Review for gene: LARP1 was set to GREEN
Added comment: Seven unrelated probands (6 males and 1 female) with ASD or another variable NDD phenotype (ID, hypotonia, motor delay and/or ASD). Variants were showed to be de novo null variants or missense variants that resulted in haploinsufficiency.

Ex vivo (knockout CRISPR-Cas9) functional assay using lymphoblasts that was collected and immortilised from one proband was conducted to assess the functional impact of the LARP1 variant. The results showed a reduction in protein compared to WT causing reduced rates of aerobic respiration and glycolysis.
Sources: Other
Intellectual disability syndromic and non-syndromic v0.6126 LARP1 Sangavi Sivagnanasundram gene: LARP1 was added
gene: LARP1 was added to Intellectual disability syndromic and non-syndromic. Sources: Other
Mode of inheritance for gene: LARP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: LARP1 were set to 39182167
Phenotypes for gene: LARP1 were set to Neurodevelopmental disorder; MONDO:0700092
Review for gene: LARP1 was set to GREEN
Added comment: Seven unrelated probands (6 males and 1 female) with ASD or another variable NDD phenotype (ID, hypotonia, motor delay and/or ASD). Variants were showed to be de novo null variants or missense variants that resulted in haploinsufficiency.

Ex vivo (knockout CRISPR-Cas9) functional assay using lymphoblasts that was collected and immortilised from one proband was conducted to assess the functional impact of the LARP1 variant. The results showed a reduction in protein compared to WT causing reduced rates of aerobic respiration and glycolysis
Sources: Other
Intellectual disability syndromic and non-syndromic v0.6126 PNPLA8 Chirag Patel Classified gene: PNPLA8 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.6126 PNPLA8 Chirag Patel Gene: pnpla8 has been classified as Green List (High Evidence).
Mendeliome v1.1980 LARP1 Sangavi Sivagnanasundram gene: LARP1 was added
gene: LARP1 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: LARP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: LARP1 were set to 39182167
Phenotypes for gene: LARP1 were set to Neurodevelopmental disorder; MONDO:0700092
Review for gene: LARP1 was set to GREEN
Added comment: Seven unrelated probands (6 males and 1 female) with ASD or another variable NDD phenotype (ID, hypotonia, motor delay and/or ASD). Variants were showed to be de novo null variants or missense variants that resulted in haploinsufficiency.

Ex vivo (knockout CRISPR-Cas9) functional assay using lymphoblasts that was collected and immortilised from one proband was conducted to assess the functional impact of the LARP1 variant. The results showed a reduction in protein compared to WT causing reduced rates of aerobic respiration and glycolysis.
Sources: Other
Genetic Epilepsy v1.47 PNPLA8 Chirag Patel gene: PNPLA8 was added
gene: PNPLA8 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: PNPLA8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PNPLA8 were set to PMID: 39082157
Phenotypes for gene: PNPLA8 were set to PNPLA8-related neurological diseases
Review for gene: PNPLA8 was set to GREEN
gene: PNPLA8 was marked as current diagnostic
Added comment: Cohort analysis of clinical features of new and previously reported individuals with biallelic PNPLA8 variants (25 affected individuals across 20 families). They showed that PNPLA8-related neurological diseases manifest as a continuum ranging from variable developmental and/or degenerative epileptic-dyskinetic encephalopathy to childhood-onset neurodegeneration. Complete loss of PNPLA8 was associated with the more profound end of the spectrum. 19/25 individuals had seizures (onset 1 day to 31 years).

Using cerebral organoids generated from human induced pluripotent stem cells, they found that loss of PNPLA8 led to developmental defects by reducing the number of basal radial glial cells and upper-layer neurons. Neural progenitor cells lacking PNPLA8 showed a reduced amount of lysophosphatidic acid, lysophosphatidylethanolamine and phosphatidic acid. They show that PNPLA8 is crucial to meet phospholipid synthetic needs and to produce abundant basal radial glial cells in human brain development.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.6125 PNPLA8 Chirag Patel Classified gene: PNPLA8 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.6125 PNPLA8 Chirag Patel Gene: pnpla8 has been classified as Green List (High Evidence).
Mendeliome v1.1980 PNPLA8 Chirag Patel edited their review of gene: PNPLA8: Added comment: Cohort analysis of clinical features of new and previously reported individuals with biallelic PNPLA8 variants (25 affected individuals across 20 families). They showed that PNPLA8-related neurological diseases manifest as a continuum ranging from variable developmental and/or degenerative epileptic-dyskinetic encephalopathy to childhood-onset neurodegeneration. Complete loss of PNPLA8 was associated with the more profound end of the spectrum.

Using cerebral organoids generated from human induced pluripotent stem cells, they found that loss of PNPLA8 led to developmental defects by reducing the number of basal radial glial cells and upper-layer neurons. Neural progenitor cells lacking PNPLA8 showed a reduced amount of lysophosphatidic acid, lysophosphatidylethanolamine and phosphatidic acid. They show that PNPLA8 is crucial to meet phospholipid synthetic needs and to produce abundant basal radial glial cells in human brain development.; Set current diagnostic: yes
Mendeliome v1.1980 PNPLA8 Chirag Patel reviewed gene: PNPLA8: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 39082157; Phenotypes: PNPLA8-related neurological diseases; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.6124 PNPLA8 Chirag Patel gene: PNPLA8 was added
gene: PNPLA8 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: PNPLA8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PNPLA8 were set to PMID: 39082157
Phenotypes for gene: PNPLA8 were set to PNPLA8-related neurological diseases
Review for gene: PNPLA8 was set to GREEN
gene: PNPLA8 was marked as current diagnostic
Added comment: Cohort analysis of clinical features of new and previously reported individuals with biallelic PNPLA8 variants (25 affected individuals across 20 families). They showed that PNPLA8-related neurological diseases manifest as a continuum ranging from variable developmental and/or degenerative epileptic-dyskinetic encephalopathy to childhood-onset neurodegeneration. Complete loss of PNPLA8 was associated with the more profound end of the spectrum. 13/19 individuals (info available) had developmental delay and/or severe intellectual disability.

Using cerebral organoids generated from human induced pluripotent stem cells, they found that loss of PNPLA8 led to developmental defects by reducing the number of basal radial glial cells and upper-layer neurons. Neural progenitor cells lacking PNPLA8 showed a reduced amount of lysophosphatidic acid, lysophosphatidylethanolamine and phosphatidic acid. They show that PNPLA8 is crucial to meet phospholipid synthetic needs and to produce abundant basal radial glial cells in human brain development.
Sources: Literature
Microcephaly v1.275 PNPLA8 Chirag Patel Phenotypes for gene: PNPLA8 were changed from PNPLA8-related neurological diseases; Mitochondrial myopathy with lactic acidosis, OMIM # 251950 to PNPLA8-related neurological diseases
Microcephaly v1.274 PNPLA8 Chirag Patel Classified gene: PNPLA8 as Green List (high evidence)
Microcephaly v1.274 PNPLA8 Chirag Patel Gene: pnpla8 has been classified as Green List (High Evidence).
Microcephaly v1.273 PNPLA8 Chirag Patel gene: PNPLA8 was added
gene: PNPLA8 was added to Microcephaly. Sources: Literature
Mode of inheritance for gene: PNPLA8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PNPLA8 were set to PMID: 39082157
Phenotypes for gene: PNPLA8 were set to PNPLA8-related neurological diseases; Mitochondrial myopathy with lactic acidosis, OMIM # 251950
Review for gene: PNPLA8 was set to GREEN
gene: PNPLA8 was marked as current diagnostic
Added comment: Cohort analysis of clinical features of new and previously reported individuals with biallelic PNPLA8 variants (25 affected individuals across 20 families). They showed that PNPLA8-related neurological diseases manifest as a continuum ranging from variable developmental and/or degenerative epileptic-dyskinetic encephalopathy to childhood-onset neurodegeneration. Complete loss of PNPLA8 was associated with the more profound end of the spectrum. 17/25 individuals had congenital and/or progressive microcephaly.

Using cerebral organoids generated from human induced pluripotent stem cells, they found that loss of PNPLA8 led to developmental defects by reducing the number of basal radial glial cells and upper-layer neurons. Neural progenitor cells lacking PNPLA8 showed a reduced amount of lysophosphatidic acid, lysophosphatidylethanolamine and phosphatidic acid. They show that PNPLA8 is crucial to meet phospholipid synthetic needs and to produce abundant basal radial glial cells in human brain development.
Sources: Literature
Mendeliome v1.1980 MED22 Mark Cleghorn gene: MED22 was added
gene: MED22 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: MED22 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: MED22 were set to complex neurodevelopmental disorder MONDO:0100038
Penetrance for gene: MED22 were set to unknown
Review for gene: MED22 was set to AMBER
Added comment: ESHG talk 2/6/24, unpublished
Elisa Cali, UCL

Recurrent homozygous MED22:c.397_399del (p.Glu133del) inframe variant in 8 individuals from 6 families w progressive NDD, microcepahly, cerebellar atrophy, dystonia, seizures

Rare in gnomad v4.1 (9 het alleles, no homozygotes)

Functional work on patient fibroblasts: quantity of protein comparable to controls, did not mentioned assays of protein function (?mechanism proposed)
Drosophilia heterozygous model with equivalent of p.Glu133del variant: structural anomalies, less movements, all died prior to pupae stage
Zebrafish: MED22 mutants less mobile, died prior to adulthood, reduced brain size
Sources: Other
Ciliopathies v1.59 TMEM216 Zornitza Stark Publications for gene: TMEM216 were set to 20036350; 20512146
Intellectual disability syndromic and non-syndromic v0.6123 MED22 Mark Cleghorn gene: MED22 was added
gene: MED22 was added to Intellectual disability syndromic and non-syndromic. Sources: Other
Mode of inheritance for gene: MED22 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: MED22 were set to complex neurodevelopmental disorder MONDO:0100038
Penetrance for gene: MED22 were set to unknown
Review for gene: MED22 was set to AMBER
Added comment: ESHG talk 2/6/24, unpublished
Elisa Cali, UCL

Recurrent homozygous MED22:c.397_399del (p.Glu133del) inframe variant in 8 individuals from 6 families w progressive NDD, microcepahly, cerebellar atrophy, dystonia, seizures

Rare in gnomad v4.1 (9 het alleles, no homozygotes)

Functional work on patient fibroblasts: quantity of protein comparable to controls, did not mentioned assays of protein function (?mechanism proposed)
Drosophilia heterozygous model with equivalent of p.Glu133del variant: structural anomalies, less movements, all died prior to pupae stage
Zebrafish: MED22 mutants less mobile, died prior to adulthood, reduced brain size
Sources: Other
Ciliopathies v1.58 TMEM216 Zornitza Stark Tag UTR tag was added to gene: TMEM216.
Ciliopathies v1.58 TMEM216 Zornitza Stark edited their review of gene: TMEM216: Added comment: PMID 39191256: Two rare nucleotide substitutions at the same genomic location on chromosome 11 (g.61392563 [GRCh38]), 69 base pairs upstream of the start codon of the ciliopathy gene TMEM216 (c.-69G>A, c.-69G>T [GenBank: NM_001173991.3]) found in individuals of South Asian and African ancestry, respectively.

This included 71 homozygotes and 3 mixed heterozygotes in trans with a predicted loss-of-function allele. Haplotype analysis showed single-nucleotide variants (SNVs) common across families, suggesting ancestral alleles within the two distinct ethnic populations.

Clinical phenotype analysis of 62 available individuals from 49 families indicated a similar clinical presentation with night blindness in the first decade and progressive peripheral field loss thereafter. No evident systemic ciliopathy features were noted.

Functional characterization of these variants by luciferase reporter gene assay showed reduced promotor activity.; Changed publications: 20036350, 20512146, 39191256; Changed phenotypes: Joubert syndrome 2, MIM# 608091, Meckel syndrome 2, MIM# 603194, Retinitis pigmentosa, MONDO:0019200, TMEM216-related
Mendeliome v1.1980 TMEM216 Zornitza Stark Phenotypes for gene: TMEM216 were changed from Joubert syndrome 2, MIM# 608091; MONDO:0011963; Meckel syndrome 2, MIM# 603194; MONDO:0011296 to Joubert syndrome 2, MIM# 608091; MONDO:0011963; Meckel syndrome 2, MIM# 603194; MONDO:0011296; Retinitis pigmentosa, MONDO:0019200, TMEM216-related
Mendeliome v1.1979 TMEM216 Zornitza Stark Publications for gene: TMEM216 were set to 20036350; 20512146
Mendeliome v1.1978 TMEM216 Zornitza Stark Tag founder tag was added to gene: TMEM216.
Tag UTR tag was added to gene: TMEM216.
Mendeliome v1.1978 TMEM216 Zornitza Stark edited their review of gene: TMEM216: Added comment: PMID 39191256: Two rare nucleotide substitutions at the same genomic location on chromosome 11 (g.61392563 [GRCh38]), 69 base pairs upstream of the start codon of the ciliopathy gene TMEM216 (c.-69G>A, c.-69G>T [GenBank: NM_001173991.3]) found in individuals of South Asian and African ancestry, respectively.

This included 71 homozygotes and 3 mixed heterozygotes in trans with a predicted loss-of-function allele. Haplotype analysis showed single-nucleotide variants (SNVs) common across families, suggesting ancestral alleles within the two distinct ethnic populations.

Clinical phenotype analysis of 62 available individuals from 49 families indicated a similar clinical presentation with night blindness in the first decade and progressive peripheral field loss thereafter. No evident systemic ciliopathy features were noted.

Functional characterization of these variants by luciferase reporter gene assay showed reduced promotor activity.; Changed publications: 20036350, 20512146, 39191256; Changed phenotypes: Joubert syndrome 2, MIM# 608091, MONDO:0011963, Meckel syndrome 2, MIM# 603194, MONDO:0011296, Retinitis pigmentosa, MONDO:0019200, TMEM216-related
Retinitis pigmentosa_Autosomal Recessive/X-linked v0.152 TMEM216 Zornitza Stark Publications for gene: TMEM216 were set to
Retinitis pigmentosa_Autosomal Recessive/X-linked v0.151 TMEM216 Zornitza Stark edited their review of gene: TMEM216: Changed publications: 39191256
Congenital diaphragmatic hernia v1.16 MED12 Chirag Patel Classified gene: MED12 as Green List (high evidence)
Congenital diaphragmatic hernia v1.16 MED12 Chirag Patel Gene: med12 has been classified as Green List (High Evidence).
Congenital diaphragmatic hernia v1.15 MED12 Chirag Patel gene: MED12 was added
gene: MED12 was added to Congenital diaphragmatic hernia. Sources: Literature
Mode of inheritance for gene: MED12 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: MED12 were set to PMID: 39215511
Phenotypes for gene: MED12 were set to MED12-related disorders; Hardikar syndrome, OMIM # 301068
Review for gene: MED12 was set to GREEN
gene: MED12 was marked as current diagnostic
Added comment: MED12-related disorders include:
1) X-linked recessive Opitz-Kaveggia syndrome, Lujan-Fryns syndrome, Ohdo syndrome, and nonspecific intellectual disability in males predominantly carrying missense variants
2) X-linked dominant Hardikar syndrome and nonspecific intellectual disability in females known to predominantly carry de novo nonsense/frameshift and nonsense/missense variants, respectively.

Paper reviews occurrence of congenital diaphragmatic hernia in 18 individuals with molecularly confirmed MED12 mutation on WES/WGS. They report CDH in 3/7 females with Hardikar syndrome or nonspecific intellectual disability, but no CDH in 11 males with MED12-related disorders.
Sources: Literature
Retinitis pigmentosa_Autosomal Recessive/X-linked v0.151 TMEM216 Zornitza Stark Marked gene: TMEM216 as ready
Retinitis pigmentosa_Autosomal Recessive/X-linked v0.151 TMEM216 Zornitza Stark Gene: tmem216 has been classified as Green List (High Evidence).
Retinitis pigmentosa_Autosomal Recessive/X-linked v0.151 TMEM216 Zornitza Stark Classified gene: TMEM216 as Green List (high evidence)
Retinitis pigmentosa_Autosomal Recessive/X-linked v0.151 TMEM216 Zornitza Stark Gene: tmem216 has been classified as Green List (High Evidence).
Retinitis pigmentosa_Autosomal Recessive/X-linked v0.150 TMEM216 Zornitza Stark gene: TMEM216 was added
gene: TMEM216 was added to Retinitis pigmentosa_Autosomal Recessive/X-linked. Sources: Literature
UTR tags were added to gene: TMEM216.
Mode of inheritance for gene: TMEM216 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: TMEM216 were set to Retinitis pigmentosa, MONDO:0019200, TMEM216-related
Review for gene: TMEM216 was set to GREEN
Added comment: Two rare nucleotide substitutions at the same genomic location on chromosome 11 (g.61392563 [GRCh38]), 69 base pairs upstream of the start codon of the ciliopathy gene TMEM216 (c.-69G>A, c.-69G>T [GenBank: NM_001173991.3]) found in individuals of South Asian and African ancestry, respectively.

This included 71 homozygotes and 3 mixed heterozygotes in trans with a predicted loss-of-function allele. Haplotype analysis showed single-nucleotide variants (SNVs) common across families, suggesting ancestral alleles within the two distinct ethnic populations.

Clinical phenotype analysis of 62 available individuals from 49 families indicated a similar clinical presentation with night blindness in the first decade and progressive peripheral field loss thereafter. No evident systemic ciliopathy features were noted.

Functional characterization of these variants by luciferase reporter gene assay showed reduced promotor activity.
Sources: Literature
Muscular dystrophy and myopathy_Paediatric v1.67 JPH1 Sangavi Sivagnanasundram gene: JPH1 was added
gene: JPH1 was added to Muscular dystrophy and myopathy_Paediatric. Sources: Other
Mode of inheritance for gene: JPH1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: JPH1 were set to 39209426
Phenotypes for gene: JPH1 were set to Congenital myopathy MONDO:0019952
Review for gene: JPH1 was set to GREEN
Added comment: 4 unrelated probands presented with congenital myopathy with facial weakness and ocular involvement. All individuals had presence of 4 different LoF variants identified in JPH1.

p.(Asp125Thrfs*30), p.(Tyr118*), p.(Leu580Trpfs*16) and p.(Glu504Serfs*3) - all variants were absent from gnomADv4.1
Sources: Other
Mendeliome v1.1978 JPH1 Sangavi Sivagnanasundram changed review comment from: 4 unrelated probands presented with congenital myopathy with prominent facial and ocular involvement. All individuals had presence of 4 different LoF variants identified in JPH1.

p.(Asp125Thrfs*30), p.(Tyr118*), p.(Leu580Trpfs*16) and p.(Glu504Serfs*3) - all variants were absent from gnomADv4.1
Sources: Other; to: 4 unrelated probands presented with congenital myopathy with facial weakness and ocular involvement. All individuals had presence of 4 different LoF variants identified in JPH1.

p.(Asp125Thrfs*30), p.(Tyr118*), p.(Leu580Trpfs*16) and p.(Glu504Serfs*3) - all variants were absent from gnomADv4.1
Sources: Other
Mendeliome v1.1978 JPH1 Sangavi Sivagnanasundram gene: JPH1 was added
gene: JPH1 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: JPH1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: JPH1 were set to 39209426
Phenotypes for gene: JPH1 were set to Congenital myopathy MONDO:0019952
Review for gene: JPH1 was set to GREEN
Added comment: 4 unrelated probands presented with congenital myopathy with prominent facial and ocular involvement. All individuals had presence of 4 different LoF variants identified in JPH1.

p.(Asp125Thrfs*30), p.(Tyr118*), p.(Leu580Trpfs*16) and p.(Glu504Serfs*3) - all variants were absent from gnomADv4.1
Sources: Other
Mendeliome v1.1978 PLEC Zornitza Stark Phenotypes for gene: PLEC were changed from ?Epidermolysis bullosa simplex with nail dystrophy, MIM# 616487; Epidermolysis bullosa simplex with muscular dystrophy, MIM# 226670; Epidermolysis bullosa simplex with pyloric atresia, MIM# 612138; Epidermolysis bullosa simplex, Ogna type MIM#131950; Muscular dystrophy, limb-girdle, autosomal recessive 17, MIM# 613723 to Epidermolysis bullosa simplex with nail dystrophy, MIM# 616487; Epidermolysis bullosa simplex with muscular dystrophy, MIM# 226670; Epidermolysis bullosa simplex with pyloric atresia, MIM# 612138; Epidermolysis bullosa simplex, Ogna type MIM#131950; Muscular dystrophy, limb-girdle, autosomal recessive 17, MIM# 613723; Progressive familial intrahepatic cholestasis, MONDO:0015762, PLEC-related
Mendeliome v1.1977 PLEC Zornitza Stark Publications for gene: PLEC were set to 22144912
Mendeliome v1.1976 PLEC Zornitza Stark reviewed gene: PLEC: Rating: AMBER; Mode of pathogenicity: None; Publications: 39168815; Phenotypes: Progressive familial intrahepatic cholestasis, MONDO:0015762, PLEC-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Cholestasis v0.244 PLEC Zornitza Stark Marked gene: PLEC as ready
Cholestasis v0.244 PLEC Zornitza Stark Gene: plec has been classified as Amber List (Moderate Evidence).
Cholestasis v0.244 PLEC Zornitza Stark Classified gene: PLEC as Amber List (moderate evidence)
Cholestasis v0.244 PLEC Zornitza Stark Gene: plec has been classified as Amber List (Moderate Evidence).
Cholestasis v0.243 PLEC Zornitza Stark gene: PLEC was added
gene: PLEC was added to Cholestasis. Sources: Literature
Mode of inheritance for gene: PLEC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLEC were set to 39168815
Phenotypes for gene: PLEC were set to Progressive familial intrahepatic cholestasis, MONDO:0015762, PLEC-related
Review for gene: PLEC was set to AMBER
Added comment: Four individuals reported with PFIC and bi-allelic variants in PLEC (one pair of sibs, and two other unrelated infants). However, limited functional data and several of the variants are missense.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.6123 BICRA Mark Cleghorn reviewed gene: BICRA: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Coffin-Siris syndrome-12, MIM#619325; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1976 SF3B1 Mark Cleghorn gene: SF3B1 was added
gene: SF3B1 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: SF3B1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: SF3B1 were set to complex neurodevelopmental disorder MONDO:0100038
Penetrance for gene: SF3B1 were set to unknown
Review for gene: SF3B1 was set to AMBER
Added comment: SF3B1
Delphine Bernard, University of Brest
ESHG talk 2/6/24, unpublished

De novo germline SF3B1 variants, proposed spliceosomopathy/NDD gene

SF3B1 is an RNA binding protein that stabilizes the U2 snRNP complex at branchpoint sequences
Somatic SF3B1 missense commonly occur in haematological malignancy (K700E recurrent)

25 patients with syndromic NDD + de novo heterozygous rare SF3B1 variants identified on WES, genematcher
13 missense (incl recurrent xxx and xxx) within HEAT domain
5 nonsense
4 splicing
1 frameshift

Patients w missense variants may have more severe phenotype incl mircocepahly, palate anomalies, cerebral anomalies, GI/cardiac anomalies

Cellular models of missense variants: erythroleukaemia K562, HEK293T
Suggest missense variants do not cause loss of function, but increase exon skipping and alternative 3’ splice site use
Sources: Other
Intellectual disability syndromic and non-syndromic v0.6123 SF3B1 Mark Cleghorn gene: SF3B1 was added
gene: SF3B1 was added to Intellectual disability syndromic and non-syndromic. Sources: Other
Mode of inheritance for gene: SF3B1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: SF3B1 were set to complex neurodevelopmental disorder MONDO:0100038
Penetrance for gene: SF3B1 were set to unknown
Review for gene: SF3B1 was set to AMBER
Added comment: SF3B1
Delphine Bernard, University of Brest
ESHG talk 2/6/24, unpublished

De novo germline SF3B1 variants, proposed spliceosomopathy/NDD gene

SF3B1 is an RNA binding protein that stabilizes the U2 snRNP complex at branchpoint sequences
Somatic SF3B1 missense commonly occur in haematological malignancy (K700E recurrent)

25 patients with syndromic NDD + de novo heterozygous rare SF3B1 variants identified on WES, genematcher
13 missense (incl recurrent xxx and xxx) within HEAT domain
5 nonsense
4 splicing
1 frameshift

Patients w missense variants may have more severe phenotype incl mircocepahly, palate anomalies, cerebral anomalies, GI/cardiac anomalies

Cellular models of missense variants: erythroluekaemia K562, HEK293T
Suggest missense variants do not cause loss of function, but increase exon skipping and alternative 3’ splice sites
Sources: Other
Cataract v0.369 GBF1 Ain Roesley Marked gene: GBF1 as ready
Cataract v0.369 GBF1 Ain Roesley Gene: gbf1 has been classified as Red List (Low Evidence).
Cataract v0.369 GBF1 Ain Roesley gene: GBF1 was added
gene: GBF1 was added to Cataract. Sources: Literature
Mode of inheritance for gene: GBF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GBF1 were set to 39110251
Phenotypes for gene: GBF1 were set to autosomal dominant cataract MONDO:0022672, GBF1-related
Penetrance for gene: GBF1 were set to Complete
Review for gene: GBF1 was set to RED
gene: GBF1 was marked as current diagnostic
Added comment: 1 missense in a multi-generational family.

however, this variant has 98 hets on gnomad v4 and low conservation (changes in 2 mammals and reptiles).

Using the human lens epithelium (HLE) cell line, we found that the p.T1287I mutation reduced GBF1 protein levels. Knockdown of endogenous GBF1 activated the unfolded protein response and enhanced autophagy, as well as increasing XBP1s protein levels and decreasing p-JNK1 protein levels. Heterozygous Gbf1 knockout (Gbf1+/-) mice also exhibited cataract malformation, while their littermate wild-type (Gbf1+/+) mice did not.
Sources: Literature
Mendeliome v1.1976 GBF1 Ain Roesley reviewed gene: GBF1: Rating: RED; Mode of pathogenicity: None; Publications: 39110251; Phenotypes: autosomal dominant cataract MONDO:0022672, GBF1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v1.1976 TLN1 Ain Roesley reviewed gene: TLN1: Rating: AMBER; Mode of pathogenicity: None; Publications: 39163585; Phenotypes: idiopathic spontaneous coronary artery dissection MONDO:0007385; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Prepair 1000+ v1.258 LGI4 Andrew Coventry reviewed gene: LGI4: Rating: GREEN; Mode of pathogenicity: None; Publications: 28318499 16341215 31513940; Phenotypes: Arthrogryposis multiplex congenita 1, neurogenic, with myelin defect MIM#617468; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinitis pigmentosa_Autosomal Recessive/X-linked v0.149 COQ8B Bryony Thompson Marked gene: COQ8B as ready
Retinitis pigmentosa_Autosomal Recessive/X-linked v0.149 COQ8B Bryony Thompson Gene: coq8b has been classified as Green List (High Evidence).
Retinitis pigmentosa_Autosomal Recessive/X-linked v0.149 COQ8B Bryony Thompson Classified gene: COQ8B as Green List (high evidence)
Retinitis pigmentosa_Autosomal Recessive/X-linked v0.149 COQ8B Bryony Thompson Gene: coq8b has been classified as Green List (High Evidence).
Retinitis pigmentosa_Autosomal Recessive/X-linked v0.148 COQ8B Bryony Thompson gene: COQ8B was added
gene: COQ8B was added to Retinitis pigmentosa_Autosomal Recessive/X-linked. Sources: Literature
Mode of inheritance for gene: COQ8B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COQ8B were set to 39226897; 25967120
Phenotypes for gene: COQ8B were set to Retinitis pigmentosa MONDO:0019200
Review for gene: COQ8B was set to GREEN
gene: COQ8B was marked as current diagnostic
Added comment: PMID: 39226897 - 5 individuals from 4 unrelated families with non-syndromic RP (normal renal function) and COQ8B chet variants (5 different variants). In vitro functional assays of the variant demonstrated a significant decrease in ligand-protein interaction compared to the wild type.
PMID: 25967120 - 1 case with a homozygous truncating variant reported with FSGS and RP
Sources: Literature
Mendeliome v1.1976 COQ8B Bryony Thompson reviewed gene: COQ8B: Rating: GREEN; Mode of pathogenicity: None; Publications: 39226897, 25967120; Phenotypes: Retinitis pigmentosa MONDO:0019200; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Prepair 1000+ v1.258 LAMB1 Andrew Coventry reviewed gene: LAMB1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23472759 25925986 29888467 25925986 32548278 34606115 32548278 34606115; Phenotypes: Lissencephaly 5 MIM#615191; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.258 KRT85 Andrew Coventry reviewed gene: KRT85: Rating: AMBER; Mode of pathogenicity: None; Publications: 16525032 19865094 31273852 37178037; Phenotypes: Ectodermal dysplasia 4, hair/nail type MIM#602032; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.258 JAK3 Andrew Coventry reviewed gene: JAK3: Rating: GREEN; Mode of pathogenicity: None; Publications: 14615376 11668610 7481767 7481769 9354668 7659163 7481768 30032486 9753072; Phenotypes: Severe combined immunodeficiency, autosomal recessive, T-negative/B-positive type MIM#600802; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.258 ITGB2 Andrew Coventry reviewed gene: ITGB2: Rating: GREEN; Mode of pathogenicity: None; Publications: 1968911 1694220 33957747 32279896 31374327; Phenotypes: Leukocyte adhesion deficiency MIM#116920; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.258 ICOS Andrew Coventry reviewed gene: ICOS: Rating: GREEN; Mode of pathogenicity: None; Publications: 12577056 15507387 19380800 28861081 31858365 11343122 16982935 8438047; Phenotypes: Immunodeficiency, common variable, 1 MIM#607594; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.258 COL4A4 Kate Scarff reviewed gene: COL4A4: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 20301386; Phenotypes: Alport syndrome 2, autosomal recessive MIM# 203780; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1976 C12orf66 Mark Cleghorn gene: C12orf66 was added
gene: C12orf66 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: C12orf66 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: C12orf66 were set to complex neurodevelopmental disorder MONDO:0100038
Penetrance for gene: C12orf66 were set to unknown
Review for gene: C12orf66 was set to AMBER
Added comment: KICS2 (previously known as C12ORF66)
Rebecca Buchert, Universitatklinikum Tubingen
ESHG talk 2/6/24, unpublished

Proposed ID + epilepsy gene

8 families w 11 affected individuals
Phenotypes: 11/11 ID, 9/11 epilepsy, 3/11 hearing impairment
3/8 homozygous missense variants (p.Asp296Glu, p.Tyr393Cys, p.Tyr393Cys), all highly conserved
1/8 compound het PTC (p.Lys262*) with 1.1Mb deletion
4/8 homozygous PTC (p.Glu3*, p.Gly79Valfs*18, p.Gly79Valfs*18, p.Lys260Asnfs*18)

Gene appears to be involved in mTOR pathway, and cilia function
mTORC1 activity in CRISPR-HEK293T cells – reduced activity in cells w variants above

Zebrafish model: otolith defects, ciliary dysfunction
?not clear that this truly mimics phenotype observed in patient cohort described
Sources: Other
Intellectual disability syndromic and non-syndromic v0.6123 C12orf66 Mark Cleghorn gene: C12orf66 was added
gene: C12orf66 was added to Intellectual disability syndromic and non-syndromic. Sources: Other
Mode of inheritance for gene: C12orf66 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: C12orf66 were set to complex neurodevelopmental disorder MONDO:0100038
Penetrance for gene: C12orf66 were set to unknown
Review for gene: C12orf66 was set to AMBER
Added comment: KICS2 (previously known as C12ORF66)
Rebecca Buchert, Universitatklinikum Tubingen
ESHG talk 2/6/24, unpublished

Proposed ID + epilepsy gene

8 families w 11 affected individuals
Phenotypes: 11/11 ID, 9/11 epilepsy, 3/11 hearing impairment
3/8 homozygous missense variants (p.Asp296Glu, p.Tyr393Cys, p.Tyr393Cys), all highly conserved
1/8 compound het PTC (p.Lys262*) with 1.1Mb deletion
4/8 homozygous PTC (p.Glu3*, p.Gly79Valfs*18, p.Gly79Valfs*18, p.Lys260Asnfs*18)

Gene appears to be involved in mTOR pathway, and cilia function
mTORC1 activity in CRISPR-HEK293T cells – reduced activity in cells w variants above

Zebrafish model: otolith defects, ciliary dysfunction
?not clear if truly mimics phenotype observed in patient cohort described
Sources: Other
Prepair 1000+ v1.258 EPM2A Lilian Downie Marked gene: EPM2A as ready
Prepair 1000+ v1.258 EPM2A Lilian Downie Gene: epm2a has been classified as Green List (High Evidence).
Mendeliome v1.1976 MYBBP1A Zornitza Stark Marked gene: MYBBP1A as ready
Mendeliome v1.1976 MYBBP1A Zornitza Stark Gene: mybbp1a has been classified as Green List (High Evidence).
Mendeliome v1.1976 MYBBP1A Zornitza Stark Classified gene: MYBBP1A as Green List (high evidence)
Mendeliome v1.1976 MYBBP1A Zornitza Stark Gene: mybbp1a has been classified as Green List (High Evidence).
Mendeliome v1.1975 MYBBP1A Zornitza Stark gene: MYBBP1A was added
gene: MYBBP1A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MYBBP1A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MYBBP1A were set to 39191491; 28425981
Phenotypes for gene: MYBBP1A were set to Hydrops fetalis, MONDO:0015193, MYBBP1A-related
Review for gene: MYBBP1A was set to GREEN
Added comment: Three unrelated fetuses with bi-allelic variants in this gene and severe hydrops.
Sources: Literature
Fetal anomalies v1.267 MYBBP1A Zornitza Stark Marked gene: MYBBP1A as ready
Fetal anomalies v1.267 MYBBP1A Zornitza Stark Gene: mybbp1a has been classified as Green List (High Evidence).
Fetal anomalies v1.267 MYBBP1A Zornitza Stark Classified gene: MYBBP1A as Green List (high evidence)
Fetal anomalies v1.267 MYBBP1A Zornitza Stark Gene: mybbp1a has been classified as Green List (High Evidence).
Prepair 1000+ v1.258 EPM2A Lilian Downie Publications for gene: EPM2A were set to 9771710 9931343 11175283 12019207 12560877 14722920; 30947044; 22036712; 16311711; 28818698
Fetal anomalies v1.266 MYBBP1A Zornitza Stark gene: MYBBP1A was added
gene: MYBBP1A was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: MYBBP1A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MYBBP1A were set to 39191491; 28425981
Phenotypes for gene: MYBBP1A were set to Hydrops fetalis, MONDO:0015193, MYBBP1A-related
Review for gene: MYBBP1A was set to GREEN
Added comment: Three unrelated fetuses with bi-allelic variants in this gene and severe hydrops.
Sources: Literature
Hydrops fetalis v0.320 MYBBP1A Zornitza Stark Marked gene: MYBBP1A as ready
Hydrops fetalis v0.320 MYBBP1A Zornitza Stark Gene: mybbp1a has been classified as Green List (High Evidence).
Hydrops fetalis v0.320 MYBBP1A Zornitza Stark Classified gene: MYBBP1A as Green List (high evidence)
Hydrops fetalis v0.320 MYBBP1A Zornitza Stark Gene: mybbp1a has been classified as Green List (High Evidence).
Prepair 1000+ v1.257 EPM2A Lilian Downie Publications for gene: EPM2A were set to
Hydrops fetalis v0.319 MYBBP1A Zornitza Stark Classified gene: MYBBP1A as Green List (high evidence)
Hydrops fetalis v0.319 MYBBP1A Zornitza Stark Gene: mybbp1a has been classified as Green List (High Evidence).
Prepair 1000+ v1.256 FREM1 Lilian Downie Marked gene: FREM1 as ready
Prepair 1000+ v1.256 FREM1 Lilian Downie Added comment: Comment when marking as ready: 2 AR phenotypes with this gene - have not been assessed by ClinGen yet but appear to be spectrum of the same condition.
Prepair 1000+ v1.256 FREM1 Lilian Downie Gene: frem1 has been classified as Green List (High Evidence).
Hydrops fetalis v0.318 MYBBP1A Zornitza Stark gene: MYBBP1A was added
gene: MYBBP1A was added to Hydrops fetalis. Sources: Literature
Mode of inheritance for gene: MYBBP1A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MYBBP1A were set to 39191491; 28425981
Phenotypes for gene: MYBBP1A were set to Hydrops fetalis, MONDO:0015193, MYBBP1A-related
Review for gene: MYBBP1A was set to GREEN
Added comment: Three unrelated fetuses with bi-allelic variants in this gene and severe hydrops.
Sources: Literature
Prepair 1000+ v1.256 FREM1 Lilian Downie Phenotypes for gene: FREM1 were changed from Bifid nose with or without anorectal and renal anomalies, 608980 (3) to Manitoba oculotrichoanal syndrome MIM# 248450; Bifid nose with or without anorectal and renal anomalies, MIM# 608980
Prepair 1000+ v1.255 FREM1 Lilian Downie Publications for gene: FREM1 were set to 32016392; 21931569; 21507892; 19732862; 20301721; 28111185; 19732862
Prepair 1000+ v1.254 FREM1 Lilian Downie Publications for gene: FREM1 were set to
Polymicrogyria and Schizencephaly v0.192 CEP83 Zornitza Stark Marked gene: CEP83 as ready
Polymicrogyria and Schizencephaly v0.192 CEP83 Zornitza Stark Gene: cep83 has been classified as Red List (Low Evidence).
Prepair 1000+ v1.253 FTO Lilian Downie Marked gene: FTO as ready
Prepair 1000+ v1.253 FTO Lilian Downie Added comment: Comment when marking as ready: Growth retardation, developmental delay, and facial dysmorphism (GDFD) is an autosomal recessive multiple congenital anomaly syndrome characterized by severe psychomotor retardation, poor overall growth, and dysmorphic facial features. Additional features may include cardiac malformations and deafness
Prepair 1000+ v1.253 FTO Lilian Downie Gene: fto has been classified as Green List (High Evidence).
Polymicrogyria and Schizencephaly v0.192 CEP83 Zornitza Stark gene: CEP83 was added
gene: CEP83 was added to Polymicrogyria and Schizencephaly. Sources: Literature
Mode of inheritance for gene: CEP83 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CEP83 were set to 39219159
Phenotypes for gene: CEP83 were set to Nephronophthisis 18, MIM# 615862
Review for gene: CEP83 was set to RED
Added comment: Single individual reported with nephronophthisis and PMG and ID. Compound het variants in CEP83.
Sources: Literature
Prepair 1000+ v1.253 FTO Lilian Downie Publications for gene: FTO were set to
Prepair 1000+ v1.252 KCNJ11 Shakira Heerah reviewed gene: KCNJ11: Rating: GREEN; Mode of pathogenicity: None; Publications: 23345197, 32252216, 9356020; Phenotypes: Hyperinsulinemic hypoglycemia, familial, 2, 601820 (3); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.252 FTO Lilian Downie Phenotypes for gene: FTO were changed from Growth retardation, developmental delay, coarse facies, and early death, 612938 (3) to Growth retardation, developmental delay, facial dysmorphism MIM#612938
Prepair 1000+ v1.251 COL17A1 Lilian Downie Marked gene: COL17A1 as ready
Prepair 1000+ v1.251 COL17A1 Lilian Downie Gene: col17a1 has been classified as Green List (High Evidence).
Prepair 1000+ v1.251 COL17A1 Lilian Downie Phenotypes for gene: COL17A1 were changed from Epidermolysis bullosa, junctional, non-Herlitz type, 226650 (3) to Epidermolysis bullosa, junctional 4, intermediate, MIM# 619787
Prepair 1000+ v1.250 COL17A1 Lilian Downie Publications for gene: COL17A1 were set to
Prepair 1000+ v1.249 GPC6 Lilian Downie Marked gene: GPC6 as ready
Prepair 1000+ v1.249 GPC6 Lilian Downie Gene: gpc6 has been classified as Green List (High Evidence).
Prepair 1000+ v1.249 GPC6 Lilian Downie Publications for gene: GPC6 were set to
Mendeliome v1.1974 ATP6V1C1 Ain Roesley edited their review of gene: ATP6V1C1: Changed phenotypes: neurodevelopmental disorder MONDO:0700092, ATP6V1C1-related
Mendeliome v1.1974 ATP6V1C1 Ain Roesley gene: ATP6V1C1 was added
gene: ATP6V1C1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ATP6V1C1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ATP6V1C1 were set to 39210597
Review for gene: ATP6V1C1 was set to AMBER
gene: ATP6V1C1 was marked as current diagnostic
Added comment: 1x de novo missense p.Glu289Lys (absent in v4 gnomad). Manual inspection of IGV found the dad was mosaic 7% VAF and he shared some of the clinical features (minor digit anomalies).

Some functional studies using patient fibroblasts were performed, demonstrating similar effects as known pathogenic variants in ATP6V1B2.
- lysosomal morphology
- autophagic flux dysregulation
- increased acidification of lysosome

borderline red/amber
Sources: Literature
Prepair 1000+ v1.248 GPC6 Andrew Coventry reviewed gene: GPC6: Rating: GREEN; Mode of pathogenicity: None; Publications: 19481194 32655339 37353964; Phenotypes: Omodysplasia 1 MIM#258315; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.248 COL17A1 Kate Scarff reviewed gene: COL17A1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 20301304, 21357940; Phenotypes: Epidermolysis bullosa, junctional 4, intermediate, MIM# 619787; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1973 REPS2 Mark Cleghorn gene: REPS2 was added
gene: REPS2 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: REPS2 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Phenotypes for gene: REPS2 were set to complex neurodevelopmental disorder MONDO:0100038; Cerebral palsy HP:0100021
Penetrance for gene: REPS2 were set to unknown
Review for gene: REPS2 was set to AMBER
Added comment: REPS2
Hao Hu, Guangzhou Women and Children’s MC
ESHG talk 1/6/24, unpublished

Proposed X-linked cerebral palsy + NDD gene

4 unrelated males with predicted deleterious hemizygous REPS2 variants, 2 PTC, 2 missense. 2 de novo, 2 maternally inherited
Phenotypes: 2 w CP + moderate ID/ASD, 2 w NDD NOS
Variants described:
c.1050_1052delGAA;p.K351del
c.1040T>C; p.I347T
c.962C>G; p.S321C
c.1736delA; p.N579Tfs*17

In vitro assay of above 4 variants suggest reduced REPS2 protein stability
Zebrafish model: REPS2 expressed in neuronal cells, REPS2 knock down have reduced motor activity and abN neuronal morphology
Mouse model hemizygous w one of above variants (not specified): reduced performance in cognitive tasks, abnormal neuronal migration pattern on post mortem examination
Mechanism may relate to dopamine signalling?
Sources: Other
Intellectual disability syndromic and non-syndromic v0.6123 REPS2 Mark Cleghorn gene: REPS2 was added
gene: REPS2 was added to Intellectual disability syndromic and non-syndromic. Sources: Other
Mode of inheritance for gene: REPS2 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Phenotypes for gene: REPS2 were set to complex neurodevelopmental disorder MONDO:0100038; Cerebral palsy HP:0100021
Penetrance for gene: REPS2 were set to unknown
Review for gene: REPS2 was set to AMBER
Added comment: REPS2
Hao Hu, Guangzhou Women and Children’s MC
ESHG talk 1/6/24, unpublished

Proposed X-linked cerebral palsy + NDD gene

4 unrelated males with predicted deleterious hemizygous REPS2 variants, 2 PTC, 2 missense. 2 de novo, 2 maternally inherited
Phenotypes: 2 w CP + moderate ID/ASD, 2 w NDD NOS
Variants described:
c.1050_1052delGAA;p.K351del
c.1040T>C; p.I347T
c.962C>G; p.S321C
c.1736delA; p.N579Tfs*17

In vitro assay of above 4 variants suggest reduced REPS2 protein stability
Zebrafish model: REPS2 expressed in neuronal cells, REPS2 knock down have reduced motor activity and abN neuronal morphology
Mouse model hemizygous w one of above variants (not specified): reduced performance in cognitive tasks, abnormal neuronal migration pattern on post mortem examination
Mechanism may relate to dopamine signalling?
Sources: Other
Cerebral Palsy v1.367 REPS2 Mark Cleghorn gene: REPS2 was added
gene: REPS2 was added to Cerebral Palsy. Sources: Other
Mode of inheritance for gene: REPS2 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Phenotypes for gene: REPS2 were set to complex neurodevelopmental disorder MONDO:0100038; Cerebral palsy HP:0100021
Penetrance for gene: REPS2 were set to unknown
Review for gene: REPS2 was set to AMBER
Added comment: REPS2
Hao Hu, Guangzhou Women and Children’s MC
ESHG talk 1/6/24, unpublished

Proposed X-linked cerebral palsy + NDD gene

4 unrelated males with predicted deleterious hemizygous REPS2 variants, 2 PTC, 2 missense. 2 de novo, 2 maternally inherited
Phenotypes: 2 w CP + moderate ID/ASD, 2 w NDD NOS
Variants described:
c.1050_1052delGAA;p.K351del
c.1040T>C; p.I347T
c.962C>G; p.S321C
c.1736delA; p.N579Tfs*17

In vitro assay of above 4 variants suggest reduced REPS2 protein stability
Zebrafish model: REPS2 expressed in neuronal cells, REPS2 knock down have reduced motor activity and abN neuronal morphology
Mouse model hemizygous w one of above variants (not specified): reduced performance in cognitive tasks, abnormal neuronal migration pattern on post mortem examination
Mechanism may relate to dopamine signalling?
Sources: Other
Mendeliome v1.1973 TTL Mark Cleghorn gene: TTL was added
gene: TTL was added to Mendeliome. Sources: Other
Mode of inheritance for gene: TTL was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: TTL were set to complex neurodevelopmental disorderMONDO:0100038
Added comment: TTL
Valentina Serpieri, University of Pavia
ESHG talk 1/6/24

FAM1 (Italy)
2 affected sisters born to consanguineous Pakistani parents
GDD, spastic tetraparesis, optic atrophy, brain anomalies resembling tubulinopathies (dysplasia of corpus callosum, basal ganglia, brainstem)
WES: homozygous TTL:c.1013G>A; p.Cys338Tyr in both affected sisters

Via genematcher
5 more families (9 individuals) w similar phenotypes and biallelic variants in TTL

FAM2 (Egypt): homozygous p.Arg46Pro
FAM3 (Egypt): homozygous p.Arg46Pro
FAM4 (Australia): homozygous p.Gln183Arg
FAM5 (France): homozygous p.Trp147*
FAM6 (Saudi Arabia): homozygous p.His243Tyr

TTL KO mice: death soon after birth, no overt malformations, but defects in organisation of cerebral layers

Functional work on patient fibroblasts
FAM1 – reduced quantity of TTL protein compared to control on Western blot, decreased function of TTL protein (increase in detyrosinated tubulin) compared to controls – infer LoF as mechanism
FAM3 – mentioned but no details
FAM4– mentioned but no details
Sources: Other
Intellectual disability syndromic and non-syndromic v0.6123 TTL Mark Cleghorn gene: TTL was added
gene: TTL was added to Intellectual disability syndromic and non-syndromic. Sources: Other
Mode of inheritance for gene: TTL was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: TTL were set to complex neurodevelopmental disorder MONDO:0100038
Review for gene: TTL was set to AMBER
Added comment: TTL
Valentina Serpieri, University of Pavia
ESHG talk 1/6/24

FAM1 (Italy)
2 affected sisters born to consanguineous Pakistani parents
GDD, spastic tetraparesis, optic atrophy, brain anomalies resembling tubulinopathies (dysplasia of corpus callosum, basal ganglia, brainstem)
WES: homozygous TTL:c.1013G>A; p.Cys338Tyr in both affected sisters

Via genematcher
5 more families (9 individuals) w similar phenotypes and biallelic variants in TTL

FAM2 (Egypt): homozygous p.Arg46Pro
FAM3 (Egypt): homozygous p.Arg46Pro
FAM4 (Australia): homozygous p.Gln183Arg
FAM5 (France): homozygous p.Trp147*
FAM6 (Saudi Arabia): homozygous p.His243Tyr

TTL KO mice: death soon after birth, no overt malformations, but defects in organisation of cerebral layers

Functional work on patient fibroblasts
FAM1 – reduced quantity of TTL protein compared to control on Western blot, decreased function of TTL protein (increase in detyrosinated tubulin) compared to controls – infer LoF as mechanism
FAM3 – mentioned but no details
FAM4– mentioned but no details
Sources: Other
Tubulinopathies v1.1 TTL Mark Cleghorn gene: TTL was added
gene: TTL was added to Tubulinopathies. Sources: Other
Mode of inheritance for gene: TTL was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: TTL were set to complex neurodevelopmental disorder MONDO:0100038
Penetrance for gene: TTL were set to unknown
Review for gene: TTL was set to AMBER
Added comment: TTL
Valentina Serpieri, University of Pavia
ESHG talk 1/6/24

FAM1 (Italy)
2 affected sisters born to consanguineous Pakistani parents
GDD, spastic tetraparesis, optic atrophy, brain anomalies resembling tubulinopathies (dysplasia of corpus callosum, basal ganglia, brainstem)
WES: homozygous TTL:c.1013G>A; p.Cys338Tyr in both affected sisters

Via genematcher
5 more families (9 individuals) w similar phenotypes and biallelic variants in TTL

FAM2 (Egypt): homozygous p.Arg46Pro
FAM3 (Egypt): homozygous p.Arg46Pro
FAM4 (Australia): homozygous p.Gln183Arg
FAM5 (France): homozygous p.Trp147*
FAM6 (Saudi Arabia): homozygous p.His243Tyr

TTL KO mice: death soon after birth, no overt malformations, but defects in organisation of cerebral layers

Functional work on patient fibroblasts
FAM1 – reduced quantity of TTL protein compared to control on Western blot, decreased function of TTL protein (increase in detyrosinated tubulin) compared to controls – infer LoF as mechanism
FAM3 – mentioned but no details
FAM4– mentioned but no details
Sources: Other
Prepair 1000+ v1.248 FTO Marta Cifuentes Ochoa reviewed gene: FTO: Rating: GREEN; Mode of pathogenicity: None; Publications: 19234441, 19559399, 26378117, 26697951, 26378117, 26740239; Phenotypes: Growth retardation, developmental delay, facial dysmorphism MIM#612938, lethal polymalformative syndrome, Boissel type MONDO:0013050; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.248 FREM1 Marta Cifuentes Ochoa reviewed gene: FREM1: Rating: ; Mode of pathogenicity: None; Publications: 32016392, 21931569, 21507892, 19732862, 20301721, 28111185, 19732862; Phenotypes: Manitoba oculotrichoanal syndrome MIM# 248450, Bifid nose with or without anorectal and renal anomalies, MIM# 608980, oculotrichoanal syndrome MONDO:0009560, BNAR syndrome MONDO:0012165; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.248 F2 Marta Cifuentes Ochoa changed review comment from: Prothrombin deficiency type I, known as true prothrombin deficiency or 'hypoprothrombinemia,' is defined as plasma levels of prothrombin being less than 10% of normal with a concomitant decrease in activity. These patients have severe bleeding from birth, including umbilical cord hemorrhage, hematomas, ecchymoses, hematuria, mucosal bleeding, hemarthroses, intracranial bleeding, gastrointestinal bleeding, and menorrhagia.

HGNC approved symbol/name: F2
Is the phenotype(s) severe and onset <18yo ? Y
Known technical challenges? N
Gene reported in >3 independent families

Type II deficiency, known as 'dysprothrombinemia,' is characterized by normal or low-normal synthesis of a dysfunctional protein; to: Prothrombin deficiency type I, known as true prothrombin deficiency or 'hypoprothrombinemia,' is defined as plasma levels of prothrombin being less than 10% of normal with a concomitant decrease in activity. These patients have severe bleeding from birth, including umbilical cord hemorrhage, hematomas, ecchymoses, hematuria, mucosal bleeding, hemarthroses, intracranial bleeding, gastrointestinal bleeding, and menorrhagia.

HGNC approved symbol/name: F2
Is the phenotype(s) severe and onset <18yo ? Y
Known technical challenges? N
Gene reported in >3 independent families

Type II deficiency, known as 'dysprothrombinemia,' is characterized by normal or low-normal synthesis of a dysfunctional protein

AD forms and multifactorial conditions described for this gene not reportable in screening context
Prepair 1000+ v1.248 EPM2A Marta Cifuentes Ochoa reviewed gene: EPM2A: Rating: GREEN; Mode of pathogenicity: None; Publications: 9771710 9931343 11175283 12019207 12560877 14722920, 30947044, 22036712, 16311711, 28818698; Phenotypes: Myoclonic epilepsy of Lafora 1 MIM#254780, MONDO:0958199; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.248 F2 Marta Cifuentes Ochoa reviewed gene: F2: Rating: GREEN; Mode of pathogenicity: None; Publications: 23852823; Phenotypes: Hypoprothrombinemia MIM# 613679, congenital prothrombin deficiency MONDO:0013361; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.248 CBS Marta Cifuentes Ochoa reviewed gene: CBS: Rating: AMBER; Mode of pathogenicity: None; Publications: 7506602, 10338090, 7967489, 27778219; Phenotypes: Homocystinuria, B6-responsive and nonresponsive types, Thrombosis, hyperhomocysteinemic MIM#236200, classic homocystinuria, MONDO:0009352; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.248 GNE Andrew Coventry changed review comment from: Nonaka myopathy - Well established gene disease relationship. However, age of onset of myopathy reported to usually occur between age 20 and 40. Marginal for childhood onset condition.

Thrombocytopenia - well reported association of affected individuals experiencing bleeding episodes that commence from neonatal to early childhood. Myopathy variably reported in those affected - possibly due to young age of individuals presenting with bleeding symptoms. Myopathy, when reported, occurs at similar age of onset to Nonaka. Publication (25257349) indicates myopathy onset in affected sibs at mid-late teens. Also reported renal complications at age 7. Mouse model for GNE knockout shows renal involvement (PMID: 17549255). Condition reported to have caused cerebral haemorrhages in neonatal period (PMID:29941673). Unsure if phenotypic variability of condition, and isolated bleeding phenotype (as in ClinGen) suitable or adequate for screening context.; to: Nonaka myopathy - Well established gene disease relationship. However, age of onset of myopathy reported to usually occur between age 20 and 40. Myopathy then progresses, usually over ~10 year period to then require wheelchair assistance for mobility. Severe condition but onset is marginal for childhood onset screening context.

Thrombocytopenia - well reported association of affected individuals experiencing bleeding episodes that commence from neonatal to early childhood. Myopathy variably reported in those affected - possibly due to young age of individuals presenting with bleeding symptoms. Myopathy, when reported, occurs at similar age of onset to Nonaka. Publication (25257349) indicates myopathy onset in affected sibs at mid-late teens. Also reported renal complications at age 7. Mouse model for GNE knockout shows renal involvement (PMID: 17549255). Condition reported to have caused cerebral haemorrhages in neonatal period (PMID:29941673). Unsure if phenotypic variability of condition, and isolated bleeding phenotype (as in ClinGen) suitable or adequate for screening context.
Prepair 1000+ v1.248 GNE Andrew Coventry reviewed gene: GNE: Rating: AMBER; Mode of pathogenicity: None; Publications: 25257349 17549255 25061177 30171045 29941673; Phenotypes: Nonaka myopathy MIM#605820, Thrombocytopenia 12 with or without myopathy MIM#620757; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.248 GNAT2 Andrew Coventry reviewed gene: GNAT2: Rating: GREEN; Mode of pathogenicity: None; Publications: 32203983 17251445 15557429 23580486 31058429 12077706 12205108 27718025 21107338 28041643; Phenotypes: Achromatopsia 4 MIM#613856; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Cerebral Palsy v1.367 TBCK Clare van Eyk gene: TBCK was added
gene: TBCK was added to Cerebral Palsy. Sources: Literature
Mode of inheritance for gene: TBCK was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TBCK were set to PMID: 39213953
Phenotypes for gene: TBCK were set to Hypotonia, infantiale with psychomotor retardation and characteristic facies 3, MIM#616900
Review for gene: TBCK was set to RED
Added comment: Single individual with biallelic variants in TBCK reported in a monocentric cohort study (PMID: 39213953). Clinically, hypotonic CP, DD, muscle weakness, hyperlaxicity, epilepsy.
Sources: Literature
Cerebral Palsy v1.367 TBCD Clare van Eyk gene: TBCD was added
gene: TBCD was added to Cerebral Palsy. Sources: Literature
Mode of inheritance for gene: TBCD was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TBCD were set to PMID: 39213953
Phenotypes for gene: TBCD were set to Encephalopathy, progressive, early-onset, with brain atrophy and thin corpus callosum MIM#617193
Review for gene: TBCD was set to RED
Added comment: Single individual with homozygous missense variant reported in a monocentric cohort study (PMID: 39213953). Clinically, spastic quadriplegia, DD, ID, regression, focal epilepsy, cerebral atrophy, atrophy corpus callosum and brainstem. Initially diagnosed with CP.
Sources: Literature
Cerebral Palsy v1.367 RTN4IP1 Clare van Eyk gene: RTN4IP1 was added
gene: RTN4IP1 was added to Cerebral Palsy. Sources: Literature
Mode of inheritance for gene: RTN4IP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RTN4IP1 were set to PMID: 39213953
Phenotypes for gene: RTN4IP1 were set to Optic atrophy 10 with or without ataxia, impaired intellectual development, and seizures, MIM#616732
Review for gene: RTN4IP1 was set to RED
Added comment: Single individual with biallelic variants in RTN4IP1 reported in a monocentric cohort study (PMID: 39213953). Clinically, ataxia, axial hypotonia, DD, epilepsy, nystagmus, opticus neuropathy, dysmorphic features.
Sources: Literature
Cerebral Palsy v1.367 COQ4 Clare van Eyk gene: COQ4 was added
gene: COQ4 was added to Cerebral Palsy. Sources: Literature
Mode of inheritance for gene: COQ4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COQ4 were set to PMID: 39213953
Phenotypes for gene: COQ4 were set to Coenzyme Q10 deficiency, primary, MIM#616276; Spastic ataxia 10, autosomal recessive, MIM#620666
Review for gene: COQ4 was set to RED
Added comment: Two individuals with homozygous p.Thr77Ile variant reported in a monocentric cohort study (PMID: 39213953), both with spastic diplegia, DD but one also with hearing loss.
Sources: Literature
Cerebral Palsy v1.367 RNU7-1 Clare van Eyk gene: RNU7-1 was added
gene: RNU7-1 was added to Cerebral Palsy. Sources: Literature
Mode of inheritance for gene: RNU7-1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNU7-1 were set to PMID: 39213953
Phenotypes for gene: RNU7-1 were set to Aicardi-Goutières syndrome 9, MIM#619487
Review for gene: RNU7-1 was set to AMBER
Added comment: Two individuals with biallelic LP/P variants in RNU7-1 reported in a monocentric cohort study (PMID: 39213953). Both have recurrent RNU7-1 40_47DEL.

One with spastic quadriplegia, epilepsy, DD, hypomyelination, cerebral atrophy, old ishemic lesions, calcifications on CT.

Other with peripheral hypertonia, axial hypotonia, dystonia, calcifications, PVL, delayed myelination.
Sources: Literature
Cerebral Palsy v1.367 KMT2D Clare van Eyk edited their review of gene: KMT2D: Added comment: Additional individual with de novo splice variant reported in a monocentric cohort study (PMID: 39213953). Clinically, hypotonia, DD, ASD, dysmorphic features. No functional assessment of variant impact.; Changed publications: PMID: 38693247, PMID: 39213953
Cerebral Palsy v1.367 CLN6 Clare van Eyk gene: CLN6 was added
gene: CLN6 was added to Cerebral Palsy. Sources: Literature
Mode of inheritance for gene: CLN6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CLN6 were set to PMID: 39213953
Phenotypes for gene: CLN6 were set to Neuronal Ceroid Lipofuscinosis 6, MIM#601780
Review for gene: CLN6 was set to RED
Added comment: Single individual with compound heterozygous LP/P variants in CLN6 reported in a monocentric cohort study (PMID: 39213953). Patient reported to have progressive dystonia, developmental regression, DD, ID, with initial diagnosis of CP.
Sources: Literature
Cerebral Palsy v1.367 SMG8 Clare van Eyk gene: SMG8 was added
gene: SMG8 was added to Cerebral Palsy. Sources: Literature
Mode of inheritance for gene: SMG8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SMG8 were set to PMID: 39213953
Phenotypes for gene: SMG8 were set to Alzahrani-Kuwahara syndrome, MIM#619268
Review for gene: SMG8 was set to RED
Added comment: Single individual with biallelic variants in SMG8 reported in a monocentric CP cohort study (PMID: 39213953). Clinically, spastic CP with DD, ID, peripheral hypertonia, dysmorphic features.
Sources: Literature
Prepair 1000+ v1.248 GLA Shakira Heerah reviewed gene: GLA: Rating: GREEN; Mode of pathogenicity: None; Publications: 17224688, 29649853, 26937390, 20301469; Phenotypes: Fabry disease, 301500, (3); Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Prepair 1000+ v1.248 FANCC Shakira Heerah reviewed gene: FANCC: Rating: GREEN; Mode of pathogenicity: None; Publications: 29376519, 31044565, 30792206, 28717661; Phenotypes: Fanconi anemia, complementation group C, 227645 (3); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Cerebral Palsy v1.367 CHD3 Clare van Eyk edited their review of gene: CHD3: Added comment: Additional individual with de novo missense variant reported in a monocentric cohort study (PMID: 39213953). Clinically, ataxic CP, DD, ID, bilateral widened frontal subarachnoid space.; Changed publications: PMID: 38168508, PMID: 39213953
Cerebral Palsy v1.367 TSEN54 Clare van Eyk gene: TSEN54 was added
gene: TSEN54 was added to Cerebral Palsy. Sources: Literature
Mode of inheritance for gene: TSEN54 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TSEN54 were set to PMID: 39213953
Phenotypes for gene: TSEN54 were set to Pontocerebellar hypoplasia type 2, MIM#277470
Review for gene: TSEN54 was set to RED
Added comment: Two individuals with recurrent homozygous variant reported in a monocentric cohort study (PMID: 39213953). Not clear if they are related.

One with spastic CP, DD, epilepsy, feeding difficulties, behavioral problems, vision problems, pontocerebellar atrophy. Other with spastic CP and axial hypotonia, peripheral hypertonia, DD, ID, cortical visual impairment, pontocerebellar atrophy.
Sources: Literature
Cerebral Palsy v1.367 KCNK9 Clare van Eyk gene: KCNK9 was added
gene: KCNK9 was added to Cerebral Palsy. Sources: Literature
Mode of inheritance for gene: KCNK9 was set to MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed)
Publications for gene: KCNK9 were set to PMID: 39213953
Phenotypes for gene: KCNK9 were set to Birk-Barel syndrome (KCNK9 imprinting syndrome), MIM#612292
Review for gene: KCNK9 was set to RED
Added comment: Single individual with de novo missense variant reported in a monocentric cohort study (PMID: 39213953). Clinically, hypotonic CP, hyperlaxicity, DD, ID.
Sources: Literature
Prepair 1000+ v1.248 GDF5 Andrew Coventry reviewed gene: GDF5: Rating: GREEN; Mode of pathogenicity: None; Publications: 33333243 20683927 33872773; Phenotypes: Acromesomelic dysplasia 2A MIM#200700, Acromesomelic dysplasia 2B MIM#228900, Brachydactyly, type A1, C MIM#615072; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Cerebral Palsy v1.367 PIK3CA Clare van Eyk gene: PIK3CA was added
gene: PIK3CA was added to Cerebral Palsy. Sources: Literature
Mode of inheritance for gene: PIK3CA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PIK3CA were set to PMID: 39213953
Phenotypes for gene: PIK3CA were set to Megalencephaly-capillary malformation-polymicrogyria syndrome, somatic, MIM#602501
Review for gene: PIK3CA was set to RED
Added comment: Single individual with novel de novo in-frame deletion reported in a monocentric cohort study (PMID: 39213953). Clinically hypotonia, hyperlaxity, bilateral polymicrogyria, incomplete inversion hippocampi, prominent cerebellum.
Sources: Literature
Cerebral Palsy v1.367 ERCC8 Clare van Eyk changed review comment from: An additional individual reported with CP and a homozygous frameshift variant in large-scale exome sequencing study (PMID: 38693247). Detailed clinical information not supplied.; to: An additional individual reported with CP and a homozygous frameshift variant in large-scale exome sequencing study (PMID: 38693247). Detailed clinical information not supplied.

Single individual with homozygous splice variant reported in a monocentric cohort study (PMID: 39213953). Clinically, spastic CP with hypertonia, DD, ID, corpus callosum hypoplasia, hyperintensities in the deep white matter.
Cerebral Palsy v1.367 ALDH7A1 Clare van Eyk gene: ALDH7A1 was added
gene: ALDH7A1 was added to Cerebral Palsy. Sources: Literature
Mode of inheritance for gene: ALDH7A1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ALDH7A1 were set to PMID: 39213953
Phenotypes for gene: ALDH7A1 were set to Epilepsy, pyridoxine-dependent, MIM#266100
Review for gene: ALDH7A1 was set to RED
Added comment: Single individual with compound heterozygous varianta reported in a monocentric cohort study (PMID: 39213953). Clinically, spastic CP with mild hypertonia, ASD, ADHD, epilepsy not reported. Movement disorders, including CP in one case, are reported in one study of young adults with PDE-ALDH7A1 (PMID: 35782612).
Sources: Literature
Cerebral Palsy v1.367 BRAF Clare van Eyk gene: BRAF was added
gene: BRAF was added to Cerebral Palsy. Sources: Literature
Mode of inheritance for gene: BRAF was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: BRAF were set to PMID: 39213953
Phenotypes for gene: BRAF were set to Cardiofaciocutaneous syndrome, MIM#115150
Review for gene: BRAF was set to AMBER
Added comment: Two individuals each with a de novo missense variant reported in a monocentric cohort study (PMID: 39213953).

One with spastic CP with spasticity, hypertonia, ASD, PFO, mild pulmonary artery stenosis, failure to thrive, nystagmus, dysmorphic features.

The other with hypotonic CP with axial and peripheral hypotonia, DD, ID, mild pulmonary artery stenosis, dysmorphic features, hypothyroidism, small subacute subdural bleeding, small intraventricular haemorrhage, small cerebellum.
Sources: Literature
Cerebral Palsy v1.367 TRIT1 Clare van Eyk gene: TRIT1 was added
gene: TRIT1 was added to Cerebral Palsy. Sources: Literature
Mode of inheritance for gene: TRIT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRIT1 were set to PMID: 39213953
Phenotypes for gene: TRIT1 were set to Combined oxidative phosphorylation deficiency 35, MIM#617873
Review for gene: TRIT1 was set to RED
Added comment: Single individual with compound heterozygous variants (nonsense and missense) reported in a monocentric cohort study (PMID: 39213953). Clinically axial hypotonia, peripheral hypertonia, microcephaly, spastic CP, widened ventricular system, widened subarachnoid space.
Sources: Literature
Prepair 1000+ v1.248 FKTN Andrew Coventry reviewed gene: FKTN: Rating: ; Mode of pathogenicity: None; Publications: 9690476 19017726 20301385 28680109 17036286; Phenotypes: Muscular dystrophy-dystroglycanopathy MONDO:0018276, Cardiomyopathy, dilated, 1X MIM#611615; Mode of inheritance: None
Cerebral Palsy v1.367 KIF5C Clare van Eyk gene: KIF5C was added
gene: KIF5C was added to Cerebral Palsy. Sources: Literature
Mode of inheritance for gene: KIF5C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KIF5C were set to PMID: 39213953
Phenotypes for gene: KIF5C were set to Cortical dysplasia, complex, with other brain malformations 2 MIM#615282
Review for gene: KIF5C was set to RED
Added comment: Single individual with de novo missense variant reported in a monocentric cohort study (PMID: 39213953). Clinically spastic diplegia, DD, severe ID, epilepsy, polymicrogyria.
Sources: Literature
Cerebral Palsy v1.367 KIAA1109 Clare van Eyk gene: KIAA1109 was added
gene: KIAA1109 was added to Cerebral Palsy. Sources: Literature
Mode of inheritance for gene: KIAA1109 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KIAA1109 were set to PMID: 39213953
Phenotypes for gene: KIAA1109 were set to Alkuraya-Kucinskas syndrome, MIM#617822
Review for gene: KIAA1109 was set to RED
Added comment: Single individual with compound heterozygous variants (1 nonsense, 1 missense) reported in a monocentric cohort study (PMID: 39213953). Clinically West syndrome with evolution to Lennox-Gastaut, severe DD, ID, vision problems, microcephaly, feeding difficulties, spasticity, corpus callosum hypoplasia, cerebral atrophy, heterotopia.
Sources: Literature
Cerebral Palsy v1.367 CYFIP2 Clare van Eyk edited their review of gene: CYFIP2: Added comment: Additional individual with de novo missense variant in CYFIP2 reported in a monocentric cohort study (PMID: 39213953). Clinically ID, spastic quadriplegia, ASD.; Changed rating: AMBER; Changed publications: PMID: 38843839, PMID: 39213953
Prepair 1000+ v1.248 FAT4 Andrew Coventry reviewed gene: FAT4: Rating: GREEN; Mode of pathogenicity: None; Publications: 29681106 24913602 24056717 22473091; Phenotypes: Hennekam lymphangiectasia-lymphedema syndrome 2 MIM#616006, Van Maldergem syndrome 2 MIM#615546; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Cerebral Palsy v1.367 CLCN4 Clare van Eyk edited their review of gene: CLCN4: Added comment: Additional hemizygous male (de novo missense mutation) in monocentric cohort study (PMID: 39213953). Clinically spastic quadriplegia, epilepsy, osteoporosis, cerebral atrophy, corpus callosum hypoplasia.; Changed publications: PMID: 38693247, PMID: 37789889, PMID: 39213953
Cerebral Palsy v1.367 TRIO Clare van Eyk gene: TRIO was added
gene: TRIO was added to Cerebral Palsy. Sources: Literature
Mode of inheritance for gene: TRIO was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TRIO were set to PMID: 39213953
Phenotypes for gene: TRIO were set to Intellectual developmental disorder, autosomal dominant 44, with microcephaly MIM#617061
Review for gene: TRIO was set to RED
Added comment: Single individual with de novo missense variant in TRIO reported in a monocentric cohort study (PMID: 39213953). Clinically spastic quadriplegia, microcephaly, cortical visual impairment, Lennox Gastaut epilepsy, cerebral atrophy, megacisterna magna, aberrant skull morphology.
Sources: Literature
Cerebral Palsy v1.367 EBF3 Clare van Eyk gene: EBF3 was added
gene: EBF3 was added to Cerebral Palsy. Sources: Literature
Mode of inheritance for gene: EBF3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: EBF3 were set to PMID: 39213953
Phenotypes for gene: EBF3 were set to Hypotonia, ataxia and delayed development syndrome MIM#617330
Review for gene: EBF3 was set to RED
Added comment: Single individual with de novo missense variant in EBF3 reported in a monocentric cohort study (PMID: 39213953). Clinically DD, ataxia, dysarthria, strabism, cortical visual impairment.
Sources: Literature
Cerebral Palsy v1.367 ZMYND11 Clare van Eyk gene: ZMYND11 was added
gene: ZMYND11 was added to Cerebral Palsy. Sources: Literature
Mode of inheritance for gene: ZMYND11 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ZMYND11 were set to PMID: 39213953
Phenotypes for gene: ZMYND11 were set to Intellectual developmental disorder 30, MIM#616083
Review for gene: ZMYND11 was set to RED
Added comment: Single individual with novel de novo missense variant and dyskinetic CP with ID, dystonia, peripheral hypertonia and delayed myelination.
Sources: Literature
Prepair 1000+ v1.248 F5 Andrew Coventry reviewed gene: F5: Rating: AMBER; Mode of pathogenicity: None; Publications: 35593819 31121608; Phenotypes: Factor V deficiency MIM#227400; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Cerebral Palsy v1.367 PGAP2 Clare van Eyk gene: PGAP2 was added
gene: PGAP2 was added to Cerebral Palsy. Sources: Literature
Mode of inheritance for gene: PGAP2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PGAP2 were set to PMID: 39213953
Phenotypes for gene: PGAP2 were set to Hyperphosphatasia with impaired intellectual development syndrome 3, MIM#614207
Review for gene: PGAP2 was set to RED
Added comment: Single individual with homozygous missense variant and severe DD, epilepsy, axial hypotonia, dyskinetic quadriplegia, feeding difficulties.
Sources: Literature
Cerebral Palsy v1.367 PUM1 Clare van Eyk gene: PUM1 was added
gene: PUM1 was added to Cerebral Palsy. Sources: Literature
Mode of inheritance for gene: PUM1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PUM1 were set to PMID: 39213953
Phenotypes for gene: PUM1 were set to Neurodevelopmental disorder with motor abnormalities, seizures, and facial dysmorphism, MIM#620719; Spinocerebellar ataxia 47, MIM#617931
Review for gene: PUM1 was set to RED
Added comment: Single individual with de novo missense variant in PUM1 reported in a monocentric cohort study (PMID: 39213953). Reported with spastic CP, severe DD, epilepsy, microcephaly, cerebral atrophy, thin corpus callosum.
Sources: Literature
Cerebral Palsy v1.367 IREB2 Clare van Eyk gene: IREB2 was added
gene: IREB2 was added to Cerebral Palsy. Sources: Literature
Mode of inheritance for gene: IREB2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: IREB2 were set to PMID: 39213953
Phenotypes for gene: IREB2 were set to Neurodegeneration, early-onset, with choreoathetoid movements and microcytic anemia, MIM#618451
Review for gene: IREB2 was set to RED
Added comment: Single individual with compound heterozygous LP/P variants in IREB2 and hypotonic quadriplegia, severe DD, microcytic anemia, elevated ferritin, retinal dystrophy.
Sources: Literature
Cerebral Palsy v1.367 FRRS1L Clare van Eyk reviewed gene: FRRS1L: Rating: GREEN; Mode of pathogenicity: None; Publications: 33528536, 27236917, 39213953; Phenotypes: Developmental and epileptic encephalopathy MIM#616981; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.248 EVC2 Andrew Coventry reviewed gene: EVC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 23220543 10700184 33050204; Phenotypes: Ellis-van Creveld syndrome MIM#225500; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.248 B3GALNT2 Shakira Heerah reviewed gene: B3GALNT2: Rating: GREEN; Mode of pathogenicity: None; Publications: 35338537, 38585583, 23453667, 33290285, 29791932, 29273094, 28688748, 28303321; Phenotypes: Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 11, 615181 (3); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.248 B3GALNT2 Shakira Heerah Deleted their review
Prepair 1000+ v1.248 B3GALNT2 Shakira Heerah reviewed gene: B3GALNT2: Rating: ; Mode of pathogenicity: None; Publications: 35338537, 38585583, 23453667, 33290285, 29791932, 29273094, 28688748, 28303321; Phenotypes: Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 11, 615181 (3); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.248 ERBB3 Andrew Coventry reviewed gene: ERBB3: Rating: AMBER; Mode of pathogenicity: None; Publications: 17701904 31752936 33497358 12548738 38009810; Phenotypes: Visceral neuropathy, familial, 1, autosomal recessive MIM#243180, Lethal congenital contractural syndrome 2 MIM#607598; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.248 EIF2B4 Andrew Coventry reviewed gene: EIF2B4: Rating: GREEN; Mode of pathogenicity: None; Publications: 11835386 12707859 18263758 25843247 25761052 30014503 39139316; Phenotypes: Leukoencephalopathy with vanishing white matter 4, with or without ovarian failure MIM#620314; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hyperinsulinism v1.23 GPC3 Ain Roesley gene: GPC3 was added
gene: GPC3 was added to Hyperinsulinism. Sources: Literature
Mode of inheritance for gene: GPC3 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: GPC3 were set to 20301398
Phenotypes for gene: GPC3 were set to Simpson-Golabi-Behmel syndrome, type 1 MIM#312870
Review for gene: GPC3 was set to RED
gene: GPC3 was marked as current diagnostic
Added comment: from genereviews:

hypoglycemia may be present in the neonatal period; however, hypoglycemia is rare in SGBS1 and is not considered to be a cardinal feature.
Sources: Literature
Hyperinsulinism v1.22 AKT2 Ain Roesley Classified gene: AKT2 as Red List (low evidence)
Hyperinsulinism v1.22 AKT2 Ain Roesley Gene: akt2 has been classified as Red List (Low Evidence).
Hyperinsulinism v1.21 AKT2 Ain Roesley edited their review of gene: AKT2: Changed rating: RED
Hyperinsulinism v1.21 AKT2 Ain Roesley Classified gene: AKT2 as Amber List (moderate evidence)
Hyperinsulinism v1.21 AKT2 Ain Roesley Gene: akt2 has been classified as Amber List (Moderate Evidence).
Hyperinsulinism v1.21 AKT2 Ain Roesley Classified gene: AKT2 as Amber List (moderate evidence)
Hyperinsulinism v1.21 AKT2 Ain Roesley Gene: akt2 has been classified as Amber List (Moderate Evidence).
Hyperinsulinism v1.20 AKT2 Ain Roesley edited their review of gene: AKT2: Changed rating: AMBER; Changed phenotypes: Diabetes mellitus, type II MIM#125853, Hypoinsulinemic hypoglycemia with hemihypertrophy MIM#240900
Hyperinsulinism v1.20 AKT2 Ain Roesley changed review comment from: at least 5x individuals with hypoglycemia and de novo missense

Glu17Lys is a hotspot and GoF as a mechanism of disease
Sources: Literature; to: at least 5x individuals with hypoglycemia and de novo missense

Glu17Lys is a hotspot and GoF as a mechanism of disease

However, undetectable levels of serum insulin and C-peptide

Sources: Literature
Hyperinsulinism v1.20 AKT2 Ain Roesley Classified gene: AKT2 as Green List (high evidence)
Hyperinsulinism v1.20 AKT2 Ain Roesley Gene: akt2 has been classified as Green List (High Evidence).
Hyperinsulinism v1.19 AKT2 Ain Roesley gene: AKT2 was added
gene: AKT2 was added to Hyperinsulinism. Sources: Literature
Mode of inheritance for gene: AKT2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: AKT2 were set to 21979934; 35602880; 24285683
Phenotypes for gene: AKT2 were set to Diabetes mellitus, type II MIM#125853; Hypoinsulinemic hypoglycemia with hemihypertrophy MIM#240900
Review for gene: AKT2 was set to GREEN
gene: AKT2 was marked as current diagnostic
Added comment: at least 5x individuals with hypoglycemia and de novo missense

Glu17Lys is a hotspot and GoF as a mechanism of disease
Sources: Literature
Mendeliome v1.1973 PLEKHM2 Bryony Thompson Marked gene: PLEKHM2 as ready
Mendeliome v1.1973 PLEKHM2 Bryony Thompson Gene: plekhm2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1973 PLEKHM2 Bryony Thompson Classified gene: PLEKHM2 as Amber List (moderate evidence)
Mendeliome v1.1973 PLEKHM2 Bryony Thompson Gene: plekhm2 has been classified as Amber List (Moderate Evidence).
Dilated Cardiomyopathy v1.37 PLEKHM2 Bryony Thompson Marked gene: PLEKHM2 as ready
Dilated Cardiomyopathy v1.37 PLEKHM2 Bryony Thompson Gene: plekhm2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1972 PLEKHM2 Bryony Thompson gene: PLEKHM2 was added
gene: PLEKHM2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PLEKHM2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLEKHM2 were set to 35862026; 26464484; 38942823; 38490981; 37349842
Phenotypes for gene: PLEKHM2 were set to Dilated cardiomyopathy MONDO:0005021
Review for gene: PLEKHM2 was set to AMBER
Added comment: 2 unrelated families reported with DCM and supporting functional evidence
PMID: 35862026 - 21 yo with DCM with bialleic PLEKHM2 variants. Loss PLEKHM2 expression was found in the proband’s myocardial tissue

PMID: 26464484 - a homozygous frameshift variant (p.Lys645AlafsTer12) segregates with early-onset (adolescent) DCM and LVNC in a large consanguineous Bedouin family

PMID: 38942823 - murine model suggests Plekhm2 acts as an autophagy modulator in cardiofibroblasts

PMID: 38490981, 37349842 - supportive PLEKHM2 knockout iPSC-cardiomyocyte models
Sources: Literature
Dilated Cardiomyopathy v1.37 PLEKHM2 Bryony Thompson Classified gene: PLEKHM2 as Amber List (moderate evidence)
Dilated Cardiomyopathy v1.37 PLEKHM2 Bryony Thompson Gene: plekhm2 has been classified as Amber List (Moderate Evidence).
Dilated Cardiomyopathy v1.36 PLEKHM2 Bryony Thompson gene: PLEKHM2 was added
gene: PLEKHM2 was added to Dilated Cardiomyopathy. Sources: Literature
Mode of inheritance for gene: PLEKHM2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLEKHM2 were set to 35862026; 26464484; 38942823; 38490981; 37349842
Phenotypes for gene: PLEKHM2 were set to Dilated cardiomyopathy MONDO:0005021
Review for gene: PLEKHM2 was set to AMBER
Added comment: 2 unrelated families reported with DCM and supporting functional evidence
PMID: 35862026 - 21 yo with DCM with bialleic PLEKHM2 variants. Loss PLEKHM2 expression was found in the proband’s myocardial tissue

PMID: 26464484 - a homozygous frameshift variant (p.Lys645AlafsTer12) segregates with early-onset (adolescent) DCM and LVNC in a large consanguineous Bedouin family

PMID: 38942823 - murine model suggests Plekhm2 acts as an autophagy modulator in cardiofibroblasts

PMID: 38490981, 37349842 - supportive PLEKHM2 knockout iPSC-cardiomyocyte models
Sources: Literature
Dilated Cardiomyopathy v1.35 BMP10 Bryony Thompson Marked gene: BMP10 as ready
Dilated Cardiomyopathy v1.35 BMP10 Bryony Thompson Gene: bmp10 has been classified as Red List (Low Evidence).
Dilated Cardiomyopathy v1.35 BMP10 Bryony Thompson gene: BMP10 was added
gene: BMP10 was added to Dilated Cardiomyopathy. Sources: Literature
Mode of inheritance for gene: BMP10 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: BMP10 were set to 36673052
Phenotypes for gene: BMP10 were set to Dilated cardiomyopathy MONDO:0005021
Review for gene: BMP10 was set to RED
Added comment: A single family cosegregating NM_014482.3:c.166C > T;p.(Gln56*) with DCM.
Sources: Literature
Dilated Cardiomyopathy v1.34 NKX2-5 Bryony Thompson Publications for gene: NKX2-5 were set to 30354339; 28690296; 25503402; 27855642
Dilated Cardiomyopathy v1.34 NKX2-5 Bryony Thompson Classified gene: NKX2-5 as Green List (high evidence)
Dilated Cardiomyopathy v1.34 NKX2-5 Bryony Thompson Gene: nkx2-5 has been classified as Green List (High Evidence).
Dilated Cardiomyopathy v1.33 NKX2-5 Bryony Thompson reviewed gene: NKX2-5: Rating: GREEN; Mode of pathogenicity: None; Publications: 39018455, 37326999, 25503402, 23661673, 27855642, 30354339; Phenotypes: Dilated cardiomyopathy MONDO:0005021; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Intellectual disability syndromic and non-syndromic v0.6123 DHTKD1 Sumudu Perera reviewed gene: DHTKD1: Rating: AMBER; Mode of pathogenicity: None; Publications: 23141293, 37499576, 1112064, 6434826, 4442872, 4430147; Phenotypes: 2-aminoadipic 2-oxoadipic aciduria MIM#204750, Disorders of histidine, tryptophan or lysine metabolism; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1971 FLT3LG Zornitza Stark Phenotypes for gene: FLT3LG were changed from Increased susceptibility to infections to Immunodeficiency 125, MIM# 620926
Mendeliome v1.1970 FLT3LG Zornitza Stark reviewed gene: FLT3LG: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Immunodeficiency 125, MIM# 620926; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Bone Marrow Failure v1.94 FLT3LG Zornitza Stark Phenotypes for gene: FLT3LG were changed from Increased susceptibility to infections to Immunodeficiency 125, MIM# 620926
Bone Marrow Failure v1.93 FLT3LG Zornitza Stark reviewed gene: FLT3LG: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Immunodeficiency 125, MIM# 620926; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.6123 DCX Sumudu Perera edited their review of gene: DCX: Changed rating: GREEN
Intellectual disability syndromic and non-syndromic v0.6123 DARS2 Sumudu Perera reviewed gene: DARS2: Rating: GREEN; Mode of pathogenicity: None; Publications: 17384640, 21815884, 20506600; Phenotypes: Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation, MIM# 611105; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.6123 DCX Sumudu Perera changed review comment from: Pathology:
PMID: 26743950 - DCX mutations usually cause anterior dominant lissencephaly in males and subcortical band heterotopia (SBH) in females

Phenotype:
Demelas et al. (2001) (PMID:11468322) demonstrated three brothers with phenotype of microcephaly, mild to moderate developmental delay, seizures and other neurologic abnormalities, as well as classic lissencephaly on MRI.

Lawrence et al. (2010) (PMID: 20726879) discuss 3 male members had severe epilepsy and intellectual disability; finding of missense mutation in DCX. Of note all 3 had been diagnosed with Lennox-Gastaut syndrome.

GeneReviews (PMID: 20301364): "Males with classic DCX-related lissencephaly typically have early and profound cognitive and language impairment, cerebral palsy, and epileptic seizures. The clinical phenotype in females with SBH varies widely with cognitive abilities that range from average or mild cognitive impairment to severe intellectual disability and language impairment."

Other papers:
1) Somatic mosaicism and variable penetrance - PMID: 12552055
2) Functional testing: PMID: 9489699; to: Pathology:
PMID: 26743950 - DCX mutations usually cause anterior dominant lissencephaly in males and subcortical band heterotopia (SBH) in females

Phenotype:
Demelas et al. (2001) (PMID:11468322) demonstrated three brothers with phenotype of microcephaly, mild to moderate developmental delay, seizures and other neurologic abnormalities, as well as classic lissencephaly on MRI.

Lawrence et al. (2010) (PMID: 20726879) discuss 3 male members had severe epilepsy and intellectual disability; finding of missense mutation in DCX. Of note all 3 had been diagnosed with Lennox-Gastaut syndrome.

GeneReviews (PMID: 20301364): "Males with classic DCX-related lissencephaly typically have early and profound cognitive and language impairment, cerebral palsy, and epileptic seizures. The clinical phenotype in females with SBH varies widely with cognitive abilities that range from average or mild cognitive impairment to severe intellectual disability and language impairment."

Other papers:
1) Somatic mosaicism and variable penetrance - PMID: 12552055
2) Functional testing: PMID: 9489699
Intellectual disability syndromic and non-syndromic v0.6123 DCX Sumudu Perera reviewed gene: DCX: Rating: ; Mode of pathogenicity: None; Publications: 26743950, 11468322, 20726879, 20301364, 12552055, 9489699; Phenotypes: Lissencephaly, X-linked, MIM# 300067, Subcortical laminal heterotopia, X-linked 300067; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Prepair 1000+ v1.248 CIB2 Lilian Downie Marked gene: CIB2 as ready
Prepair 1000+ v1.248 CIB2 Lilian Downie Gene: cib2 has been classified as Red List (Low Evidence).
Prepair 1000+ v1.248 CIB2 Lilian Downie Phenotypes for gene: CIB2 were changed from Usher syndrome, type IJ, 614869 (3) to Deafness, autosomal recessive 48 MIM#609439
Prepair 1000+ v1.247 CIB2 Lilian Downie Publications for gene: CIB2 were set to
Prepair 1000+ v1.246 CLCF1 Lilian Downie Marked gene: CLCF1 as ready
Prepair 1000+ v1.246 CLCF1 Lilian Downie Gene: clcf1 has been classified as Green List (High Evidence).
Prepair 1000+ v1.246 CLCF1 Lilian Downie Publications for gene: CLCF1 were set to
Prepair 1000+ v1.245 CLCN7 Lilian Downie Marked gene: CLCN7 as ready
Prepair 1000+ v1.245 CLCN7 Lilian Downie Gene: clcn7 has been classified as Green List (High Evidence).
Prepair 1000+ v1.245 CLCN7 Lilian Downie Publications for gene: CLCN7 were set to
Prepair 1000+ v1.244 CCDC114 Lilian Downie Marked gene: CCDC114 as ready
Prepair 1000+ v1.244 CCDC114 Lilian Downie Gene: ccdc114 has been classified as Green List (High Evidence).
Prepair 1000+ v1.244 CCDC114 Lilian Downie Publications for gene: CCDC114 were set to
Prepair 1000+ v1.243 CCDC8 Lilian Downie Marked gene: CCDC8 as ready
Prepair 1000+ v1.243 CCDC8 Lilian Downie Added comment: Comment when marking as ready: Primordial dwarfism with normal intelligence, final adult height approx -5SD from the mean, subtle facial dysmorphism
Prepair 1000+ v1.243 CCDC8 Lilian Downie Gene: ccdc8 has been classified as Green List (High Evidence).
Prepair 1000+ v1.243 CCDC8 Lilian Downie Tag for review tag was added to gene: CCDC8.
Prepair 1000+ v1.243 CCDC8 Lilian Downie Publications for gene: CCDC8 were set to
Prepair 1000+ v1.242 CHRNG Lilian Downie Marked gene: CHRNG as ready
Prepair 1000+ v1.242 CHRNG Lilian Downie Gene: chrng has been classified as Green List (High Evidence).
Prepair 1000+ v1.242 CHRNG Lilian Downie Phenotypes for gene: CHRNG were changed from Escobar syndrome, 265000 (3) to Escobar syndrome (MIM# 265000); Multiple pterygium syndrome, lethal type, (MIM# 253290)
Prepair 1000+ v1.241 CHRNG Lilian Downie Publications for gene: CHRNG were set to
Prepair 1000+ v1.240 COQ6 Lilian Downie Marked gene: COQ6 as ready
Prepair 1000+ v1.240 COQ6 Lilian Downie Gene: coq6 has been classified as Green List (High Evidence).
Prepair 1000+ v1.240 COQ6 Lilian Downie Publications for gene: COQ6 were set to
Prepair 1000+ v1.239 COQ8A Lilian Downie Marked gene: COQ8A as ready
Prepair 1000+ v1.239 COQ8A Lilian Downie Gene: coq8a has been classified as Green List (High Evidence).
Prepair 1000+ v1.239 COQ8A Lilian Downie Publications for gene: COQ8A were set to
Prepair 1000+ v1.238 COQ2 Lilian Downie Marked gene: COQ2 as ready
Prepair 1000+ v1.238 COQ2 Lilian Downie Gene: coq2 has been classified as Green List (High Evidence).
Prepair 1000+ v1.238 COQ2 Lilian Downie Publications for gene: COQ2 were set to
Prepair 1000+ v1.237 CRTAP Lilian Downie Marked gene: CRTAP as ready
Prepair 1000+ v1.237 CRTAP Lilian Downie Gene: crtap has been classified as Green List (High Evidence).
Prepair 1000+ v1.237 CRTAP Lilian Downie Publications for gene: CRTAP were set to
Intellectual disability syndromic and non-syndromic v0.6123 D2HGDH Sumudu Perera reviewed gene: D2HGDH: Rating: GREEN; Mode of pathogenicity: None; Publications: 15609246, 16081310, 31349060, 20020533, 38825343; Phenotypes: D-2-hydroxyglutaric aciduria MIM#600721; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Prepair 1000+ v1.236 CRTAP Ee Ming Wong reviewed gene: CRTAP: Rating: GREEN; Mode of pathogenicity: None; Publications: 21955071, 19846465, 17192541; Phenotypes: Osteogenesis imperfecta, type VII MIM#610682; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Prepair 1000+ v1.236 COQ2 Cassandra Muller reviewed gene: COQ2: Rating: GREEN; Mode of pathogenicity: None; Publications: 16400613, 17855635, 17332895; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.236 COQ8A Ee Ming Wong reviewed gene: COQ8A: Rating: GREEN; Mode of pathogenicity: None; Publications: 32337771; Phenotypes: Coenzyme Q10 deficiency, primary, 4 MIM#612016; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Prepair 1000+ v1.236 COQ2 Cassandra Muller Deleted their review
Prepair 1000+ v1.236 COQ2 Cassandra Muller reviewed gene: COQ2: Rating: GREEN; Mode of pathogenicity: None; Publications: 16400613, 17332895, 17855635; Phenotypes: Coenzyme Q10 deficiency, primary, 1, 607426 (3); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.236 COQ6 Ee Ming Wong reviewed gene: COQ6: Rating: GREEN; Mode of pathogenicity: None; Publications: 28125198; Phenotypes: Coenzyme Q10 deficiency, primary, 6 MIM#614650; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Prepair 1000+ v1.236 CHRNG Ee Ming Wong reviewed gene: CHRNG: Rating: GREEN; Mode of pathogenicity: None; Publications: 16826520, 16826531, 22167768; Phenotypes: Escobar syndrome (MIM# 265000), Multiple pterygium syndrome, lethal type, (MIM# 253290); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Prepair 1000+ v1.236 CCDC8 Ee Ming Wong reviewed gene: CCDC8: Rating: GREEN; Mode of pathogenicity: None; Publications: 21737058; Phenotypes: 3-M syndrome 3, MIM#614205; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Prepair 1000+ v1.236 CCDC114 Ee Ming Wong reviewed gene: CCDC114: Rating: GREEN; Mode of pathogenicity: None; Publications: 23261303, 23261302, 32855706, 23506398; Phenotypes: Ciliary dyskinesia, primary, 20, MIM# 615067; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Prepair 1000+ v1.236 CLCN7 Cassandra Muller reviewed gene: CLCN7: Rating: GREEN; Mode of pathogenicity: None; Publications: 19507210, 11207362, 11741829, 14584882, 19953639; Phenotypes: Osteopetrosis, autosomal recessive 4, 611490 (3); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.236 CLCF1 Cassandra Muller changed review comment from: Severe early in life, can result in death. Features typically improve after 2 years.; to: Severe early in life and can result in early death.
Cerebral Palsy v1.367 CACNA1B Clare van Eyk Deleted their comment
Cerebral Palsy v1.367 CACNA1B Clare van Eyk edited their review of gene: CACNA1B: Added comment: 1 individual reported with biallelic variants (1 missense, 1 splice variant but functional assessment not performed) in large-scale CP exome sequencing study (PMID: 38693247). Detailed clinical information not supplied.

Additional case study reporting compound heterozygous frameshift variants in a child with epilepsy and cerebral palsy (PMID: 39005920).
Sources: Literature; Changed publications: PMID: 38693247, PMID: 39005920
Cerebral Palsy v1.367 CACNA1B Clare van Eyk changed review comment from: 1 individual reported with biallelic variants (1 missense, 1 splice) in large-scale CP exome sequencing study (PMID: 38693247). Detailed clinical information not supplied.
Sources: Literature; to: 1 individual reported with biallelic variants (1 missense, 1 splice variant but functional assessment not performed) in large-scale CP exome sequencing study (PMID: 38693247). Detailed clinical information not supplied.

Additional case study reporting compound heterozygous frameshift variants in a child with epilepsy and cerebral palsy (PMID: 39005920).
Sources: Literature
Prepair 1000+ v1.236 CLCF1 Cassandra Muller reviewed gene: CLCF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 16782820, 21370513, 20400119; Phenotypes: Cold-induced sweating syndrome 2, 610313 (3); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.236 CIB2 Cassandra Muller reviewed gene: CIB2: Rating: RED; Mode of pathogenicity: None; Publications: 29112224; Phenotypes: Usher syndrome, type IJ 614869; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Osteogenesis Imperfecta and Osteoporosis v0.115 WNT1 Bryony Thompson Mode of inheritance for gene: WNT1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Fetal anomalies v1.265 LAMA5 Tashunka Taylor-Miller reviewed gene: LAMA5: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 36322204; Phenotypes: cleft lip, cleft palate; Mode of inheritance: Unknown
Intellectual disability syndromic and non-syndromic v0.6123 GTPBP1 Zornitza Stark Phenotypes for gene: GTPBP1 were changed from Neurodevelopmental disorder (MONDO#0700092), GTPBP1-related to Neurodevelopmental disorder with characteristic facial and ectodermal features and tetraparesis 1, MIM# 620888
Intellectual disability syndromic and non-syndromic v0.6122 GTPBP1 Zornitza Stark reviewed gene: GTPBP1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with characteristic facial and ectodermal features and tetraparesis 1, MIM# 620888; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Microcephaly v1.272 GTPBP1 Zornitza Stark Phenotypes for gene: GTPBP1 were changed from Neurodevelopmental disorder (MONDO#0700092), GTPBP1-related to Neurodevelopmental disorder with characteristic facial and ectodermal features and tetraparesis 1, MIM# 620888
Microcephaly v1.271 GTPBP1 Zornitza Stark reviewed gene: GTPBP1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with characteristic facial and ectodermal features and tetraparesis 1, MIM# 620888; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1970 GTPBP1 Zornitza Stark Phenotypes for gene: GTPBP1 were changed from Neurodevelopmental disorder (MONDO#0700092), GTPBP1-related to Neurodevelopmental disorder with characteristic facial and ectodermal features and tetraparesis 1, MIM# 620888
Mendeliome v1.1969 GTPBP1 Zornitza Stark reviewed gene: GTPBP1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with characteristic facial and ectodermal features and tetraparesis 1, MIM# 620888; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.265 NME8 Achchuthan Shanmugasundram reviewed gene: NME8: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Mendeliome v1.1969 LRP1 Zornitza Stark Phenotypes for gene: LRP1 were changed from to Developmental dysplasia of the hip 3, MIM# 620690; Keratosis pilaris atrophicans MIM#604093
Mendeliome v1.1968 LRP1 Zornitza Stark Publications for gene: LRP1 were set to
Mendeliome v1.1967 LRP1 Zornitza Stark Mode of inheritance for gene: LRP1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1966 LRP1 Zornitza Stark Classified gene: LRP1 as Amber List (moderate evidence)
Mendeliome v1.1966 LRP1 Zornitza Stark Gene: lrp1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1965 LRP1 Zornitza Stark reviewed gene: LRP1: Rating: AMBER; Mode of pathogenicity: None; Publications: 36067312; Phenotypes: Developmental dysplasia of the hip 3, MIM# 620690; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1965 RAB32 Zornitza Stark Phenotypes for gene: RAB32 were changed from Parkinson disease MONDO:0005180 to {Parkinson disease 26, autosomal dominant, susceptibility to}, MIM# 620923
Mendeliome v1.1964 RAB32 Zornitza Stark Publications for gene: RAB32 were set to 38614108
Mendeliome v1.1963 RAB32 Zornitza Stark Classified gene: RAB32 as Amber List (moderate evidence)
Mendeliome v1.1963 RAB32 Zornitza Stark Gene: rab32 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1962 RAB32 Zornitza Stark reviewed gene: RAB32: Rating: AMBER; Mode of pathogenicity: None; Publications: 38858457; Phenotypes: {Parkinson disease 26, autosomal dominant, susceptibility to}, MIM# 620923; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early-onset Parkinson disease v2.7 RAB32 Zornitza Stark Phenotypes for gene: RAB32 were changed from Parkinson disease MONDO:0005180 to {Parkinson disease 26, autosomal dominant, susceptibility to}, MIM# 620923
Early-onset Parkinson disease v2.6 RAB32 Zornitza Stark Publications for gene: RAB32 were set to 38614108; 38858457
Early-onset Parkinson disease v2.5 RAB32 Zornitza Stark Publications for gene: RAB32 were set to 38614108
Early-onset Parkinson disease v2.4 RAB32 Zornitza Stark Classified gene: RAB32 as Amber List (moderate evidence)
Early-onset Parkinson disease v2.4 RAB32 Zornitza Stark Gene: rab32 has been classified as Amber List (Moderate Evidence).
Early-onset Parkinson disease v2.3 RAB32 Zornitza Stark reviewed gene: RAB32: Rating: AMBER; Mode of pathogenicity: None; Publications: 38858457; Phenotypes: {Parkinson disease 26, autosomal dominant, susceptibility to}, MIM# 620923; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1962 VPS52 Bryony Thompson Marked gene: VPS52 as ready
Mendeliome v1.1962 VPS52 Bryony Thompson Gene: vps52 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1962 VPS52 Bryony Thompson Classified gene: VPS52 as Amber List (moderate evidence)
Mendeliome v1.1962 VPS52 Bryony Thompson Gene: vps52 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1961 VPS52 Bryony Thompson gene: VPS52 was added
gene: VPS52 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: VPS52 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: VPS52 were set to complex neurodevelopmental disorder with or without congenital anomalies MONDO:0100465
Review for gene: VPS52 was set to AMBER
Added comment: HGSA poster (P110) from Louise Bicknell's group at the University of Otago. 11 cases from 8 families (USA, NZ, Saudi Arabia) with a broad syndromic developmental delay phenotype with biallelic variants (both missense & truncating).
Sources: Other
Hyperinsulinism v1.18 CACNA1D Chirag Patel edited their review of gene: CACNA1D: Added comment: 2nd case reported of child with persistent diazoxide-responsive HH, mild aortic insufficiency, severe hypotonia, and developmental delay. WES identified a de novo CACNA1D mutation (p.G403D). CACNA1D encodes the main L-type voltage-gated calcium channel in the pancreatic β-cell, a key component of the insulin secretion pathway. The p.G403D mutation had been reported previously as an activating mutation in an individual with primary hyper-aldosteronism, neuromuscular abnormalities, and transient hypoglycaemia.; Changed mode of pathogenicity: Other; Changed phenotypes: hyperinsulinaemic hypoglycaemia, heart defects, and severe hypotonia; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hyperinsulinism v1.18 MAFA Chirag Patel Classified gene: MAFA as Green List (high evidence)
Hyperinsulinism v1.18 MAFA Chirag Patel Gene: mafa has been classified as Green List (High Evidence).
Hyperinsulinism v1.17 MAFA Chirag Patel gene: MAFA was added
gene: MAFA was added to Hyperinsulinism. Sources: Literature
Mode of inheritance for gene: MAFA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MAFA were set to PMID: 29339498
Phenotypes for gene: MAFA were set to Insulinomatosis and diabetes mellitus, OMIM #:147630
Review for gene: MAFA was set to GREEN
gene: MAFA was marked as current diagnostic
Added comment: 2 families with 36 individuals with AD inheritance of diabetes mellitus or insulinomatosis (adult-onset recurrent hyperinsulinemic hypoglycemia caused by multiple insulin-secreting neuroendocrine tumours of pancreas). WES identified the same missense MAFA mutation (p.Ser64Phe, c.191C>T) segregating with both phenotypes of insulinomatosis and diabetes in both families. The p.Ser64Phe mutation was found to impair phosphorylation within the transactivation domain of MAFA and profoundly increased MAFA protein stability under both high and low glucose concentrations in β-cell lines. In addition, the transactivation potential of p.Ser64Phe MAFA in β-cell lines was enhanced compared with wild-type MAFA. The human phenotypes associated with the p.Ser64Phe MAFA missense mutation reflect both the oncogenic capacity of MAFA and its key role in islet β-cell activity.
Sources: Literature
Hypertrophic cardiomyopathy_HCM v1.0 Bryony Thompson promoted panel to version 1.0
Hypertrophic cardiomyopathy_HCM v0.196 Bryony Thompson Panel types changed to Victorian Clinical Genetics Services; Royal Melbourne Hospital; Rare Disease
Hypertrophic cardiomyopathy_HCM v0.195 RIT1 Bryony Thompson Marked gene: RIT1 as ready
Hypertrophic cardiomyopathy_HCM v0.195 RIT1 Bryony Thompson Gene: rit1 has been classified as Green List (High Evidence).
Hypertrophic cardiomyopathy_HCM v0.195 RIT1 Bryony Thompson Classified gene: RIT1 as Green List (high evidence)
Hypertrophic cardiomyopathy_HCM v0.195 RIT1 Bryony Thompson Gene: rit1 has been classified as Green List (High Evidence).
Hypertrophic cardiomyopathy_HCM v0.194 RIT1 Bryony Thompson gene: RIT1 was added
gene: RIT1 was added to Hypertrophic cardiomyopathy_HCM. Sources: ClinGen
Mode of inheritance for gene: RIT1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RIT1 were set to 39132495
Phenotypes for gene: RIT1 were set to Noonan syndrome MONDO:0018997
Mode of pathogenicity for gene: RIT1 was set to Other
Review for gene: RIT1 was set to GREEN
gene: RIT1 was marked as current diagnostic
Added comment: Included as one of the recommended 29 HCM genes to test by the ClinGen HCVD GCEP due to syndromic LVH being a feature of the condition that can be mistaken for HCM
Sources: ClinGen
Hypertrophic cardiomyopathy_HCM v0.193 RAF1 Bryony Thompson Publications for gene: RAF1 were set to 24777450
Hypertrophic cardiomyopathy_HCM v0.192 RAF1 Bryony Thompson Classified gene: RAF1 as Green List (high evidence)
Hypertrophic cardiomyopathy_HCM v0.192 RAF1 Bryony Thompson Added comment: Comment on list classification: Included as one of the recommended 29 HCM genes to test by the ClinGen HCVD GCEP due to syndromic LVH being a feature of the condition that can be mistaken for HCM
Hypertrophic cardiomyopathy_HCM v0.192 RAF1 Bryony Thompson Gene: raf1 has been classified as Green List (High Evidence).
Hypertrophic cardiomyopathy_HCM v0.191 PTPN11 Bryony Thompson Publications for gene: PTPN11 were set to
Hypertrophic cardiomyopathy_HCM v0.190 PTPN11 Bryony Thompson Classified gene: PTPN11 as Green List (high evidence)
Hypertrophic cardiomyopathy_HCM v0.190 PTPN11 Bryony Thompson Added comment: Comment on list classification: Included as one of the recommended 29 HCM genes to test by the ClinGen HCVD GCEP due to syndromic LVH being a feature of the condition that can be mistaken for HCM
Hypertrophic cardiomyopathy_HCM v0.190 PTPN11 Bryony Thompson Gene: ptpn11 has been classified as Green List (High Evidence).
Hypertrophic cardiomyopathy_HCM v0.189 DES Bryony Thompson Publications for gene: DES were set to
Hypertrophic cardiomyopathy_HCM v0.188 DES Bryony Thompson Phenotypes for gene: DES were changed from Hypertrophic cardiomyopathy; Dilated cardiomyopathy; Myofibrillar myopathy; ARVC to Desminopathy
Hypertrophic cardiomyopathy_HCM v0.187 DES Bryony Thompson Classified gene: DES as Green List (high evidence)
Hypertrophic cardiomyopathy_HCM v0.187 DES Bryony Thompson Added comment: Comment on list classification: Included as one of the 29 recommended HCM genes to test by the ClinGen HCVD GCEP for a syndromic LVH association - LV cardiomyopathy (including hypertrophy, dilation, restrictive, hypertrabeculation/ LVNC) is part of the phenotype of desminopathy
Hypertrophic cardiomyopathy_HCM v0.187 DES Bryony Thompson Gene: des has been classified as Green List (High Evidence).
Hypertrophic cardiomyopathy_HCM v0.186 DES Bryony Thompson Mode of inheritance for gene: DES was changed from BIALLELIC, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hypertrophic cardiomyopathy_HCM v0.185 CACNA1C Bryony Thompson Publications for gene: CACNA1C were set to 26253506; 28490369; 28866666
Hypertrophic cardiomyopathy_HCM v0.184 CACNA1C Bryony Thompson Classified gene: CACNA1C as Green List (high evidence)
Hypertrophic cardiomyopathy_HCM v0.184 CACNA1C Bryony Thompson Added comment: Comment on list classification: Classified as Definitive by the ClinGen HCVD GCEP for Timothy Syndrome, including left ventricular hypertrophy as a feature of the condition associated with some specific missense variants - https://search.clinicalgenome.org/CCID:008324. One of the 29 recommended HCM genes.
Hypertrophic cardiomyopathy_HCM v0.184 CACNA1C Bryony Thompson Gene: cacna1c has been classified as Green List (High Evidence).
Hypertrophic cardiomyopathy_HCM v0.183 UQCRFS1 Bryony Thompson Classified gene: UQCRFS1 as Red List (low evidence)
Hypertrophic cardiomyopathy_HCM v0.183 UQCRFS1 Bryony Thompson Added comment: Comment on list classification: Paediatric onset condition. This gene is on the paediatric cardiomyopathy panel. Not one of the 29 genes recommended for HCM testing by the ClinGen HCVD GCEP.
Hypertrophic cardiomyopathy_HCM v0.183 UQCRFS1 Bryony Thompson Gene: uqcrfs1 has been classified as Red List (Low Evidence).
Hypertrophic cardiomyopathy_HCM v0.182 TULP3 Bryony Thompson Classified gene: TULP3 as Amber List (moderate evidence)
Hypertrophic cardiomyopathy_HCM v0.182 TULP3 Bryony Thompson Added comment: Comment on list classification: Currently, only 3 adult individuals from 2 unrelated families presented with hypertrophic non-obstructive cardiomyopathy (HNCM). More evidence required for the HCM association
Hypertrophic cardiomyopathy_HCM v0.182 TULP3 Bryony Thompson Gene: tulp3 has been classified as Amber List (Moderate Evidence).
Hypertrophic cardiomyopathy_HCM v0.181 C1QBP Bryony Thompson Classified gene: C1QBP as Red List (low evidence)
Hypertrophic cardiomyopathy_HCM v0.181 C1QBP Bryony Thompson Added comment: Comment on list classification: Paediatric onset condition. Has been moved to the paediatric cardiomyopathy panel. Not one of the 29 genes the ClinGen HCVD GCEP recommends for HCM testing
Hypertrophic cardiomyopathy_HCM v0.181 C1QBP Bryony Thompson Gene: c1qbp has been classified as Red List (Low Evidence).
Cardiomyopathy_Paediatric v0.196 C1QBP Bryony Thompson Classified gene: C1QBP as Green List (high evidence)
Cardiomyopathy_Paediatric v0.196 C1QBP Bryony Thompson Gene: c1qbp has been classified as Green List (High Evidence).
Cardiomyopathy_Paediatric v0.194 C1QBP Bryony Thompson gene: C1QBP was added
gene: C1QBP was added to Cardiomyopathy_Paediatric. Sources: Literature
Mode of inheritance for gene: C1QBP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C1QBP were set to 28942965
Phenotypes for gene: C1QBP were set to Combined oxidative phosphorylation deficiency 33, MIM#617713
Cardiomyopathy_Paediatric v0.193 MYH6 Bryony Thompson Marked gene: MYH6 as ready
Cardiomyopathy_Paediatric v0.193 MYH6 Bryony Thompson Gene: myh6 has been classified as Red List (Low Evidence).
Cardiomyopathy_Paediatric v0.193 MYH6 Bryony Thompson Classified gene: MYH6 as Red List (low evidence)
Cardiomyopathy_Paediatric v0.193 MYH6 Bryony Thompson Added comment: Comment on list classification: ClinGen HCVD GCEP has classified the HCM association as Disputed (https://search.clinicalgenome.org/CCID:008325) and the DCM association as Limited (https://search.clinicalgenome.org/CCID:005520)
Cardiomyopathy_Paediatric v0.193 MYH6 Bryony Thompson Gene: myh6 has been classified as Red List (Low Evidence).
Hypertrophic cardiomyopathy_HCM v0.180 RPS6KB1 Bryony Thompson Classified gene: RPS6KB1 as Amber List (moderate evidence)
Hypertrophic cardiomyopathy_HCM v0.180 RPS6KB1 Bryony Thompson Added comment: Comment on list classification: ClinGen HCVD GCEP has classified this gene as Limited for HCM on 13/09/2023 - https://search.clinicalgenome.org/CCID:006034
Hypertrophic cardiomyopathy_HCM v0.180 RPS6KB1 Bryony Thompson Gene: rps6kb1 has been classified as Amber List (Moderate Evidence).
Prepair 1000+ v1.236 ALG2 Lana Giameos reviewed gene: ALG2: Rating: AMBER; Mode of pathogenicity: None; Publications: 33644825, 23404334, 24461433, 12684507, 30397276, 34980536, 34106226; Phenotypes: Congenital disorder of glycosylation, type Ii, MIM# 607906, Myasthenic syndrome, congenital, 14, MIM# 616228; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.236 DYSF Zornitza Stark Marked gene: DYSF as ready
Prepair 1000+ v1.236 DYSF Zornitza Stark Gene: dysf has been classified as Green List (High Evidence).
Prepair 1000+ v1.236 DYSF Zornitza Stark Phenotypes for gene: DYSF were changed from Muscular dystrophy, limb-girdle, type 2B, 253601 (3) to Miyoshi muscular dystrophy 1 MIM#254130; MONDO:0024545; Muscular dystrophy, limb-girdle, autosomal recessive 2 MIM#253601; MONDO:0009676; Myopathy, distal, with anterior tibial onset MIM#606768; MONDO:0011721
Prepair 1000+ v1.235 DYSF Zornitza Stark Publications for gene: DYSF were set to
Prepair 1000+ v1.234 DYSF Zornitza Stark reviewed gene: DYSF: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Miyoshi muscular dystrophy 1 MIM#254130, MONDO:0024545, Muscular dystrophy, limb-girdle, autosomal recessive 2 MIM#253601, MONDO:0009676, Myopathy, distal, with anterior tibial onset MIM#606768, MONDO:0011721; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.234 DYSF Marta Cifuentes Ochoa reviewed gene: DYSF: Rating: GREEN; Mode of pathogenicity: None; Publications: 37762951, 38540676, 36542547, 32400077; Phenotypes: Miyoshi muscular dystrophy 1 MIM#254130, MONDO:0024545, Muscular dystrophy, limb-girdle, autosomal recessive 2 MIM#253601, MONDO:0009676, Myopathy, distal, with anterior tibial onset MIM#606768, MONDO:0011721; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.234 DYSF Marta Cifuentes Ochoa Deleted their review
Prepair 1000+ v1.234 SURF1 Zornitza Stark Marked gene: SURF1 as ready
Prepair 1000+ v1.234 SURF1 Zornitza Stark Added comment: Comment when marking as ready: Agree Mitochondrial complex IV deficiency, nuclear type 1, MIM# 220110 is the appropriate term to use.
Prepair 1000+ v1.234 SURF1 Zornitza Stark Gene: surf1 has been classified as Green List (High Evidence).
Prepair 1000+ v1.234 SURF1 Zornitza Stark Phenotypes for gene: SURF1 were changed from Leigh syndrome, due to COX deficiency, 256000 (3) to Mitochondrial complex IV deficiency, nuclear type 1, MIM# 220110
Prepair 1000+ v1.233 YIF1B Zornitza Stark Marked gene: YIF1B as ready
Prepair 1000+ v1.233 YIF1B Zornitza Stark Gene: yif1b has been classified as Red List (Low Evidence).
Prepair 1000+ v1.233 YIF1B Zornitza Stark Phenotypes for gene: YIF1B were changed from Abnormality of movement; Seizures; Failure to thrive; Spasticity; Central hypotonia; Intellectual disability; Global developmental delay; Microcephaly to Kaya-Barakat-Masson syndrome, MIM# 619125
Prepair 1000+ v1.232 GTPBP2 Zornitza Stark Marked gene: GTPBP2 as ready
Prepair 1000+ v1.232 GTPBP2 Zornitza Stark Gene: gtpbp2 has been classified as Red List (Low Evidence).
Prepair 1000+ v1.232 CSMD1 Zornitza Stark Marked gene: CSMD1 as ready
Prepair 1000+ v1.232 CSMD1 Zornitza Stark Gene: csmd1 has been classified as Red List (Low Evidence).
Prepair 1000+ v1.232 AFF2 Zornitza Stark Marked gene: AFF2 as ready
Prepair 1000+ v1.232 AFF2 Zornitza Stark Gene: aff2 has been classified as Amber List (Moderate Evidence).
Prepair 1000+ v1.232 AFF2 Zornitza Stark Phenotypes for gene: AFF2 were changed from Mental retardation, X-linked, FRAXE type, #309548 to Intellectual disability, X-linked, FRAXE type 309548
Prepair 1000+ v1.231 AFF2 Zornitza Stark Publications for gene: AFF2 were set to
Prepair 1000+ v1.230 AFF2 Zornitza Stark Classified gene: AFF2 as Amber List (moderate evidence)
Prepair 1000+ v1.230 AFF2 Zornitza Stark Gene: aff2 has been classified as Amber List (Moderate Evidence).
Prepair 1000+ v1.229 AFF2 Zornitza Stark reviewed gene: AFF2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual disability, X-linked, FRAXE type 309548; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Prepair 1000+ v1.229 ACY1 Zornitza Stark Marked gene: ACY1 as ready
Prepair 1000+ v1.229 ACY1 Zornitza Stark Gene: acy1 has been classified as Red List (Low Evidence).
Prepair 1000+ v1.229 DYSF Marta Cifuentes Ochoa Deleted their comment
Prepair 1000+ v1.229 DYSF Marta Cifuentes Ochoa commented on gene: DYSF: Miyoshi myopathy (MM) is the most common form of recessive distal myopathy in populations with founder mutations such as Libyan and Israeli Jewish population, Italian and Spanish populations.The typical age of onset of MM lies between 15 and 30 years

Autosomal recessive limb-girdle muscular dystrophy type 2B (LGMD2B) is a subtype of autosomal recessive limb-girdle muscular dystrophy characterized by an onset in late adolescence or early adulthood of slowly progressive, proximal weakness and atrophy of shoulder and pelvic girdle muscles. Cardiac and respiratory muscles are not involved. Hypertrophy of the calf muscles and highly elevated serum creatine kinase levels are frequently observed.

Myopathy, distal, with anterior tibial onset is a rare genetic neuromuscular disease with characteristics of a progressive muscle weakness starting in the anterior tibial muscles, later involving lower and upper limb muscles, associated with an increased serum creatine kinase levels and absence of dysferlin on muscle biopsy. Patients become wheelchair dependent.

HGNC approved symbol/name: DYSF
Is the phenotype(s) severe and onset <18yo ? ? chidhood, early adulthood to late onset
Known technical challenges? N but large‐scale copy number variants have been identified.
Gene reported in >3 independent families

Unsure due genotype/phenotype correlation and onset
Prepair 1000+ v1.229 DYSF Marta Cifuentes Ochoa reviewed gene: DYSF: Rating: AMBER; Mode of pathogenicity: None; Publications: 37762951, 38540676, 36542547, 32400077; Phenotypes: Miyoshi muscular dystrophy 1 MIM#254130, MONDO:0024545, Muscular dystrophy, limb-girdle, autosomal recessive 2 MIM#253601, MONDO:0009676, Myopathy, distal, with anterior tibial onset MIM#606768, MONDO:0011721; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.229 LIG4 Zornitza Stark Marked gene: LIG4 as ready
Prepair 1000+ v1.229 LIG4 Zornitza Stark Gene: lig4 has been classified as Green List (High Evidence).
Prepair 1000+ v1.229 LIG4 Zornitza Stark Phenotypes for gene: LIG4 were changed from LIG4 syndrome, MIM# 606593 DNA ligase IV deficiency, MONDO:0011686 to LIG4 syndrome, MIM# 606593; DNA ligase IV deficiency, MONDO:0011686
Prepair 1000+ v1.228 LIG4 Zornitza Stark Phenotypes for gene: LIG4 were changed from LIG4 syndrome, 606593 (3) to LIG4 syndrome, MIM# 606593 DNA ligase IV deficiency, MONDO:0011686
Prepair 1000+ v1.227 LIG4 Zornitza Stark Publications for gene: LIG4 were set to
Prepair 1000+ v1.226 LIG4 Zornitza Stark commented on gene: LIG4: Congenital onset, presents with combined immunodeficiency and features of radiosensitivity, chromosomal instability, pancytopenia, and developmental and growth delay.
Prepair 1000+ v1.226 LIG4 Zornitza Stark reviewed gene: LIG4: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: LIG4 syndrome, MIM# 606593 DNA ligase IV deficiency, MONDO:0011686; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.226 ECHS1 Zornitza Stark Marked gene: ECHS1 as ready
Prepair 1000+ v1.226 ECHS1 Zornitza Stark Gene: echs1 has been classified as Green List (High Evidence).
Prepair 1000+ v1.226 ECHS1 Zornitza Stark Publications for gene: ECHS1 were set to
Prepair 1000+ v1.225 CHM Zornitza Stark Tag for review tag was added to gene: CHM.
Prepair 1000+ v1.225 CISD2 Zornitza Stark Marked gene: CISD2 as ready
Prepair 1000+ v1.225 CISD2 Zornitza Stark Gene: cisd2 has been classified as Green List (High Evidence).
Prepair 1000+ v1.225 CISD2 Zornitza Stark Phenotypes for gene: CISD2 were changed from Wolfram syndrome 2, 604928 (3) to Wolfram syndrome 2 MIM#604928; MONDO:0011502
Prepair 1000+ v1.224 CISD2 Zornitza Stark Publications for gene: CISD2 were set to
Prepair 1000+ v1.223 CLCN2 Zornitza Stark Marked gene: CLCN2 as ready
Prepair 1000+ v1.223 CLCN2 Zornitza Stark Gene: clcn2 has been classified as Green List (High Evidence).
Prepair 1000+ v1.223 CLCN2 Zornitza Stark Phenotypes for gene: CLCN2 were changed from Leukoencephalopathy with ataxia, 615651 (3) to Leukoencephalopathy with ataxia MIM#615651; leukoencephalopathy with mild cerebellar ataxia and white matter oedema MONDO:0014292
Prepair 1000+ v1.222 CLCN2 Zornitza Stark Publications for gene: CLCN2 were set to
Prepair 1000+ v1.221 CLN3 Zornitza Stark Marked gene: CLN3 as ready
Prepair 1000+ v1.221 CLN3 Zornitza Stark Gene: cln3 has been classified as Green List (High Evidence).
Prepair 1000+ v1.221 CLN3 Zornitza Stark Phenotypes for gene: CLN3 were changed from Ceroid lipofuscinosis, neuronal, 3, 204200 (3) to Ceroid lipofuscinosis, neuronal, 3, MIM# 204200; MONDO:0008767
Prepair 1000+ v1.220 CLN3 Zornitza Stark Publications for gene: CLN3 were set to
Prepair 1000+ v1.219 COL4A3 Zornitza Stark Marked gene: COL4A3 as ready
Prepair 1000+ v1.219 COL4A3 Zornitza Stark Gene: col4a3 has been classified as Green List (High Evidence).
Prepair 1000+ v1.219 COL4A3 Zornitza Stark Phenotypes for gene: COL4A3 were changed from Alport syndrome, autosomal recessive, 203780 (3) to Alport syndrome 3b, autosomal recessive MIM#620536; MONDO:0957811
Prepair 1000+ v1.218 COL4A3 Zornitza Stark Publications for gene: COL4A3 were set to
Prepair 1000+ v1.217 COLEC11 Zornitza Stark Marked gene: COLEC11 as ready
Prepair 1000+ v1.217 COLEC11 Zornitza Stark Gene: colec11 has been classified as Green List (High Evidence).
Prepair 1000+ v1.217 COLEC11 Zornitza Stark Phenotypes for gene: COLEC11 were changed from 3MC syndrome 2, 265050 (3) to 3MC syndrome 2, MIM# 265050; MONDO:0009927
Prepair 1000+ v1.216 COLEC11 Zornitza Stark Publications for gene: COLEC11 were set to
Prepair 1000+ v1.215 COLQ Zornitza Stark Marked gene: COLQ as ready
Prepair 1000+ v1.215 COLQ Zornitza Stark Gene: colq has been classified as Green List (High Evidence).
Prepair 1000+ v1.215 COLQ Zornitza Stark Phenotypes for gene: COLQ were changed from Myasthenic syndrome, congenital, 5, 603034 (3) to Myasthenic syndrome, congenital, 5 MIM#603034; MONDO:0011281
Prepair 1000+ v1.214 COLQ Zornitza Stark Publications for gene: COLQ were set to
Prepair 1000+ v1.213 CRB2 Zornitza Stark Marked gene: CRB2 as ready
Prepair 1000+ v1.213 CRB2 Zornitza Stark Gene: crb2 has been classified as Green List (High Evidence).
Prepair 1000+ v1.213 CRB2 Zornitza Stark Phenotypes for gene: CRB2 were changed from Ventriculomegaly with cystic kidney disease, 219730 (3) to Ventriculomegaly with cystic kidney disease, MIM# 219730; MONDO:0009063; Focal segmental glomerulosclerosis 9, MIM# 616220; MONDO:0014539
Prepair 1000+ v1.212 CRB2 Zornitza Stark Publications for gene: CRB2 were set to
Prepair 1000+ v1.211 DGAT1 Zornitza Stark Marked gene: DGAT1 as ready
Prepair 1000+ v1.211 DGAT1 Zornitza Stark Gene: dgat1 has been classified as Green List (High Evidence).
Prepair 1000+ v1.211 DGAT1 Zornitza Stark Phenotypes for gene: DGAT1 were changed from ?Diarrhea 7, protein-losing enteropathy type to Diarrhoea 7, protein-losing enteropathy type, MIM# 615863; congenital diarrhoea 7 with exudative enteropathy MONDO:0014375
Prepair 1000+ v1.210 DGAT1 Zornitza Stark Publications for gene: DGAT1 were set to
Prepair 1000+ v1.209 B3GALT6 Zornitza Stark Marked gene: B3GALT6 as ready
Prepair 1000+ v1.209 B3GALT6 Zornitza Stark Gene: b3galt6 has been classified as Green List (High Evidence).
Prepair 1000+ v1.209 B3GALT6 Zornitza Stark Phenotypes for gene: B3GALT6 were changed from Spondyloepimetaphyseal dysplasia with joint laxity, type 1, with or without fractures, 271640 (3) to Al-Gazali syndrome, MIM# 609465; Ehlers-Danlos syndrome, spondylodysplastic type, 2, MIM# 615349; Spondyloepimetaphyseal dysplasia with joint laxity, type 1, with or without fractures, MIM#271640
Prepair 1000+ v1.208 B3GLCT Zornitza Stark Marked gene: B3GLCT as ready
Prepair 1000+ v1.208 B3GLCT Zornitza Stark Gene: b3glct has been classified as Green List (High Evidence).
Prepair 1000+ v1.208 B3GLCT Zornitza Stark Phenotypes for gene: B3GLCT were changed from Peters-plus syndrome, 261540 (3) to Peters-plus syndrome, MIM# 261540
Prepair 1000+ v1.207 B3GLCT Zornitza Stark Publications for gene: B3GLCT were set to
Prepair 1000+ v1.206 APOPT1 Zornitza Stark Marked gene: APOPT1 as ready
Prepair 1000+ v1.206 APOPT1 Zornitza Stark Gene: apopt1 has been classified as Green List (High Evidence).
Prepair 1000+ v1.206 APOPT1 Zornitza Stark Phenotypes for gene: APOPT1 were changed from Mitochondrial complex IV deficiency, 220110 (3) to Mitochondrial complex IV deficiency, MIM#220110
Prepair 1000+ v1.205 APOPT1 Zornitza Stark Publications for gene: APOPT1 were set to
Prepair 1000+ v1.204 APOPT1 Zornitza Stark Tag new gene name tag was added to gene: APOPT1.
Prepair 1000+ v1.204 ARFGEF2 Zornitza Stark Marked gene: ARFGEF2 as ready
Prepair 1000+ v1.204 ARFGEF2 Zornitza Stark Gene: arfgef2 has been classified as Green List (High Evidence).
Prepair 1000+ v1.204 ARFGEF2 Zornitza Stark Phenotypes for gene: ARFGEF2 were changed from Periventricular heterotopia with microcephaly, 608097 (3) to Periventricular heterotopia with microcephaly, MIM#608097
Prepair 1000+ v1.203 ARFGEF2 Zornitza Stark Publications for gene: ARFGEF2 were set to
Prepair 1000+ v1.202 ARL13B Zornitza Stark Marked gene: ARL13B as ready
Prepair 1000+ v1.202 ARL13B Zornitza Stark Gene: arl13b has been classified as Green List (High Evidence).
Prepair 1000+ v1.202 ARL13B Zornitza Stark Publications for gene: ARL13B were set to
Prepair 1000+ v1.201 ARL13B Zornitza Stark reviewed gene: ARL13B: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Joubert syndrome 8, MIM# 612291; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.201 ASNS Zornitza Stark Marked gene: ASNS as ready
Prepair 1000+ v1.201 ASNS Zornitza Stark Gene: asns has been classified as Green List (High Evidence).
Prepair 1000+ v1.201 ASNS Zornitza Stark Phenotypes for gene: ASNS were changed from Asparagine synthetase deficiency, 615574 (3) to Asparagine synthetase deficiency, MIM#615574
Prepair 1000+ v1.200 ASNS Zornitza Stark Publications for gene: ASNS were set to
Prepair 1000+ v1.199 ATP8B1 Zornitza Stark Marked gene: ATP8B1 as ready
Prepair 1000+ v1.199 ATP8B1 Zornitza Stark Gene: atp8b1 has been classified as Green List (High Evidence).
Prepair 1000+ v1.199 CSMD1 Zornitza Stark Tag for review tag was added to gene: CSMD1.
Prepair 1000+ v1.199 ASCC1 Zornitza Stark Marked gene: ASCC1 as ready
Prepair 1000+ v1.199 ASCC1 Zornitza Stark Gene: ascc1 has been classified as Green List (High Evidence).
Prepair 1000+ v1.199 ASCC1 Zornitza Stark Phenotypes for gene: ASCC1 were changed from Spinal muscular atrophy with congenital bone fractures 2, MIM#616867 to Spinal muscular atrophy with congenital bone fractures 2, MIM#616867; spinal muscular atrophy with congenital bone fractures 2 MONDO:0014807
Prepair 1000+ v1.198 ASCC1 Zornitza Stark Publications for gene: ASCC1 were set to
Prepair 1000+ v1.197 AUH Zornitza Stark Marked gene: AUH as ready
Prepair 1000+ v1.197 AUH Zornitza Stark Gene: auh has been classified as Green List (High Evidence).
Prepair 1000+ v1.197 AUH Zornitza Stark Phenotypes for gene: AUH were changed from 3-methylglutaconic aciduria, type I, 250950 (3) to 3-methylglutaconic aciduria, type I, MIM# 250950; MONDO:0009610
Prepair 1000+ v1.196 AUH Zornitza Stark Publications for gene: AUH were set to
Prepair 1000+ v1.195 B4GALT7 Zornitza Stark Marked gene: B4GALT7 as ready
Prepair 1000+ v1.195 B4GALT7 Zornitza Stark Gene: b4galt7 has been classified as Green List (High Evidence).
Prepair 1000+ v1.195 B4GALT7 Zornitza Stark Phenotypes for gene: B4GALT7 were changed from Ehlers-Danlos syndrome, progeroid type, 1, 130070 (3) to Ehlers-Danlos syndrome, spondylodysplastic type, 1, MIM# 130070; MONDO:0020682
Prepair 1000+ v1.194 B4GALT7 Zornitza Stark Publications for gene: B4GALT7 were set to
Prepair 1000+ v1.193 BRF1 Zornitza Stark Marked gene: BRF1 as ready
Prepair 1000+ v1.193 BRF1 Zornitza Stark Gene: brf1 has been classified as Green List (High Evidence).
Prepair 1000+ v1.193 BRF1 Zornitza Stark Phenotypes for gene: BRF1 were changed from Cerebellofaciodental syndrome, 616202 (3) to Cerebellofaciodental syndrome, MIM# 616202; Cerebellar-facial-dental syndrome MONDO:0014529
Prepair 1000+ v1.192 BRF1 Zornitza Stark Publications for gene: BRF1 were set to
Prepair 1000+ v1.191 DLL3 Marta Cifuentes Ochoa reviewed gene: DLL3: Rating: GREEN; Mode of pathogenicity: None; Publications: 10742114, 12746394, 36506336; Phenotypes: Spondylocostal dysostosis 1, autosomal recessive, MIM# 277300, MONDO:0020692; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.191 HBA1 Zornitza Stark Publications for gene: HBA1 were set to
Prepair 1000+ v1.190 HBA1 Zornitza Stark Tag for review tag was added to gene: HBA1.
Prepair 1000+ v1.190 HBA2 Zornitza Stark Publications for gene: HBA2 were set to
Prepair 1000+ v1.189 HBA2 Zornitza Stark Tag for review tag was added to gene: HBA2.
Prepair 1000+ v1.189 BTK Zornitza Stark Marked gene: BTK as ready
Prepair 1000+ v1.189 BTK Zornitza Stark Gene: btk has been classified as Green List (High Evidence).
Prepair 1000+ v1.189 BTK Zornitza Stark Phenotypes for gene: BTK were changed from Agammaglobulinemia and isolated hormone deficiency, 307200 (3) to Agammaglobulinemia, X-linked 1 MIM#300755; Bruton-type agammaglobulinemia MONDO:0010421; Isolated growth hormone deficiency, type III, with agammaglobulinemia MIM#307200 MONDO:0010615
Prepair 1000+ v1.188 BTK Zornitza Stark Publications for gene: BTK were set to
Prepair 1000+ v1.187 DGAT1 Marta Cifuentes Ochoa reviewed gene: DGAT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33261563, 32786057, 31778854, 28373485, 29604290, 31778854; Phenotypes: Diarrhoea 7, protein-losing enteropathy type, MIM# 615863, congenital diarrhea 7 with exudative enteropathy MONDO:0014375; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.187 CRB2 Marta Cifuentes Ochoa reviewed gene: CRB2: Rating: GREEN; Mode of pathogenicity: None; Publications: 25557780, 33687977, 32051522, 30212996, 33575434, 31438467, 30593785, 25557779, 27004616; Phenotypes: Ventriculomegaly with cystic kidney disease, MIM# 219730, MONDO:0009063 Focal segmental glomerulosclerosis 9, MIM# 616220, MONDO:0014539; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.187 CEP152 Marta Cifuentes Ochoa changed review comment from: Primary microcephaly (head circumference more than 3 standard deviations below the age- and sex-matched population mean). Causes Intellectual disability.

Seckel syndrome is a rare autosomal recessive inherited disorder, which is mainly characterized by intrauterine and postnatal growth restrictions, microcephaly, intellectual disability, and a typical “bird-head” facial appearance.

Established gene-disease association.

Congenital onset, severe disorder

HGNC approved symbol/name: CEP152

Is the phenotype(s) severe and onset <18yo ? Y

Known technical challenges? N

Gene reported in >3 independent families; to: Primary microcephaly (head circumference more than 3 standard deviations below the age- and sex-matched population mean). Causes Intellectual disability.

Seckel syndrome is a rare autosomal recessive inherited disorder, which is mainly characterized by intrauterine and postnatal growth restrictions, microcephaly, intellectual disability, facial dysmorphic features.

Established gene-disease association.

Congenital onset, severe disorder

HGNC approved symbol/name: CEP152

Is the phenotype(s) severe and onset <18yo ? Y

Known technical challenges? N

Gene reported in >3 independent families
Prepair 1000+ v1.187 COLQ Marta Cifuentes Ochoa changed review comment from: Patients with congenital myasthenic syndromes present clinically with onset of variable muscle weakness between infancy and adulthood.

Well established gene-disease association, more than 10 families reported.
HGNC approved symbol/name: COLQ
Is the phenotype(s) severe and onset <18yo ? Y
Known technical challenges?N; to: Patients with congenital myasthenic syndromes present clinically with onset of variable muscle weakness between infancy and adulthood.
Presentations:
-neonatal: respiratory insufficiency, multiple joint contractures (often described as arthrogryposis multiplex congenita) resulting from a lack of fetal movement in utero. Feeding difficulties, poor suck and cry, choking spells, eyelid ptosis, and facial, bulbar, and generalized weakness.In some individuals, long face, narrow jaw, and a high-arched palate have been reported
-childhood: delayed motr milestones, fluctuating eyelid ptosis and fixed or fluctuating extraocular muscle weakness. Ptosis may involve one or both eyelids. Facial and bulbar weakness with nasal speech and difficulties in coughing and swallowing may be present.Spinal deformity or muscle atrophy may occur
-limb-girdle

Well established gene-disease association, more than 10 families reported.
HGNC approved symbol/name: COLQ
Is the phenotype(s) severe and onset <18yo ? Y
Known technical challenges?N
Prepair 1000+ v1.187 COLQ Marta Cifuentes Ochoa reviewed gene: COLQ: Rating: GREEN; Mode of pathogenicity: None; Publications: 9689136, 9758617, 11865139, 32978031, 31831253, 29478601, 23995276, 36835142; Phenotypes: Myasthenic syndrome, congenital, 5 MIM#603034, MONDO:0011281; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v1.46 Zornitza Stark List of related panels changed from Seizure; HP:0001250; Epileptic encephalopathy; HP:0200134 to Seizure; HP:0001250; Epileptic encephalopathy; HP:0200134; EEG abnormality; HP:0002353
Prepair 1000+ v1.187 COLEC11 Marta Cifuentes Ochoa reviewed gene: COLEC11: Rating: GREEN; Mode of pathogenicity: None; Publications: 21258343, 26789649, 28301481; Phenotypes: 3MC syndrome 2, MIM# 265050, MONDO:0009927; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.187 COL4A3 Marta Cifuentes Ochoa reviewed gene: COL4A3: Rating: GREEN; Mode of pathogenicity: None; Publications: 24052634, 35419377, 39071776; Phenotypes: Alport syndrome 3b, autosomal recessive MIM#620536, MONDO:0957811; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.187 CLN3 Marta Cifuentes Ochoa Deleted their comment
Prepair 1000+ v1.187 CLN3 Marta Cifuentes Ochoa commented on gene: CLN3: Well established gene disease association.

Severe neurodegenerative disorder.

HGNC approved symbol/name: CLN3
Is the phenotype(s) severe and onset <18yo ? Y
Known technical challenges? N
Gene reported in >3 independent families
Prepair 1000+ v1.187 CLN3 Marta Cifuentes Ochoa reviewed gene: CLN3: Rating: GREEN; Mode of pathogenicity: None; Publications: 7553855, 31926949; Phenotypes: Ceroid lipofuscinosis, neuronal, 3, MIM# 204200, MONDO:0008767; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.187 CLCN2 Marta Cifuentes Ochoa reviewed gene: CLCN2: Rating: GREEN; Mode of pathogenicity: None; Publications: 23707145, 38173802, 29403011, 29403012; Phenotypes: Leukoencephalopathy with ataxia MIM#615651, leukoencephalopathy with mild cerebellar ataxia and white matter edema MONDO:0014292; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.187 CISD2 Marta Cifuentes Ochoa reviewed gene: CISD2: Rating: GREEN; Mode of pathogenicity: None; Publications: 35055657, 29237418, 28335035, 27459537, 26230298, 17846994; Phenotypes: Wolfram syndrome 2 MIM#604928, MONDO:0011502; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.187 CHM Marta Cifuentes Ochoa reviewed gene: CHM: Rating: AMBER; Mode of pathogenicity: None; Publications: 31021898, 27506488, 27820636, 33110609; Phenotypes: Choroideremia MIM#303100, MONDO:0010557; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Ciliary Dyskinesia v1.39 SCNN1G Jonathon Bradshaw reviewed gene: SCNN1G: Rating: RED; Mode of pathogenicity: None; Publications: 29997923, 30801930, 18507830; Phenotypes: Bronchiectasis with or without elevated sweat chloride 3, MIM# 613071; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Ciliary Dyskinesia v1.39 SCNN1G Jonathon Bradshaw Deleted their review
Ciliary Dyskinesia v1.39 SCNN1G Jonathon Bradshaw changed review comment from: Context: The Epithelial sodium channel (ENaC) is a heterotrimer composed of 3 subunits coded by the SCNN1A, SCNN1B, SCNN1G, and SCNN1D genes.

Bush, A and Floto, R. (2019): The classical single gene disorder is α-1 antitrypsin deficiency (MIM#613490), which also causes liver disease. ENaC mutations, especially in-trans with a CFTR mutation, are thought to be risk factors for bronchiectasis, rather than actually causative. However, bronchiectasis is likely to be a very complex disease, of heterogeneous etiology, and genetic studies are likely to approach the complexity of those of asthma, rather than the classic single gene disorders such as CF.

Fajac, I. et al. (2008): Identified 3 idiopathic bronchiectasis affected individuals without CFTR variants. They found 2 variants - one of which is reported ten times as B/LB in ClinVar, and the other is reported nine times as B/LB in ClinVar.

Guan, W. et al. (2018): NGS screening study. 192 bronchiectasis patients and 100 healthy subjects. 32 genes thought to be clinically relevant were screened. No SCNN1G variants were detected in healthy or affected groups. 6 affected individuals had variants in SCNN1A and SCNN1B.; to: Context: The Epithelial sodium channel (ENaC) is a heterotrimer composed of 3 subunits coded by the SCNN1A, SCNN1B, SCNN1G, and SCNN1D genes.

Bush, A and Floto, R. (2019): The classical single gene disorder is α-1 antitrypsin deficiency (MIM#613490), which also causes liver disease. ENaC mutations, especially in-trans with a CFTR mutation, are thought to be risk factors for bronchiectasis, rather than actually causative. However, bronchiectasis is likely to be a very complex disease, of heterogeneous etiology, and genetic studies are likely to approach the complexity of those of asthma, rather than the classic single gene disorders such as CF.

Fajac, I. et al. (2008): Identified 3 idiopathic bronchiectasis affected individuals without CFTR variants. They found 2 variants - one of which is reported ten times as B/LB in ClinVar, and the other is reported nine times as B/LB in ClinVar.

Guan, W. et al. (2018): NGS screening study. 192 bronchiectasis patients and 100 healthy subjects. 32 genes thought to be clinically relevant were screened. No SCNN1G variants were detected in healthy or affected groups. 6 affected individuals had variants in SCNN1A and SCNN1B.
Ciliary Dyskinesia v1.39 SCNN1G Jonathon Bradshaw reviewed gene: SCNN1G: Rating: RED; Mode of pathogenicity: None; Publications: 30801930, 18507830, 29997923; Phenotypes: Bronchiectasis with or without elevated sweat chloride 3, MIM# 613071; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hypertrophic cardiomyopathy_HCM v0.179 TNNC1 Bryony Thompson Classified gene: TNNC1 as Green List (high evidence)
Hypertrophic cardiomyopathy_HCM v0.179 TNNC1 Bryony Thompson Added comment: Comment on list classification: Classified as Definitive by ClinGen Hereditary Cardiovascular Disease GCEP - 13/09/2023
Hypertrophic cardiomyopathy_HCM v0.179 TNNC1 Bryony Thompson Gene: tnnc1 has been classified as Green List (High Evidence).
Syndromic Retinopathy v0.213 MPDZ Bryony Thompson Marked gene: MPDZ as ready
Syndromic Retinopathy v0.213 MPDZ Bryony Thompson Gene: mpdz has been classified as Amber List (Moderate Evidence).
Syndromic Retinopathy v0.213 MPDZ Bryony Thompson Classified gene: MPDZ as Amber List (moderate evidence)
Syndromic Retinopathy v0.213 MPDZ Bryony Thompson Gene: mpdz has been classified as Amber List (Moderate Evidence).
Syndromic Retinopathy v0.212 MPDZ Bryony Thompson gene: MPDZ was added
gene: MPDZ was added to Syndromic Retinopathy. Sources: Literature
Mode of inheritance for gene: MPDZ was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MPDZ were set to 36594712; 22159006; 21862650
Phenotypes for gene: MPDZ were set to hydrocephalus, congenital, 2, with or without brain or eye anomalies MIM:615219
Review for gene: MPDZ was set to AMBER
gene: MPDZ was marked as current diagnostic
Added comment: 2 reported siblings with syndromic maculopathy and 1 unpublished case with syndromic macular dystrophy (RMH). Multiple animal models with retinal degeneration consistent with RP/LCA.
Sources: Literature
Monogenic Diabetes v0.135 PPARG Bryony Thompson Classified gene: PPARG as Green List (high evidence)
Monogenic Diabetes v0.135 PPARG Bryony Thompson Added comment: Comment on list classification: Diabetes can be a feature of lipodystrophy which is an established gene-disease association for PPARG
Monogenic Diabetes v0.135 PPARG Bryony Thompson Gene: pparg has been classified as Green List (High Evidence).
Prepair 1000+ v1.187 CEP152 Zornitza Stark Marked gene: CEP152 as ready
Prepair 1000+ v1.187 CEP152 Zornitza Stark Gene: cep152 has been classified as Green List (High Evidence).
Prepair 1000+ v1.187 CEP152 Zornitza Stark Phenotypes for gene: CEP152 were changed from Seckel syndrome 5, 613823 (3) to Microcephaly 9, primary, autosomal recessive, MIM# 614852; MONDO:0013923; Seckel syndrome 5, MIM# 613823; MONDO:0013443
Prepair 1000+ v1.186 CEP152 Zornitza Stark Publications for gene: CEP152 were set to
Prepair 1000+ v1.185 C1QC Zornitza Stark Marked gene: C1QC as ready
Prepair 1000+ v1.185 C1QC Zornitza Stark Gene: c1qc has been classified as Green List (High Evidence).
Prepair 1000+ v1.185 C1QC Zornitza Stark Phenotypes for gene: C1QC were changed from C1q deficiency, 613652 (3) to C1q deficiency, MIM# 613652
Prepair 1000+ v1.184 C1QC Zornitza Stark Publications for gene: C1QC were set to
Prepair 1000+ v1.183 C1QC Zornitza Stark reviewed gene: C1QC: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: C1q deficiency, MIM# 613652; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.183 CEP41 Zornitza Stark Marked gene: CEP41 as ready
Prepair 1000+ v1.183 CEP41 Zornitza Stark Gene: cep41 has been classified as Green List (High Evidence).
Prepair 1000+ v1.183 CEP41 Zornitza Stark Phenotypes for gene: CEP41 were changed from Joubert syndrome 15, 614464 (3) to Joubert syndrome 15, MIM# 614464
Prepair 1000+ v1.182 CEP41 Zornitza Stark Publications for gene: CEP41 were set to
Prepair 1000+ v1.181 CEP41 Zornitza Stark reviewed gene: CEP41: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Joubert syndrome 15, MIM# 614464; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.181 CHRNA1 Zornitza Stark Marked gene: CHRNA1 as ready
Prepair 1000+ v1.181 CHRNA1 Zornitza Stark Gene: chrna1 has been classified as Green List (High Evidence).
Prepair 1000+ v1.181 CHRNA1 Zornitza Stark Phenotypes for gene: CHRNA1 were changed from Multiple pterygium syndrome, lethal type, 253290 (3) to Multiple pterygium syndrome, lethal type, MIM#253290; Myasthenic syndrome, congenital, 1B, fast-channel , MIM#608930; Myasthenic syndrome, congenital, 1B, fast-channel , MIM#608930
Prepair 1000+ v1.180 CHRNA1 Zornitza Stark Publications for gene: CHRNA1 were set to
Prepair 1000+ v1.179 ETFA Zornitza Stark Marked gene: ETFA as ready
Prepair 1000+ v1.179 ETFA Zornitza Stark Gene: etfa has been classified as Green List (High Evidence).
Prepair 1000+ v1.179 ETFA Zornitza Stark Publications for gene: ETFA were set to
Prepair 1000+ v1.178 FANCB Zornitza Stark Marked gene: FANCB as ready
Prepair 1000+ v1.178 FANCB Zornitza Stark Gene: fancb has been classified as Green List (High Evidence).
Prepair 1000+ v1.178 CERS3 Zornitza Stark Marked gene: CERS3 as ready
Prepair 1000+ v1.178 CERS3 Zornitza Stark Gene: cers3 has been classified as Green List (High Evidence).
Prepair 1000+ v1.178 CERS3 Zornitza Stark Phenotypes for gene: CERS3 were changed from Ichthyosis, congenital, autosomal recessive 9, 615023 (3) to Ichthyosis, congenital, autosomal recessive 9, MIM# 615023; MONDO:0014010
Prepair 1000+ v1.177 CERS3 Zornitza Stark Publications for gene: CERS3 were set to
Prepair 1000+ v1.176 FUCA1 Zornitza Stark Marked gene: FUCA1 as ready
Prepair 1000+ v1.176 FUCA1 Zornitza Stark Gene: fuca1 has been classified as Green List (High Evidence).
Prepair 1000+ v1.176 FUCA1 Zornitza Stark Phenotypes for gene: FUCA1 were changed from Fucosidosis, 230000 (3) to Fucosidosis, MIM# 230000
Prepair 1000+ v1.175 G6PC3 Zornitza Stark Marked gene: G6PC3 as ready
Prepair 1000+ v1.175 G6PC3 Zornitza Stark Gene: g6pc3 has been classified as Green List (High Evidence).
Prepair 1000+ v1.175 G6PC3 Zornitza Stark Phenotypes for gene: G6PC3 were changed from Dursun syndrome, 612541 (3) to Dursun syndrome, MIM# 612541; Neutropenia, severe congenital 4, autosomal recessive, MIM# 612541
Prepair 1000+ v1.174 G6PC3 Zornitza Stark reviewed gene: G6PC3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Dursun syndrome, MIM# 612541, Neutropenia, severe congenital 4, autosomal recessive, MIM# 612541; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.174 GALT Zornitza Stark Marked gene: GALT as ready
Prepair 1000+ v1.174 GALT Zornitza Stark Gene: galt has been classified as Green List (High Evidence).
Prepair 1000+ v1.174 GALT Zornitza Stark Phenotypes for gene: GALT were changed from Galactosemia, 230400 (3) to Galactosemia MIM# 230400
Prepair 1000+ v1.173 CFTR Zornitza Stark Marked gene: CFTR as ready
Prepair 1000+ v1.173 CFTR Zornitza Stark Gene: cftr has been classified as Green List (High Evidence).
Prepair 1000+ v1.173 CFTR Zornitza Stark Phenotypes for gene: CFTR were changed from Cystic fibrosis, 219700 (3) to Cystic fibrosis, MIM#219700; MONDO:0009061
Prepair 1000+ v1.172 CFTR Zornitza Stark Publications for gene: CFTR were set to
Prepair 1000+ v1.171 ABCC8 Zornitza Stark Marked gene: ABCC8 as ready
Prepair 1000+ v1.171 ABCC8 Zornitza Stark Gene: abcc8 has been classified as Green List (High Evidence).
Prepair 1000+ v1.171 ABCC8 Zornitza Stark Phenotypes for gene: ABCC8 were changed from Hyperinsulinemic hypoglycemia, familial, 1, 256450 (3) to Diabetes mellitus, permanent neonatal 3, with or without neurologic features MIM#618857; Hyperinsulinemic hypoglycemia, familial, 1 MIM#256450
Prepair 1000+ v1.170 ABCC8 Zornitza Stark Publications for gene: ABCC8 were set to
Prepair 1000+ v1.169 ISPD Zornitza Stark Marked gene: ISPD as ready
Prepair 1000+ v1.169 ISPD Zornitza Stark Gene: ispd has been classified as Green List (High Evidence).
Prepair 1000+ v1.169 ISPD Zornitza Stark Publications for gene: ISPD were set to
Prepair 1000+ v1.168 ISPD Zornitza Stark Tag new gene name tag was added to gene: ISPD.
Pulmonary Fibrosis_Interstitial Lung Disease v0.77 CCBE1 Zornitza Stark Mode of inheritance for gene: CCBE1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BIALLELIC, autosomal or pseudoautosomal
Pulmonary Fibrosis_Interstitial Lung Disease v0.76 CCBE1 Zornitza Stark edited their review of gene: CCBE1: Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.168 BCAP31 Zornitza Stark Marked gene: BCAP31 as ready
Prepair 1000+ v1.168 BCAP31 Zornitza Stark Added comment: Comment when marking as ready: Promote to Green at V2.
Prepair 1000+ v1.168 BCAP31 Zornitza Stark Gene: bcap31 has been classified as Red List (Low Evidence).
Prepair 1000+ v1.168 BCAP31 Zornitza Stark Tag for review tag was added to gene: BCAP31.
Mendeliome v1.1960 ELMOD3 Zornitza Stark Classified gene: ELMOD3 as Red List (low evidence)
Mendeliome v1.1960 ELMOD3 Zornitza Stark Gene: elmod3 has been classified as Red List (Low Evidence).
Mendeliome v1.1959 ELMOD3 Zornitza Stark edited their review of gene: ELMOD3: Added comment: Discussed at GenCC: limited.; Changed rating: RED
Deafness_IsolatedAndComplex v1.196 ELMOD3 Zornitza Stark Classified gene: ELMOD3 as Red List (low evidence)
Deafness_IsolatedAndComplex v1.196 ELMOD3 Zornitza Stark Gene: elmod3 has been classified as Red List (Low Evidence).
Deafness_IsolatedAndComplex v1.195 ELMOD3 Zornitza Stark edited their review of gene: ELMOD3: Added comment: Discussed at GenCC: LIMITED.; Changed rating: RED
Deafness_Isolated v1.64 ELMOD3 Zornitza Stark Classified gene: ELMOD3 as Red List (low evidence)
Deafness_Isolated v1.64 ELMOD3 Zornitza Stark Gene: elmod3 has been classified as Red List (Low Evidence).
Deafness_Isolated v1.63 ELMOD3 Zornitza Stark edited their review of gene: ELMOD3: Added comment: Discussed at GenCC: LIMITED.; Changed rating: RED
Prepair 1000+ v1.168 GTPBP2 Zornitza Stark Tag for review tag was added to gene: GTPBP2.
Prepair 1000+ v1.168 GTPBP2 Zornitza Stark reviewed gene: GTPBP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 26675814, 28454995, 29449720, 30790272, 38852771, 38118446; Phenotypes: Jaberi-Elahi syndrome, MIM#617988; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v1.45 YIF1B Zornitza Stark Classified gene: YIF1B as Green List (high evidence)
Genetic Epilepsy v1.45 YIF1B Zornitza Stark Gene: yif1b has been classified as Green List (High Evidence).
Genetic Epilepsy v1.44 YIF1B Zornitza Stark edited their review of gene: YIF1B: Changed rating: GREEN
Genetic Epilepsy v1.44 YIF1B Zornitza Stark edited their review of gene: YIF1B: Added comment: Multiple additional individuals now reported, including others with seizures. DEFINITIVE by ClinGen.; Changed publications: 36948290, 33103737
Prepair 1000+ v1.168 YIF1B Zornitza Stark Tag for review tag was added to gene: YIF1B.
Prepair 1000+ v1.168 YIF1B Zornitza Stark edited their review of gene: YIF1B: Added comment: DEFINITIVE gene-disease association by ClinGen. Over 20 individuals now reported in the literature.; Changed publications: 33103737, 32006098, 36948290, 34373908
Prepair 1000+ v1.168 YIF1B Zornitza Stark reviewed gene: YIF1B: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Kaya-Barakat-Masson syndrome, MIM# 619125; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1959 CFAP57 Zornitza Stark Phenotypes for gene: CFAP57 were changed from to Spermatogenic failure 95, MIM# 620917; Van der Woude Syndrome; Primary ciliary dyskinesia
Mendeliome v1.1958 CFAP57 Zornitza Stark Publications for gene: CFAP57 were set to
Mendeliome v1.1957 CFAP57 Zornitza Stark Classified gene: CFAP57 as Green List (high evidence)
Mendeliome v1.1957 CFAP57 Zornitza Stark Gene: cfap57 has been classified as Green List (High Evidence).
Mendeliome v1.1956 CFAP57 Zornitza Stark edited their review of gene: CFAP57: Added comment: PMID 36752199: 5 individuals from three families reported with biallelic LoF variants (two homozygous variants) and spermatogenic failure. Mouse model recapitulated the phenotype.; Changed rating: GREEN; Changed publications: 21574244, 32764743, 36752199; Changed phenotypes: Spermatogenic failure 95, MIM# 620917, Van der Woude Syndrome, Primary ciliary dyskinesia
Hereditary Neuropathy_CMT - isolated v1.49 FICD Zornitza Stark Phenotypes for gene: FICD were changed from Hereditary motor neurone disease, FICD-related, MONDO:0024257 to Spastic paraplegia 92, autosomal recessive, MIM# 620911
Hereditary Spastic Paraplegia - paediatric v1.80 FICD Zornitza Stark Phenotypes for gene: FICD were changed from Hereditary motor neurone disease, FICD-related, MONDO:0024257 to Spastic paraplegia 92, autosomal recessive, MIM# 620911
Mendeliome v1.1956 FICD Zornitza Stark Phenotypes for gene: FICD were changed from Hereditary motor neurone disease, FICD-related, MONDO:0024257 to Spastic paraplegia 92, autosomal recessive, MIM# 620911
Prepair 1000+ v1.168 CFTR Marta Cifuentes Ochoa reviewed gene: CFTR: Rating: GREEN; Mode of pathogenicity: None; Publications: 31199594, 19092437, 38153325, 26708955, 32172939; Phenotypes: Cystic fibrosis, MIM#219700, MONDO:0009061; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.168 GALT Lucy Spencer reviewed gene: GALT: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Galactosemia MIM# 230400; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.168 G6PC3 Lucy Spencer reviewed gene: G6PC3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.168 FUCA1 Lucy Spencer reviewed gene: FUCA1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Fucosidosis, MIM# 230000; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.168 CERS3 Marta Cifuentes Ochoa reviewed gene: CERS3: Rating: GREEN; Mode of pathogenicity: None; Publications: 23754960, 23549421, 31168818, 30578701, 37128664; Phenotypes: Ichthyosis, congenital, autosomal recessive 9, MIM# 615023, MONDO:0014010; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.168 FANCB Lucy Spencer reviewed gene: FANCB: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Fanconi anaemia, complementation group B, MIM#300514; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Prepair 1000+ v1.168 ETFA Lucy Spencer reviewed gene: ETFA: Rating: GREEN; Mode of pathogenicity: None; Publications: 31904027; Phenotypes: Glutaric acidemia IIA, MIM# 231680; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ciliopathies v1.58 PSKH1 Chirag Patel Classified gene: PSKH1 as Green List (high evidence)
Ciliopathies v1.58 PSKH1 Chirag Patel Gene: pskh1 has been classified as Green List (High Evidence).
Renal Ciliopathies and Nephronophthisis v1.25 PSKH1 Chirag Patel Classified gene: PSKH1 as Green List (high evidence)
Renal Ciliopathies and Nephronophthisis v1.25 PSKH1 Chirag Patel Gene: pskh1 has been classified as Green List (High Evidence).
Cholestasis v0.242 PSKH1 Chirag Patel Classified gene: PSKH1 as Green List (high evidence)
Cholestasis v0.242 PSKH1 Chirag Patel Gene: pskh1 has been classified as Green List (High Evidence).
Renal Ciliopathies and Nephronophthisis v1.24 PSKH1 Chirag Patel gene: PSKH1 was added
gene: PSKH1 was added to Renal Ciliopathies and Nephronophthisis. Sources: Literature
Mode of inheritance for gene: PSKH1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PSKH1 were set to PMID: 39132680
Phenotypes for gene: PSKH1 were set to Hepatorenal syndrome, MONDO:0001382
Review for gene: PSKH1 was set to GREEN
gene: PSKH1 was marked as current diagnostic
Added comment: 4 consanguineous families (out of 279 families) with intrahepatic cholestasis:
-1 patient died at 10mths with cholestasis/liver impairment and kidney impairment
-3 cousins with cholestasis (2 with liver failure needing transplant) and kidney features (2 with kidney failure, 1 with renal echogenicity)
-2 siblings with hepatic fibrosis (1 with unilateral renal agenesis)
-2 siblings with unexplained liver cirrhosis (1 needing transplant) but normal kidney function

WES identified 3 different homozygous variants in PSKH1 (Arg121Trp, Ile126Val, Arg183Cys). Patient fibroblasts displayed abnormal cilia that are long and show abnormal transport. A homozygous Pskh1 mutant mouse faithfully recapitulated the human phenotype and displayed abnormally long cilia. The phenotype could be rationalized by the loss of catalytic activity observed for each recombinant PSKH1 variant using in vitro kinase assays. Human PSKH1 is a poorly understood gene that may play important role in intracellular trafficking, is sensitive to intracellular Ca2+ concentration, and is localized to centrosomes, suggesting a link to cystogenesis.
Sources: Literature
Ciliopathies v1.57 PSKH1 Chirag Patel gene: PSKH1 was added
gene: PSKH1 was added to Ciliopathies. Sources: Literature
Mode of inheritance for gene: PSKH1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PSKH1 were set to PMID: 39132680
Phenotypes for gene: PSKH1 were set to Hepatorenal syndrome, MONDO:0001382
Review for gene: PSKH1 was set to GREEN
gene: PSKH1 was marked as current diagnostic
Added comment: 4 consanguineous families (out of 279 families) with intrahepatic cholestasis:
-1 patient died at 10mths with cholestasis/liver impairment and kidney impairment
-3 cousins with cholestasis (2 with liver failure needing transplant) and kidney features (2 with kidney failure, 1 with renal echogenicity)
-2 siblings with hepatic fibrosis (1 with unilateral renal agenesis)
-2 siblings with unexplained liver cirrhosis (1 needing transplant) but normal kidney function

WES identified 3 different homozygous variants in PSKH1 (Arg121Trp, Ile126Val, Arg183Cys). Patient fibroblasts displayed abnormal cilia that are long and show abnormal transport. A homozygous Pskh1 mutant mouse faithfully recapitulated the human phenotype and displayed abnormally long cilia. The phenotype could be rationalized by the loss of catalytic activity observed for each recombinant PSKH1 variant using in vitro kinase assays. Human PSKH1 is a poorly understood gene that may play important role in intracellular trafficking, is sensitive to intracellular Ca2+ concentration, and is localized to centrosomes, suggesting a link to cystogenesis.
Sources: Literature
Cholestasis v0.241 PSKH1 Chirag Patel gene: PSKH1 was added
gene: PSKH1 was added to Cholestasis. Sources: Literature
Mode of inheritance for gene: PSKH1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PSKH1 were set to PMID: 39132680
Phenotypes for gene: PSKH1 were set to Hepatorenal syndrome, MONDO:0001382
Review for gene: PSKH1 was set to GREEN
gene: PSKH1 was marked as current diagnostic
Added comment: 4 consanguineous families (out of 279 families) with intrahepatic cholestasis:
-1 patient died at 10mths with cholestasis/liver impairment and kidney impairment
-3 cousins with cholestasis (2 with liver failure needing transplant) and kidney features (2 with kidney failure, 1 with renal echogenicity)
-2 siblings with hepatic fibrosis (1 with unilateral renal agenesis)
-2 siblings with unexplained liver cirrhosis (1 needing transplant) but normal kidney function

WES identified 3 different homozygous variants in PSKH1 (Arg121Trp, Ile126Val, Arg183Cys). Patient fibroblasts displayed abnormal cilia that are long and show abnormal transport. A homozygous Pskh1 mutant mouse faithfully recapitulated the human phenotype and displayed abnormally long cilia. The phenotype could be rationalized by the loss of catalytic activity observed for each recombinant PSKH1 variant using in vitro kinase assays. Human PSKH1 is a poorly understood gene that may play important role in intracellular trafficking, is sensitive to intracellular Ca2+ concentration, and is localized to centrosomes, suggesting a link to cystogenesis.
Sources: Literature
Renal Ciliopathies and Nephronophthisis v1.23 IFT140 Chirag Patel reviewed gene: IFT140: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 39136524; Phenotypes: Cystic Kidney Disease, MONDO# 0002473; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Renal Macrocystic Disease v0.70 IFT140 Chirag Patel edited their review of gene: IFT140: Added comment: 368 patients with IFT140 LoF variants and a spectrum of phenotypic findings that support the association of IFT140 with PKD. A cystic phenotype was reported in 223 of the 368 (60.6%) individuals harboring an IFT140 LoF variant, 98% of which had no other identified cause for their cystic disease. Of 122 unique LoF IFT140 variants identified, 56 (46%) were frameshift, 38 (31%) nonsense, 22 (18%) splice site and 6 (5%) exon-level deletions. Only six IFT140 individuals were reported with end-stage kidney disease, consistent with observed milder clinical presentations in IFT140-related PKD.; Changed publications: PMID: 39136524; Changed phenotypes: Cystic Kidney Disease, MONDO# 0002473; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Set current diagnostic: yes
Mendeliome v1.1955 FIG4 Zornitza Stark Marked gene: FIG4 as ready
Mendeliome v1.1955 FIG4 Zornitza Stark Gene: fig4 has been classified as Green List (High Evidence).
Incidentalome v0.308 FIG4 Zornitza Stark Marked gene: FIG4 as ready
Incidentalome v0.308 FIG4 Zornitza Stark Added comment: Comment when marking as ready: Moved to Mendeliome. Associations with CMT and Yunis-Varon are well established whereas association with ALS/FTD is not.
Incidentalome v0.308 FIG4 Zornitza Stark Gene: fig4 has been removed from the panel.
Incidentalome v0.308 FIG4 Zornitza Stark Classified gene: FIG4 as No list
Incidentalome v0.308 FIG4 Zornitza Stark Gene: fig4 has been removed from the panel.
Mendeliome v1.1955 FIG4 Zornitza Stark Classified gene: FIG4 as Green List (high evidence)
Mendeliome v1.1955 FIG4 Zornitza Stark Gene: fig4 has been classified as Green List (High Evidence).
Mendeliome v1.1954 FIG4 Zornitza Stark gene: FIG4 was added
gene: FIG4 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: FIG4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FIG4 were set to 23623387; 17572665; 21705420; 24878229; 18758830; 24598713
Phenotypes for gene: FIG4 were set to Yunis-Varon syndrome - MIM#216340; Polymicrogyria with epilepsy MIM# 612691; Charcot-Marie-Tooth disease, type 4J 611228; Amyotrophic lateral sclerosis 11, MIM# 612577
Review for gene: FIG4 was set to GREEN
Added comment: Associations between biallelic variants and CMT and Yunis Varon syndrome are well established.

Limited evidence for association with brain malformations and with ALS/FTD.
Sources: Expert Review
Incidentalome v0.307 DICER1 Zornitza Stark Mode of inheritance for gene: DICER1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Incidentalome v0.306 CDH1 Zornitza Stark Mode of inheritance for gene: CDH1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Incidentalome v0.305 CACNA1S Zornitza Stark Marked gene: CACNA1S as ready
Incidentalome v0.305 CACNA1S Zornitza Stark Gene: cacna1s has been classified as Green List (High Evidence).
Incidentalome v0.305 CACNA1S Zornitza Stark Phenotypes for gene: CACNA1S were changed from to Malignant hyperthermia susceptibility 5, MIM# 601887
Incidentalome v0.304 CACNA1S Zornitza Stark Mode of inheritance for gene: CACNA1S was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Incidentalome v0.303 APOE Zornitza Stark Marked gene: APOE as ready
Incidentalome v0.303 APOE Zornitza Stark Gene: apoe has been classified as Green List (High Evidence).
Incidentalome v0.303 APOE Zornitza Stark Publications for gene: APOE were set to
Incidentalome v0.302 APOE Zornitza Stark Mode of inheritance for gene: APOE was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Proteinuria v0.227 WT1 Zornitza Stark Marked gene: WT1 as ready
Proteinuria v0.227 WT1 Zornitza Stark Gene: wt1 has been classified as Green List (High Evidence).
Proteinuria v0.227 WT1 Zornitza Stark Phenotypes for gene: WT1 were changed from to Denys-Drash syndrome, MIM# 194080; Frasier syndrome, MIM#136680; Wilms tumor, type 1, MIM#194070; Nephrotic syndrome, type 4, MIM#256370
Proteinuria v0.226 WT1 Zornitza Stark Mode of inheritance for gene: WT1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Prepair 1000+ v1.168 CHRNA1 Cassandra Muller reviewed gene: CHRNA1: Rating: GREEN; Mode of pathogenicity: None; Publications: 18806275, 10195214, 12588888, 18252226, 36092864; Phenotypes: Myasthenic syndrome, congenital, 1B, fast-channel , MIM#608930, Myasthenic syndrome, congenital, 1B, fast-channel , MIM#608930; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Dystonia - complex v0.235 NACC1 Shekeeb Mohammad gene: NACC1 was added
gene: NACC1 was added to Dystonia - complex. Sources: Literature
Mode of inheritance for gene: NACC1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NACC1 were set to 38698576
Phenotypes for gene: NACC1 were set to chorea; dystonia; epilepsy; microcephaly; cataracts; dysautonomia; iron deficiency anemia; stereotypies
Penetrance for gene: NACC1 were set to unknown
Review for gene: NACC1 was set to GREEN
gene: NACC1 was marked as current diagnostic
Added comment: Sources: Literature
BabyScreen+ newborn screening v1.114 GCH1 Lilian Downie Mode of inheritance for gene: GCH1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v1.113 GCH1 Lilian Downie reviewed gene: GCH1: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301681; Phenotypes: Dystonia, DOPA-responsive MIM#128230; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.168 MAN2B1 Lilian Downie Marked gene: MAN2B1 as ready
Prepair 1000+ v1.168 MAN2B1 Lilian Downie Gene: man2b1 has been classified as Green List (High Evidence).
Prepair 1000+ v1.168 MAN2B1 Lilian Downie Publications for gene: MAN2B1 were set to
Prepair 1000+ v1.167 MEGF8 Lilian Downie Marked gene: MEGF8 as ready
Prepair 1000+ v1.167 MEGF8 Lilian Downie Gene: megf8 has been classified as Green List (High Evidence).
Prepair 1000+ v1.167 MEGF8 Lilian Downie Publications for gene: MEGF8 were set to 23063620
Prepair 1000+ v1.166 MEGF8 Lilian Downie Publications for gene: MEGF8 were set to
Prepair 1000+ v1.165 MMADHC Lilian Downie Marked gene: MMADHC as ready
Prepair 1000+ v1.165 MMADHC Lilian Downie Gene: mmadhc has been classified as Green List (High Evidence).
Prepair 1000+ v1.165 MMADHC Lilian Downie Publications for gene: MMADHC were set to
Prepair 1000+ v1.164 MOCS2 Lilian Downie Marked gene: MOCS2 as ready
Prepair 1000+ v1.164 MOCS2 Lilian Downie Gene: mocs2 has been classified as Green List (High Evidence).
Prepair 1000+ v1.164 MOCS2 Lilian Downie Publications for gene: MOCS2 were set to
Prepair 1000+ v1.163 MOGS Lilian Downie Marked gene: MOGS as ready
Prepair 1000+ v1.163 MOGS Lilian Downie Added comment: Comment when marking as ready: To upgrade to green
Prepair 1000+ v1.163 MOGS Lilian Downie Gene: mogs has been classified as Amber List (Moderate Evidence).
Prepair 1000+ v1.163 MOGS Lilian Downie Tag for review tag was added to gene: MOGS.
Prepair 1000+ v1.163 MOGS Lilian Downie Publications for gene: MOGS were set to 30587846; 33058492; 31925597
Prepair 1000+ v1.162 NGLY1 Lilian Downie Marked gene: NGLY1 as ready
Prepair 1000+ v1.162 NGLY1 Lilian Downie Gene: ngly1 has been classified as Green List (High Evidence).
Prepair 1000+ v1.162 NGLY1 Lilian Downie Publications for gene: NGLY1 were set to
Prepair 1000+ v1.161 NKX3-2 Lilian Downie Marked gene: NKX3-2 as ready
Prepair 1000+ v1.161 NKX3-2 Lilian Downie Gene: nkx3-2 has been classified as Green List (High Evidence).
Prepair 1000+ v1.161 NKX3-2 Lilian Downie Publications for gene: NKX3-2 were set to
Prepair 1000+ v1.160 NTNG2 Lilian Downie Marked gene: NTNG2 as ready
Prepair 1000+ v1.160 NTNG2 Lilian Downie Added comment: Comment when marking as ready: To be upgraded to green
Prepair 1000+ v1.160 NTNG2 Lilian Downie Gene: ntng2 has been classified as Amber List (Moderate Evidence).
Prepair 1000+ v1.160 NTNG2 Lilian Downie Tag for review tag was added to gene: NTNG2.
Prepair 1000+ v1.160 OBSL1 Lilian Downie Marked gene: OBSL1 as ready
Prepair 1000+ v1.160 OBSL1 Lilian Downie Gene: obsl1 has been classified as Green List (High Evidence).
Prepair 1000+ v1.160 OBSL1 Lilian Downie Publications for gene: OBSL1 were set to
Prepair 1000+ v1.159 CEP41 Cassandra Muller reviewed gene: CEP41: Rating: ; Mode of pathogenicity: None; Publications: 22246503, 36580738; Phenotypes: Joubert syndrome 15, 614464 (3); Mode of inheritance: None
Prepair 1000+ v1.159 C1QC Cassandra Muller reviewed gene: C1QC: Rating: GREEN; Mode of pathogenicity: None; Publications: 21654842, 8630118, 31357913; Phenotypes: C1q deficiency, 613652 (3); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.159 CEP152 Marta Cifuentes Ochoa reviewed gene: CEP152: Rating: GREEN; Mode of pathogenicity: None; Publications: 20598275, 22775483, 21131973, 23199753, 36685824; Phenotypes: Microcephaly 9, primary, autosomal recessive, MIM# 614852, MONDO:0013923, Seckel syndrome 5, MIM# 613823, MONDO:0013443; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.159 BTK Marta Cifuentes Ochoa reviewed gene: BTK: Rating: GREEN; Mode of pathogenicity: None; Publications: 8013627, 7849697, 31481959, 15024743, 34182127, 16951917; Phenotypes: Agammaglobulinemia, X-linked 1 MIM#300755, Bruton-type agammaglobulinemia MONDO:0010421, Isolated growth hormone deficiency, type III, with agammaglobulinemia MIM#307200 MONDO:0010615; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Prepair 1000+ v1.159 HBA2 Andrew Coventry reviewed gene: HBA2: Rating: AMBER; Mode of pathogenicity: None; Publications: 21345100 12393486 23715323 6725554 6725554 36907606; Phenotypes: Thalassemias, alpha- MIM#604131, Hemoglobin H disease, nondeletional MIM#613978; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.159 HBA2 Andrew Coventry Deleted their review
Prepair 1000+ v1.159 HBA2 Andrew Coventry changed review comment from: Well established and strong gene-disease association. Alpha-thalassemia result in anaemias from early childhood when fetal haemoglobin expression is diminished. Haemoglobinopathies of alpha-globin can result from variants at either of the 2 alpha-globin loci, HBA1 or HBA2.

Subtypes:
Haemoglobin H disease is a subtype of alpha-thalassemia:
Deletional' Hb H disease is caused by the combination of alpha(0)-thalassemia with deletional alpha(+)-thalassemia.
Deletional Haemoglobin H - phenotypic variability ranging from asymptomatic, to needing periodic transfusions, to severe anaemia with haemolysis and hepatosplenomegaly, to fatal hydrops fetalis in utero. Variable age of onset and features - see PMID: 21345100

'Nondeletional' Hb H disease is caused by an alpha(0)-thalassemia plus an alpha(+)-thalassemia point mutation or small insertion/deletion. Disease phenotype is usually are greater levels of anaemia, more symptomatic, more likely to have significant hepatosplenomegaly, and greater likelihood to require transfusions.

Note: Deletions are well known and frequent cause of these alpha thalassemia phenotypes and subtypes. Diverse range of non-deletional HBA2 variants also described. Possible technological challenge due to deletions which are prevalent.; to: Well established gene-disease association. The alpha-thalassemia phenotype ranges from asymptomatic to lethal. The severity of the disorder is usually well correlated with the number of non-functional copies of the alpha-globin genes (HBA1/HBA2). Gene function can be lost by deletion, or by SNVs (total loss or partial).The clinically relevant forms of alpha-thalassemia usually involve alpha(0)-thalassemia, either coinherited with alpha(+)-thalassemia and resulting in HbH disease, or inherited from both parents and resulting in haemoglobin Bart hydrops fetalis.

Note: Deletions are well known and frequent cause of these alpha thalassemia phenotypes and subtypes. Diverse range of non-deletional HBA2 variants also described. Possible technological challenge due to deletions which are prevalent.
Prepair 1000+ v1.159 HBA1 Andrew Coventry reviewed gene: HBA1: Rating: AMBER; Mode of pathogenicity: None; Publications: 21381239 11722414 36907606; Phenotypes: Thalassemias, alpha- MIM#604131, Hemoglobin H disease, nondeletional MIM#613978; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.159 BRF1 Marta Cifuentes Ochoa reviewed gene: BRF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 25561519, 25561519, 27748960, 33645901, 32896090, 34628026; Phenotypes: Cerebellofaciodental syndrome, MIM# 616202, Cerebellar-facial-dental syndrome MONDO:0014529; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.159 BRF1 Marta Cifuentes Ochoa Deleted their review
Prepair 1000+ v1.159 BRF1 Marta Cifuentes Ochoa reviewed gene: BRF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 25561519, 25561519, 27748960, 33645901, 32896090, 34628026; Phenotypes: Cerebellofaciodental syndrome, MIM# 616202, Cerebellar-facial-dental syndrome MONDO:0014529; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.159 HBA2 Andrew Coventry reviewed gene: HBA2: Rating: AMBER; Mode of pathogenicity: None; Publications: 21345100 12393486 23715323 6725554 6725554; Phenotypes: Thalassemias, alpha- MIM#604131, Hemoglobin H disease, deletional and nondeletional MIM#613978; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.159 B4GALT7 Marta Cifuentes Ochoa reviewed gene: B4GALT7: Rating: GREEN; Mode of pathogenicity: None; Publications: 23956117, 24755949, 31614862, 34193099, 26940150; Phenotypes: Ehlers-Danlos syndrome, spondylodysplastic type, 1, MIM# 130070, MONDO:0020682; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.159 AUH Marta Cifuentes Ochoa reviewed gene: AUH: Rating: GREEN; Mode of pathogenicity: None; Publications: 12434311, 16354225, 20855850, 21840233; Phenotypes: 3-methylglutaconic aciduria, type I, MIM# 250950, MONDO:0009610; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.159 AUH Marta Cifuentes Ochoa Deleted their review
Prepair 1000+ v1.159 AUH Marta Cifuentes Ochoa reviewed gene: AUH: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 12434311, 16354225, 20855850, 21840233; Phenotypes: 3-methylglutaconic aciduria, type I MIM#250950, MONDO:0009610; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.159 ASCC1 Marta Cifuentes Ochoa reviewed gene: ASCC1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 30327447, 12077347, 26924529, 31880396, 26503956; Phenotypes: Arthrogryposis, congenital bone fractures, spinal muscular atrophy, spinal muscular atrophy with congenital bone fractures 2 MONDO:0014807, SMABF2 MIM#616867; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.159 PGM1 Lilian Downie Marked gene: PGM1 as ready
Prepair 1000+ v1.159 PGM1 Lilian Downie Gene: pgm1 has been classified as Green List (High Evidence).
Prepair 1000+ v1.159 PGM1 Lilian Downie Publications for gene: PGM1 were set to
Prepair 1000+ v1.158 ORC1 Lilian Downie Marked gene: ORC1 as ready
Prepair 1000+ v1.158 ORC1 Lilian Downie Gene: orc1 has been classified as Green List (High Evidence).
Prepair 1000+ v1.158 ORC1 Lilian Downie Publications for gene: ORC1 were set to
Prepair 1000+ v1.157 PGM3 Lilian Downie Marked gene: PGM3 as ready
Prepair 1000+ v1.157 PGM3 Lilian Downie Gene: pgm3 has been classified as Green List (High Evidence).
Prepair 1000+ v1.157 PGM3 Lilian Downie Publications for gene: PGM3 were set to
Prepair 1000+ v1.156 PIGA Lilian Downie Publications for gene: PIGA were set to
Prepair 1000+ v1.155 PIGA Lilian Downie Marked gene: PIGA as ready
Prepair 1000+ v1.155 PIGA Lilian Downie Gene: piga has been classified as Green List (High Evidence).
Prepair 1000+ v1.155 PIGA Lilian Downie Phenotypes for gene: PIGA were changed from Multiple congenital anomalies-hypotonia-seizures syndrome 2, 300868 (3) to Multiple congenital anomalies-hypotonia-seizures syndrome 2, MIM#300868; Neurodevelopmental disorder with epilepsy and hemochromatosis, MIM#301072
Prepair 1000+ v1.154 PLPBP Lilian Downie Marked gene: PLPBP as ready
Prepair 1000+ v1.154 PLPBP Lilian Downie Gene: plpbp has been classified as Green List (High Evidence).
Prepair 1000+ v1.154 PLPBP Lilian Downie Publications for gene: PLPBP were set to
Prepair 1000+ v1.153 PMM2 Lilian Downie Marked gene: PMM2 as ready
Prepair 1000+ v1.153 PMM2 Lilian Downie Gene: pmm2 has been classified as Green List (High Evidence).
Prepair 1000+ v1.153 PMM2 Lilian Downie Publications for gene: PMM2 were set to
Prepair 1000+ v1.152 RAB3GAP1 Lilian Downie Marked gene: RAB3GAP1 as ready
Prepair 1000+ v1.152 RAB3GAP1 Lilian Downie Gene: rab3gap1 has been classified as Green List (High Evidence).
Prepair 1000+ v1.152 RIN2 Lilian Downie Marked gene: RIN2 as ready
Prepair 1000+ v1.152 RIN2 Lilian Downie Gene: rin2 has been classified as Green List (High Evidence).
Prepair 1000+ v1.152 RIN2 Lilian Downie Publications for gene: RIN2 were set to
Prepair 1000+ v1.151 RNASEH2C Lilian Downie Marked gene: RNASEH2C as ready
Prepair 1000+ v1.151 RNASEH2C Lilian Downie Gene: rnaseh2c has been classified as Green List (High Evidence).
Prepair 1000+ v1.151 RNASEH2C Lilian Downie Publications for gene: RNASEH2C were set to
Prepair 1000+ v1.150 SGCG Lilian Downie Marked gene: SGCG as ready
Prepair 1000+ v1.150 SGCG Lilian Downie Gene: sgcg has been classified as Green List (High Evidence).
Prepair 1000+ v1.150 SGCG Lilian Downie Publications for gene: SGCG were set to
Prepair 1000+ v1.149 SLC46A1 Lilian Downie Marked gene: SLC46A1 as ready
Prepair 1000+ v1.149 SLC46A1 Lilian Downie Gene: slc46a1 has been classified as Green List (High Evidence).
Prepair 1000+ v1.149 SLC46A1 Lilian Downie Publications for gene: SLC46A1 were set to
Prepair 1000+ v1.148 SUCLG1 Lilian Downie Marked gene: SUCLG1 as ready
Prepair 1000+ v1.148 SUCLG1 Lilian Downie Gene: suclg1 has been classified as Green List (High Evidence).
Prepair 1000+ v1.148 SUCLG1 Lilian Downie Publications for gene: SUCLG1 were set to
Prepair 1000+ v1.147 SURF1 Lilian Downie Marked gene: SURF1 as ready
Prepair 1000+ v1.147 SURF1 Lilian Downie Added comment: Comment when marking as ready: Consider most appropriate name- literature commonly refers to as Leigh syndrome but MIM 256000 doesn't have SURF1 attached to it. No overarching MONDO. Maybe MItochondrial complex IV deficiency MIM220110 is the most appropriate
Prepair 1000+ v1.147 SURF1 Lilian Downie Gene: surf1 has been classified as Green List (High Evidence).
Prepair 1000+ v1.147 SURF1 Lilian Downie Tag for review tag was added to gene: SURF1.
Prepair 1000+ v1.147 SURF1 Lilian Downie Publications for gene: SURF1 were set to
Prepair 1000+ v1.146 TPK1 Lilian Downie Marked gene: TPK1 as ready
Prepair 1000+ v1.146 TPK1 Lilian Downie Gene: tpk1 has been classified as Green List (High Evidence).
Prepair 1000+ v1.146 TPK1 Lilian Downie Publications for gene: TPK1 were set to
Prepair 1000+ v1.145 TUBGCP4 Lilian Downie Marked gene: TUBGCP4 as ready
Prepair 1000+ v1.145 TUBGCP4 Lilian Downie Gene: tubgcp4 has been classified as Green List (High Evidence).
Prepair 1000+ v1.145 TUBGCP4 Lilian Downie Publications for gene: TUBGCP4 were set to
Prepair 1000+ v1.144 TUFM Lilian Downie Marked gene: TUFM as ready
Prepair 1000+ v1.144 TUFM Lilian Downie Added comment: Comment when marking as ready: PMID: 37433570 can have a milder, later onset
Prepair 1000+ v1.144 TUFM Lilian Downie Gene: tufm has been classified as Green List (High Evidence).
Prepair 1000+ v1.144 TUFM Lilian Downie Publications for gene: TUFM were set to
Prepair 1000+ v1.143 CSMD1 Krithika Murali gene: CSMD1 was added
gene: CSMD1 was added to Prepair 1000+. Sources: Literature
Mode of inheritance for gene: CSMD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CSMD1 were set to PMID:38816421
Phenotypes for gene: CSMD1 were set to complex neurodevelopmental disorder MONDO:0100038
Review for gene: CSMD1 was set to GREEN
Added comment: PMID 38816421 Werren et al 2024 report 8 individuals from 6 families with biallelic missense CSMD1 variants identified through exome sequencing and subsequent gene-sharing efforts. Shared phenotypic features included: GDD, ID, microcephaly and polymicrogyria. Other features included dysmorphism, IUGR, hypotonia, arthrogryposis, seizures, opthalmological anomalies and other brain white matter anomalies Heterozygous parents were unaffected.

Loss of function is the postulated mechanism based on experimental data involving early-stage forebrain organoids differentiated from CSMD1 knockout human embryonic stem cells. ClinGen haploinsufficiency score of 1, however, this curation was last reviewed in 2018. This gene is within the scope of review for the ClinGen Autism and ID GCEP.
Sources: Literature
Prepair 1000+ v1.142 ATP8B1 Cassandra Muller reviewed gene: ATP8B1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Cholestasis, progressive familial intrahepatic 1, 211600 (3); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Spontaneous coronary artery dissection v0.52 Zornitza Stark Panel status changed from internal to public
Panel types changed to Victorian Clinical Genetics Services; Rare Disease
Spontaneous coronary artery dissection v0.51 YY1AP1 Zornitza Stark reviewed gene: YY1AP1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Grange syndrome, MIM# 602531; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.6122 CSNK1G1 Rylee Peters reviewed gene: CSNK1G1: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 33009664; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, CSNK1G-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1953 CSNK1G1 Rylee Peters reviewed gene: CSNK1G1: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 33009664; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, CSNK1G-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Spontaneous coronary artery dissection v0.51 TGFBR1 Zornitza Stark reviewed gene: TGFBR1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Loeys-Dietz syndrome 1, MIM# 609192; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Spontaneous coronary artery dissection v0.51 MYLK Zornitza Stark Marked gene: MYLK as ready
Spontaneous coronary artery dissection v0.51 MYLK Zornitza Stark Gene: mylk has been classified as Amber List (Moderate Evidence).
Spontaneous coronary artery dissection v0.51 MYLK Zornitza Stark reviewed gene: MYLK: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Aortic aneurysm, familial thoracic 7 MIM#613780; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Spontaneous coronary artery dissection v0.51 LOX Zornitza Stark reviewed gene: LOX: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Aortic aneurysm, familial thoracic 10 MIM#617168; Mode of inheritance: None
Spontaneous coronary artery dissection v0.51 LMX1B Zornitza Stark Classified gene: LMX1B as Red List (low evidence)
Spontaneous coronary artery dissection v0.51 LMX1B Zornitza Stark Gene: lmx1b has been classified as Red List (Low Evidence).
Spontaneous coronary artery dissection v0.50 LMX1B Zornitza Stark reviewed gene: LMX1B: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Nail-patella syndrome MIM#161200; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Spontaneous coronary artery dissection v0.50 FLNA Zornitza Stark reviewed gene: FLNA: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: periventricular heterotopia 1 MIM#300049; Mode of inheritance: None
Mendeliome v1.1953 REXO2 Zornitza Stark Marked gene: REXO2 as ready
Mendeliome v1.1953 REXO2 Zornitza Stark Gene: rexo2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1953 REXO2 Zornitza Stark Classified gene: REXO2 as Amber List (moderate evidence)
Mendeliome v1.1953 REXO2 Zornitza Stark Gene: rexo2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1952 REXO2 Zornitza Stark gene: REXO2 was added
gene: REXO2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: REXO2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: REXO2 were set to 39107301
Phenotypes for gene: REXO2 were set to Type 1 interferonopathy of childhood, MONDO:0957408, REXO2-related
Review for gene: REXO2 was set to AMBER
Added comment: Female infant of Chinese ancestry, presented at 2 years of age with whole-body rash with histological features of hyperkeratosis, parakeratosis and acanthosis with elongated rete ridges, focal liquefaction and degeneration of the basal layers of epidermis, vascular proliferation in the superficial dermis, infiltration of lymphocytes and eosinophils around small blood vessels in the dermis. She has recurrent infections (frequent and severe pneumonia). Extensive functional validation demonstrating heterozygous de novo mutation (p.T132A) impairs REXO2’s ability to cleave RNA leading to activation of the dsRNA sensor MDA5 leading to a Type 1 interferonopathy.
Sources: Literature
Autoinflammatory Disorders v1.50 REXO2 Zornitza Stark Marked gene: REXO2 as ready
Autoinflammatory Disorders v1.50 REXO2 Zornitza Stark Gene: rexo2 has been classified as Amber List (Moderate Evidence).
Autoinflammatory Disorders v1.50 REXO2 Zornitza Stark Phenotypes for gene: REXO2 were changed from type 1 interferonopathy to Type 1 interferonopathy of childhood, MONDO:0957408, REXO2-related
Autoinflammatory Disorders v1.49 REXO2 Zornitza Stark Classified gene: REXO2 as Amber List (moderate evidence)
Autoinflammatory Disorders v1.49 REXO2 Zornitza Stark Gene: rexo2 has been classified as Amber List (Moderate Evidence).
Autoinflammatory Disorders v1.48 REXO2 Zornitza Stark reviewed gene: REXO2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Type 1 interferonopathy of childhood, MONDO:0957408, REXO2-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1951 TMEFF1 Zornitza Stark Marked gene: TMEFF1 as ready
Mendeliome v1.1951 TMEFF1 Zornitza Stark Gene: tmeff1 has been classified as Green List (High Evidence).
Mendeliome v1.1951 TMEFF1 Zornitza Stark Classified gene: TMEFF1 as Green List (high evidence)
Mendeliome v1.1951 TMEFF1 Zornitza Stark Gene: tmeff1 has been classified as Green List (High Evidence).
Mendeliome v1.1950 TMEFF1 Zornitza Stark gene: TMEFF1 was added
gene: TMEFF1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TMEFF1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEFF1 were set to 39048830
Phenotypes for gene: TMEFF1 were set to Hereditary susceptibility to infections, MONDO:0015979, TMEFF1-related; HSV encephalitis
Review for gene: TMEFF1 was set to GREEN
Added comment: 2 unrelated patients with severe HSV encephalitis. Functional validation showing that human TMEFF1 encodes a type I IFN-independent, cortical neuron- and CNS-intrinsic restriction factor that is effective against HSV-1 that operates by impairing the entry of HSV-1 into cortical neurons.
Sources: Literature
Susceptibility to Viral Infections v0.128 TMEFF1 Zornitza Stark Marked gene: TMEFF1 as ready
Susceptibility to Viral Infections v0.128 TMEFF1 Zornitza Stark Gene: tmeff1 has been classified as Green List (High Evidence).
Prepair 1000+ v1.142 ASNS Cassandra Muller reviewed gene: ASNS: Rating: GREEN; Mode of pathogenicity: None; Publications: 24139043, 27469131, 29375865, 28776279; Phenotypes: Asparagine synthetase deficiency, 615574; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Susceptibility to Viral Infections v0.128 TMEFF1 Zornitza Stark Phenotypes for gene: TMEFF1 were changed from hsv encephalitis to Hereditary susceptibility to infections, MONDO:0015979, TMEFF1-related; HSV encephalitis
Susceptibility to Viral Infections v0.127 TMEFF1 Zornitza Stark Classified gene: TMEFF1 as Green List (high evidence)
Susceptibility to Viral Infections v0.127 TMEFF1 Zornitza Stark Gene: tmeff1 has been classified as Green List (High Evidence).
Susceptibility to Viral Infections v0.126 TMEFF1 Zornitza Stark reviewed gene: TMEFF1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hereditary susceptibility to infections, MONDO:0015979, TMEFF1-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Bleeding and Platelet Disorders v1.52 PROS1 Zornitza Stark Marked gene: PROS1 as ready
Bleeding and Platelet Disorders v1.52 PROS1 Zornitza Stark Gene: pros1 has been classified as Green List (High Evidence).
Bleeding and Platelet Disorders v1.52 PROS1 Zornitza Stark Classified gene: PROS1 as Green List (high evidence)
Bleeding and Platelet Disorders v1.52 PROS1 Zornitza Stark Gene: pros1 has been classified as Green List (High Evidence).
Bleeding and Platelet Disorders v1.51 SERPINC1 Zornitza Stark Marked gene: SERPINC1 as ready
Bleeding and Platelet Disorders v1.51 SERPINC1 Zornitza Stark Gene: serpinc1 has been classified as Green List (High Evidence).
Bleeding and Platelet Disorders v1.51 SERPINC1 Zornitza Stark edited their review of gene: SERPINC1: Changed mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Bleeding and Platelet Disorders v1.51 SERPINC1 Zornitza Stark Classified gene: SERPINC1 as Green List (high evidence)
Bleeding and Platelet Disorders v1.51 SERPINC1 Zornitza Stark Gene: serpinc1 has been classified as Green List (High Evidence).
Bleeding and Platelet Disorders v1.50 SERPINC1 Zornitza Stark reviewed gene: SERPINC1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Thrombophilia 7 due to antithrombin III deficiency #613118; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Bleeding and Platelet Disorders v1.50 SERPIND1 Zornitza Stark Marked gene: SERPIND1 as ready
Bleeding and Platelet Disorders v1.50 SERPIND1 Zornitza Stark Gene: serpind1 has been classified as Green List (High Evidence).
Bleeding and Platelet Disorders v1.50 SERPIND1 Zornitza Stark Phenotypes for gene: SERPIND1 were changed from HEPARIN COFACTOR II DEFICIENCY #612356 to heparin cofactor 2 deficiency, MONDO:0012876; Thrombophilia 10 due to heparin cofactor II deficiency, MIM#612356
Bleeding and Platelet Disorders v1.49 SERPIND1 Zornitza Stark Publications for gene: SERPIND1 were set to PMID: 12421148; PMID: 35592395; PMID: 2647747; PMID: 11204559; PMID: 10494755
Bleeding and Platelet Disorders v1.48 SERPIND1 Zornitza Stark Classified gene: SERPIND1 as Green List (high evidence)
Bleeding and Platelet Disorders v1.48 SERPIND1 Zornitza Stark Gene: serpind1 has been classified as Green List (High Evidence).
Bleeding and Platelet Disorders v1.47 SERPIND1 Zornitza Stark reviewed gene: SERPIND1: Rating: GREEN; Mode of pathogenicity: None; Publications: 8902986, 15337701, 31064749, 11204559, 8562924, 29296762, 2863444, 2647747, 17549254, 11805133; Phenotypes: heparin cofactor 2 deficiency, MONDO:0012876, Thrombophilia 10 due to heparin cofactor II deficiency, MIM#612356; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Prepair 1000+ v1.142 ARL13B Cassandra Muller reviewed gene: ARL13B: Rating: GREEN; Mode of pathogenicity: None; Publications: 38219074, 18674751, 25138100, 26092869, 27894351, 29255182; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.265 CSMD1 Zornitza Stark Marked gene: CSMD1 as ready
Fetal anomalies v1.265 CSMD1 Zornitza Stark Gene: csmd1 has been classified as Green List (High Evidence).
Fetal anomalies v1.265 CSMD1 Zornitza Stark Classified gene: CSMD1 as Green List (high evidence)
Fetal anomalies v1.265 CSMD1 Zornitza Stark Gene: csmd1 has been classified as Green List (High Evidence).
Leukodystrophy - paediatric v0.310 CSMD1 Zornitza Stark Marked gene: CSMD1 as ready
Leukodystrophy - paediatric v0.310 CSMD1 Zornitza Stark Gene: csmd1 has been classified as Green List (High Evidence).
Leukodystrophy - paediatric v0.310 CSMD1 Zornitza Stark Classified gene: CSMD1 as Green List (high evidence)
Leukodystrophy - paediatric v0.310 CSMD1 Zornitza Stark Gene: csmd1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.6122 CSMD1 Zornitza Stark Marked gene: CSMD1 as ready
Intellectual disability syndromic and non-syndromic v0.6122 CSMD1 Zornitza Stark Gene: csmd1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.6122 CSMD1 Zornitza Stark Classified gene: CSMD1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.6122 CSMD1 Zornitza Stark Gene: csmd1 has been classified as Green List (High Evidence).
Callosome v0.527 CSMD1 Zornitza Stark Marked gene: CSMD1 as ready
Callosome v0.527 CSMD1 Zornitza Stark Gene: csmd1 has been classified as Green List (High Evidence).
Callosome v0.527 CSMD1 Zornitza Stark Classified gene: CSMD1 as Green List (high evidence)
Callosome v0.527 CSMD1 Zornitza Stark Gene: csmd1 has been classified as Green List (High Evidence).
Genetic Epilepsy v1.44 CSMD1 Zornitza Stark Marked gene: CSMD1 as ready
Genetic Epilepsy v1.44 CSMD1 Zornitza Stark Gene: csmd1 has been classified as Green List (High Evidence).
Genetic Epilepsy v1.44 CSMD1 Zornitza Stark Classified gene: CSMD1 as Green List (high evidence)
Genetic Epilepsy v1.44 CSMD1 Zornitza Stark Gene: csmd1 has been classified as Green List (High Evidence).
Muscular dystrophy and myopathy_Paediatric v1.67 CSMD1 Zornitza Stark Marked gene: CSMD1 as ready
Muscular dystrophy and myopathy_Paediatric v1.67 CSMD1 Zornitza Stark Gene: csmd1 has been classified as Green List (High Evidence).
Muscular dystrophy and myopathy_Paediatric v1.67 CSMD1 Zornitza Stark Classified gene: CSMD1 as Green List (high evidence)
Muscular dystrophy and myopathy_Paediatric v1.67 CSMD1 Zornitza Stark Gene: csmd1 has been classified as Green List (High Evidence).
Microcephaly v1.271 CSMD1 Zornitza Stark Marked gene: CSMD1 as ready
Microcephaly v1.271 CSMD1 Zornitza Stark Gene: csmd1 has been classified as Green List (High Evidence).
Microcephaly v1.271 CSMD1 Zornitza Stark Classified gene: CSMD1 as Green List (high evidence)
Microcephaly v1.271 CSMD1 Zornitza Stark Gene: csmd1 has been classified as Green List (High Evidence).
Mendeliome v1.1949 CSMD1 Zornitza Stark Marked gene: CSMD1 as ready
Mendeliome v1.1949 CSMD1 Zornitza Stark Gene: csmd1 has been classified as Green List (High Evidence).
Mendeliome v1.1949 CSMD1 Zornitza Stark Classified gene: CSMD1 as Green List (high evidence)
Mendeliome v1.1949 CSMD1 Zornitza Stark Gene: csmd1 has been classified as Green List (High Evidence).
Arthrogryposis v0.413 CSMD1 Zornitza Stark Marked gene: CSMD1 as ready
Arthrogryposis v0.413 CSMD1 Zornitza Stark Gene: csmd1 has been classified as Green List (High Evidence).
Arthrogryposis v0.413 CSMD1 Zornitza Stark Classified gene: CSMD1 as Green List (high evidence)
Arthrogryposis v0.413 CSMD1 Zornitza Stark Gene: csmd1 has been classified as Green List (High Evidence).
Polymicrogyria and Schizencephaly v0.191 CSMD1 Zornitza Stark Marked gene: CSMD1 as ready
Polymicrogyria and Schizencephaly v0.191 CSMD1 Zornitza Stark Gene: csmd1 has been classified as Green List (High Evidence).
Polymicrogyria and Schizencephaly v0.191 CSMD1 Zornitza Stark Classified gene: CSMD1 as Green List (high evidence)
Polymicrogyria and Schizencephaly v0.191 CSMD1 Zornitza Stark Gene: csmd1 has been classified as Green List (High Evidence).
Cerebral Palsy v1.367 CSMD1 Zornitza Stark Marked gene: CSMD1 as ready
Cerebral Palsy v1.367 CSMD1 Zornitza Stark Gene: csmd1 has been classified as Green List (High Evidence).
Cerebral Palsy v1.367 CSMD1 Zornitza Stark Classified gene: CSMD1 as Green List (high evidence)
Cerebral Palsy v1.367 CSMD1 Zornitza Stark Gene: csmd1 has been classified as Green List (High Evidence).
Bleeding and Platelet Disorders v1.47 SERPIND1 Jane Lin gene: SERPIND1 was added
gene: SERPIND1 was added to Bleeding and Platelet Disorders. Sources: Expert list
Mode of inheritance for gene: SERPIND1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SERPIND1 were set to PMID: 12421148; PMID: 35592395; PMID: 2647747; PMID: 11204559; PMID: 10494755
Phenotypes for gene: SERPIND1 were set to HEPARIN COFACTOR II DEFICIENCY #612356
Review for gene: SERPIND1 was set to AMBER
gene: SERPIND1 was marked as current diagnostic
Added comment: Also known as HCF2. There is evidence of protein to phenotype links but not many recent papers linking specific genetic variants to phenotype. Expect more given the first link to inherited thrombosis was published in 1985 (PMID: 2863444). There are two papers that used PCR to determine mutation in an affected individual (PMID: 2647747) published in 1989 and a paper in 2001 (PMID: 11204559). There is a paper reporting homozygous HCII but could not access paper (abstract only) (PMID: 10494755). This 2002 review (PMID: 12421148) lists 5 publications with 5 different molecular mutations linked to Heparin Cofactor II Deficiency. This review also notes that most of the case reports concluded that "inherited HCII deficiency is not a strong risk factor for thrombosis or that it contributes to thrombotic risk only when combined with other deficiencies." A more recent review (PMID: 35592395) has similar view and literature searches don't reveal recent papers with reports of variants linked to thrombosis.
Sources: Expert list
Cerebral Palsy v1.366 CSMD1 Krithika Murali gene: CSMD1 was added
gene: CSMD1 was added to Cerebral Palsy. Sources: Literature
Mode of inheritance for gene: CSMD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CSMD1 were set to PMID: 38816421
Phenotypes for gene: CSMD1 were set to complex neurodevelopmental disorder MONDO:0100038
Review for gene: CSMD1 was set to GREEN
Added comment: PMID 38816421 Werren et al 2024 report 8 individuals from 6 families with biallelic missense CSMD1 variants identified through exome sequencing and subsequent gene-sharing efforts. Shared phenotypic features included: GDD, ID, microcephaly and polymicrogyria. Other features included dysmorphism, IUGR, hypotonia, arthrogryposis, seizures, opthalmological anomalies and other brain white matter anomalies Heterozygous parents were unaffected.

Loss of function is the postulated mechanism based on experimental data involving early-stage forebrain organoids differentiated from CSMD1 knockout human embryonic stem cells. ClinGen haploinsufficiency score of 1, however, this curation was last reviewed in 2018. This gene is within the scope of review for the ClinGen Autism and ID GCEP.
Sources: Literature
Genetic Epilepsy v1.43 CSMD1 Krithika Murali gene: CSMD1 was added
gene: CSMD1 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: CSMD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CSMD1 were set to PMID: 38816421
Phenotypes for gene: CSMD1 were set to complex neurodevelopmental disorder MONDO:0100038
Review for gene: CSMD1 was set to GREEN
Added comment: PMID 38816421 Werren et al 2024 report 8 individuals from 6 families with biallelic missense CSMD1 variants identified through exome sequencing and subsequent gene-sharing efforts. Shared phenotypic features included: GDD, ID, microcephaly and polymicrogyria. Other features included dysmorphism, IUGR, hypotonia, arthrogryposis, seizures, opthalmological anomalies and other brain white matter anomalies Heterozygous parents were unaffected.

Loss of function is the postulated mechanism based on experimental data involving early-stage forebrain organoids differentiated from CSMD1 knockout human embryonic stem cells. ClinGen haploinsufficiency score of 1, however, this curation was last reviewed in 2018. This gene is within the scope of review for the ClinGen Autism and ID GCEP.
Sources: Literature
Leukodystrophy - paediatric v0.309 CSMD1 Krithika Murali gene: CSMD1 was added
gene: CSMD1 was added to Leukodystrophy - paediatric. Sources: Literature
Mode of inheritance for gene: CSMD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CSMD1 were set to PMID 38816421
Phenotypes for gene: CSMD1 were set to complex neurodevelopmental disorder MONDO:0100038
Review for gene: CSMD1 was set to GREEN
Added comment: PMID 38816421 Werren et al 2024 report 8 individuals from 6 families with biallelic missense CSMD1 variants identified through exome sequencing and subsequent gene-sharing efforts. Shared phenotypic features included: GDD, ID, microcephaly and polymicrogyria. Other features included dysmorphism, IUGR, hypotonia, arthrogryposis, seizures, opthalmological anomalies and other brain white matter anomalies Heterozygous parents were unaffected.

Loss of function is the postulated mechanism based on experimental data involving early-stage forebrain organoids differentiated from CSMD1 knockout human embryonic stem cells. ClinGen haploinsufficiency score of 1, however, this curation was last reviewed in 2018. This gene is within the scope of review for the ClinGen Autism and ID GCEP.
Sources: Literature
Microcephaly v1.270 CSMD1 Krithika Murali gene: CSMD1 was added
gene: CSMD1 was added to Microcephaly. Sources: Literature
Mode of inheritance for gene: CSMD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CSMD1 were set to PMID:38816421
Phenotypes for gene: CSMD1 were set to complex neurodevelopmental disorder MONDO:0100038
Review for gene: CSMD1 was set to GREEN
Added comment: PMID 38816421 Werren et al 2024 report 8 individuals from 6 families with biallelic missense CSMD1 variants identified through exome sequencing and subsequent gene-sharing efforts. Shared phenotypic features included: GDD, ID, microcephaly and polymicrogyria. Other features included dysmorphism, IUGR, hypotonia, arthrogryposis, seizures, opthalmological anomalies and other brain white matter anomalies Heterozygous parents were unaffected.

Loss of function is the postulated mechanism based on experimental data involving early-stage forebrain organoids differentiated from CSMD1 knockout human embryonic stem cells. ClinGen haploinsufficiency score of 1, however, this curation was last reviewed in 2018. This gene is within the scope of review for the ClinGen Autism and ID GCEP.
Sources: Literature
Callosome v0.526 CSMD1 Krithika Murali gene: CSMD1 was added
gene: CSMD1 was added to Callosome. Sources: Literature
Mode of inheritance for gene: CSMD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CSMD1 were set to PMID: 38816421
Phenotypes for gene: CSMD1 were set to complex neurodevelopmental disorder MONDO:0100038
Review for gene: CSMD1 was set to GREEN
Added comment: PMID 38816421 Werren et al 2024 report 8 individuals from 6 families with biallelic missense CSMD1 variants identified through exome sequencing and subsequent gene-sharing efforts. Shared phenotypic features included: GDD, ID, microcephaly and polymicrogyria. Other features included dysmorphism, IUGR, hypotonia, arthrogryposis, seizures, opthalmological anomalies and other brain white matter anomalies Heterozygous parents were unaffected.

Loss of function is the postulated mechanism based on experimental data involving early-stage forebrain organoids differentiated from CSMD1 knockout human embryonic stem cells. ClinGen haploinsufficiency score of 1, however, this curation was last reviewed in 2018. This gene is within the scope of review for the ClinGen Autism and ID GCEP.
Sources: Literature
Arthrogryposis v0.412 CSMD1 Krithika Murali gene: CSMD1 was added
gene: CSMD1 was added to Arthrogryposis. Sources: Literature
Mode of inheritance for gene: CSMD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CSMD1 were set to PMID 38816421
Phenotypes for gene: CSMD1 were set to complex neurodevelopmental disorder MONDO:0100038
Review for gene: CSMD1 was set to GREEN
Added comment: PMID 38816421 Werren et al 2024 report 8 individuals from 6 families with biallelic missense CSMD1 variants identified through exome sequencing and subsequent gene-sharing efforts. Shared phenotypic features included: GDD, ID, microcephaly and polymicrogyria. Other features included dysmorphism, IUGR, hypotonia, arthrogryposis, seizures, opthalmological anomalies and other brain white matter anomalies Heterozygous parents were unaffected.

Loss of function is the postulated mechanism based on experimental data involving early-stage forebrain organoids differentiated from CSMD1 knockout human embryonic stem cells. ClinGen haploinsufficiency score of 1, however, this curation was last reviewed in 2018. This gene is within the scope of review for the ClinGen Autism and ID GCEP.
Sources: Literature
Fetal anomalies v1.264 CSMD1 Krithika Murali gene: CSMD1 was added
gene: CSMD1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: CSMD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CSMD1 were set to PMID: 38816421
Phenotypes for gene: CSMD1 were set to complex neurodevelopmental disorder MONDO:0100038
Review for gene: CSMD1 was set to GREEN
Added comment: Prenatal features reported include polyhydramnios, IUGR, preterm labour. Other reported features such as brain anomalies, arthrogryposis have the potential to be ascertained prenatally also.
--
PMID 38816421 Werren et al 2024 report 8 individuals from 6 families with biallelic missense CSMD1 variants identified through exome sequencing and subsequent gene-sharing efforts. Shared phenotypic features included: GDD, ID, microcephaly and polymicrogyria. Other features included dysmorphism, IUGR, hypotonia, arthrogryposis, seizures, opthalmological anomalies and other brain white matter anomalies Heterozygous parents were unaffected.

Loss of function is the postulated mechanism based on experimental data involving early-stage forebrain organoids differentiated from CSMD1 knockout human embryonic stem cells. ClinGen haploinsufficiency score of 1, however, this curation was last reviewed in 2018. This gene is within the scope of review for the ClinGen Autism and ID GCEP.
Sources: Literature
Muscular dystrophy and myopathy_Paediatric v1.66 CSMD1 Krithika Murali gene: CSMD1 was added
gene: CSMD1 was added to Muscular dystrophy and myopathy_Paediatric. Sources: Literature
Mode of inheritance for gene: CSMD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CSMD1 were set to PMID 38816421
Phenotypes for gene: CSMD1 were set to complex neurodevelopmental disorder MONDO:0100038
Added comment: PMID 38816421 Werren et al 2024 report 8 individuals from 6 families with biallelic missense CSMD1 variants identified through exome sequencing and subsequent gene-sharing efforts. Shared phenotypic features included: GDD, ID, microcephaly and polymicrogyria. Other features included dysmorphism, IUGR, hypotonia, arthrogryposis, seizures, opthalmological anomalies and other brain white matter anomalies Heterozygous parents were unaffected.

Loss of function is the postulated mechanism based on experimental data involving early-stage forebrain organoids differentiated from CSMD1 knockout human embryonic stem cells. ClinGen haploinsufficiency score of 1, however, this curation was last reviewed in 2018. This gene is within the scope of review for the ClinGen Autisim and ID GCEP.
Sources: Literature
Polymicrogyria and Schizencephaly v0.190 CSMD1 Krithika Murali gene: CSMD1 was added
gene: CSMD1 was added to Polymicrogyria and Schizencephaly. Sources: Literature
Mode of inheritance for gene: CSMD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CSMD1 were set to PMID 38816421
Phenotypes for gene: CSMD1 were set to complex neurodevelopmental disorder MONDO:0100038
Review for gene: CSMD1 was set to GREEN
Added comment: PMID 38816421 Werren et al 2024 report 8 individuals from 6 families with biallelic missense CSMD1 variants identified through exome sequencing and subsequent gene-sharing efforts. Shared phenotypic features included: GDD, ID, microcephaly and polymicrogyria. Other features included dysmorphism, IUGR, hypotonia, arthrogryposis, seizures, opthalmological anomalies and other brain white matter anomalies Heterozygous parents were unaffected.

Loss of function is the postulated mechanism based on experimental data involving early-stage forebrain organoids differentiated from CSMD1 knockout human embryonic stem cells. ClinGen haploinsufficiency score of 1, however, this curation was last reviewed in 2018. This gene is within the scope of review for the ClinGen Autisim and ID GCEP.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.6121 CSMD1 Krithika Murali gene: CSMD1 was added
gene: CSMD1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: CSMD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CSMD1 were set to PMID 38816421
Phenotypes for gene: CSMD1 were set to complex neurodevelopmental disorder MONDO:0100038
Review for gene: CSMD1 was set to GREEN
Added comment: PMID 38816421 Werren et al 2024 report 8 individuals from 6 families with biallelic missense CSMD1 variants identified through exome sequencing and subsequent gene-sharing efforts. Shared phenotypic features included: GDD, ID, microcephaly and polymicrogyria. Other features included dysmorphism, IUGR, hypotonia, arthrogryposis, seizures, opthalmological anomalies and other brain white matter anomalies Heterozygous parents were unaffected.

Loss of function is the postulated mechanism based on experimental data involving early-stage forebrain organoids differentiated from CSMD1 knockout human embryonic stem cells. ClinGen haploinsufficiency score of 1, however, this curation was last reviewed in 2018. This gene is within the scope of review for the ClinGen Autisim and ID GCEP.
Sources: Literature
Mendeliome v1.1948 CSMD1 Krithika Murali gene: CSMD1 was added
gene: CSMD1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CSMD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CSMD1 were set to PMID:38816421
Phenotypes for gene: CSMD1 were set to complex neurodevelopmental disorder MONDO:0100038
Review for gene: CSMD1 was set to GREEN
Added comment: PMID 38816421 Werren et al 2024 report 8 individuals from 6 families identified through exome sequencing and subsequent gene-sharing efforts with biallelic missense CSMD1 variants. Shared phenotypic features included: GDD, ID, microcephaly and polymicrogyria. Other features included dysmorphism, IUGR, hypotonia, arthrogryposis, seizures, opthalmological anomalies and other brain white matter anomalies Heterozygous parents were unaffected.

Loss of function is the postulated mechanism based on experimental data involving early-stage forebrain organoids differentiated from CSMD1 knockout human embryonic stem cells (hESCs).

ClinGen haploinsufficiency score of 1, however, this curation was last reviewed in 2018. This gene is within the scope of review for the ClinGen Autisim and ID GCEP.
Sources: Literature
Bleeding and Platelet Disorders v1.47 SERPINC1 Jane Lin gene: SERPINC1 was added
gene: SERPINC1 was added to Bleeding and Platelet Disorders. Sources: Expert list
Mode of inheritance for gene: SERPINC1 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Publications for gene: SERPINC1 were set to PMID: 14347873; PMID: 36624481; PMID: 28300866
Phenotypes for gene: SERPINC1 were set to Thrombophilia 7 due to antithrombin III deficiency #613118
Review for gene: SERPINC1 was set to GREEN
gene: SERPINC1 was marked as current diagnostic
Added comment: Well established gene-phenotype relationship. Mostly autosomal dominant inheritance (autosomal recessive inheritance is rare but has been published). Have listed an early publication (1965) establishing this link and two more recent papers.
Sources: Expert list
Prepair 1000+ v1.142 ARFGEF2 Cassandra Muller reviewed gene: ARFGEF2: Rating: GREEN; Mode of pathogenicity: None; Publications: 25160555, 26126837, 23812912, 23755938; Phenotypes: Periventricular heterotopia with microcephaly, 608097 (3); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Bleeding and Platelet Disorders v1.47 PROS1 Jane Lin gene: PROS1 was added
gene: PROS1 was added to Bleeding and Platelet Disorders. Sources: Expert list
Mode of inheritance for gene: PROS1 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Publications for gene: PROS1 were set to PMID: 2521801; PMID: 7545463; PMID: 2231208; PMID: 10063989
Phenotypes for gene: PROS1 were set to Thrombophilia 5 due to protein S deficiency, autosomal dominant #612336; Thrombophilia 5 due to protein S deficiency, autosomal recessive #614514
Review for gene: PROS1 was set to GREEN
gene: PROS1 was marked as current diagnostic
Added comment: Strong gene-phenotype link. Many publications for both both autosomal dominant and autosomal recessive inheritance of PROS1 variants and thrombosis phenotype.
Sources: Expert list
Bleeding and Platelet Disorders v1.47 PIGA Jane Lin changed review comment from: PIGA variants linked to Paroxysmal nocturnal hemoglobinuria (PNH), clinical features which include thrombosis, but as somatic changes.
Sources: Expert list; to: PIGA variants linked to Paroxysmal nocturnal hemoglobinuria (PNH), clinical features which include thrombosis, but as somatic changes.
Sources: Expert list

Note: a few publications on constitutive PIGA mutations don't describe thrombosis as part of the phenotype. Note that homozygous/hemizygous mutations are rare and quite lethal.

PMID: 22305531
PMID: 34875027
Susceptibility to Viral Infections v0.126 TMEFF1 Peter McNaughton gene: TMEFF1 was added
gene: TMEFF1 was added to Susceptibility to Viral Infections. Sources: Literature
Mode of inheritance for gene: TMEFF1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEFF1 were set to PMID: 39048830
Phenotypes for gene: TMEFF1 were set to hsv encephalitis
Review for gene: TMEFF1 was set to GREEN
Added comment: 2 unrelated patients with severe HSV encephalitis. Functional validation showing that human TMEFF1 encodes a type I IFN-independent, cortical neuron- and CNS-intrinsic restriction factor that is effective against HSV-1 that operates by impairing the entry of HSV-1 into cortical neurons.
Sources: Literature
Autoinflammatory Disorders v1.48 REXO2 Peter McNaughton gene: REXO2 was added
gene: REXO2 was added to Systemic Autoinflammatory Disease_Periodic Fever. Sources: Literature
Mode of inheritance for gene: REXO2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: REXO2 were set to PMID: 39107301
Phenotypes for gene: REXO2 were set to type 1 interferonopathy
Mode of pathogenicity for gene: REXO2 was set to Other
Review for gene: REXO2 was set to AMBER
Added comment: Female infant of Chinese ancestry, presented at 2 years of age with whole-body rash with histological features of hyperkeratosis, parakeratosis and acanthosis with elongated rete ridges, focal liquefaction and degeneration of the basal layers of epidermis, vascular proliferation in the superficial dermis, infiltration of lymphocytes and eosinophils around small blood vessels in the dermis. She has recurrent infections (frequent and severe pneumonia).
Extensive functional validation demonstrating heterozygous de novo mutation (p.T132A) impairs REXO2’s ability to cleave RNA leading to activation of the dsRNA sensor MDA5 leading to a Type 1 interferonopathy.
Sources: Literature
Pulmonary Fibrosis_Interstitial Lung Disease v0.76 NKX2-1 Zornitza Stark Marked gene: NKX2-1 as ready
Pulmonary Fibrosis_Interstitial Lung Disease v0.76 NKX2-1 Zornitza Stark Gene: nkx2-1 has been classified as Green List (High Evidence).
Pulmonary Fibrosis_Interstitial Lung Disease v0.76 NKX2-1 Zornitza Stark Publications for gene: NKX2-1 were set to
Pulmonary Fibrosis_Interstitial Lung Disease v0.75 NKX2-1 Zornitza Stark Phenotypes for gene: NKX2-1 were changed from to Choreoathetosis, hypothyroidism, and neonatal respiratory distress MIM#610978
Pulmonary Fibrosis_Interstitial Lung Disease v0.74 NKX2-1 Zornitza Stark Mode of inheritance for gene: NKX2-1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Prepair 1000+ v1.142 APOPT1 Cassandra Muller reviewed gene: APOPT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 25175347, 32637636; Phenotypes: Mitochondrial complex IV deficiency, 220110 (3); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.142 B3GLCT Karina Sandoval reviewed gene: B3GLCT: Rating: GREEN; Mode of pathogenicity: None; Publications: 23161355, 18798333, 19796186, 32533185, 32204707, 31795264, 20301637, 16909395; Phenotypes: Peters-plus syndrome(MIM#261540); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Clefting disorders v0.254 CREBBP Zornitza Stark Marked gene: CREBBP as ready
Clefting disorders v0.254 CREBBP Zornitza Stark Gene: crebbp has been classified as Green List (High Evidence).
Clefting disorders v0.254 CREBBP Zornitza Stark Classified gene: CREBBP as Green List (high evidence)
Clefting disorders v0.254 CREBBP Zornitza Stark Gene: crebbp has been classified as Green List (High Evidence).
Clefting disorders v0.253 CREBBP Zornitza Stark gene: CREBBP was added
gene: CREBBP was added to Clefting disorders. Sources: Expert Review
Mode of inheritance for gene: CREBBP was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CREBBP were set to 35626936
Phenotypes for gene: CREBBP were set to Menke-Hennekam syndrome 1, MIM# 618332
Review for gene: CREBBP was set to GREEN
Added comment: Cleft palate is a reported feature in several patients.
Sources: Expert Review
Prepair 1000+ v1.142 B3GALT6 Karina Sandoval reviewed gene: B3GALT6: Rating: GREEN; Mode of pathogenicity: None; Publications: 23664117, 29931299, 29443383, 23664118, 28306229, 25149931; Phenotypes: Al-Gazali syndrome(MIM#609465), Ehlers-Danlos syndrome, spondylodysplastic type, 2(MIM#615349), Spondyloepimetaphyseal dysplasia with joint laxity, type 1, with or without fractures(MIM#271640); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.142 MFRP Zornitza Stark Marked gene: MFRP as ready
Prepair 1000+ v1.142 MFRP Zornitza Stark Added comment: Comment when marking as ready: Promote to Green for V2.
Prepair 1000+ v1.142 MFRP Zornitza Stark Gene: mfrp has been classified as Red List (Low Evidence).
Prepair 1000+ v1.142 MFRP Zornitza Stark gene: MFRP was added
gene: MFRP was added to Prepair 1000+. Sources: Expert Review
Mode of inheritance for gene: MFRP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MFRP were set to 17167404; 18554571; 20361016
Phenotypes for gene: MFRP were set to Microphthalmia, isolated 5, MIM# 611040
Review for gene: MFRP was set to GREEN
Added comment: More than 10 unrelated families reported with bi-allelic variants in this gene associated with posterior microphthalmia with retinitis pigmentosa, foveoschisis, and optic disc drusen. Causes congenital visual impairment.
Sources: Expert Review
Spontaneous coronary artery dissection v0.50 TLN1 Ain Roesley changed review comment from: PMID: 30888838
10x families with a single affected, all missense
5x unknown inheritance
5x inherited from n unaffected parent

1x 2 generational fam with an unaffected obligate carrier, missense variant

variants reported and their counts in gnomad v4:
Ala2013Thr 1091 hets 1 hom
Arg297His 97 hets
Thr585Met 36 hets
Pro942Leu 62 hets
Ala1219Val 44 hets
Arg1241Trp 13 hets
Ser1333Thr absent
Val1964Ile 185 hets
Thr2098Met 358 hets
Val2440Glu absent

PMID: 36103205
2x individual however only 1 has a personal history of R-SCAD
Ala1574Val

Sources: Literature; to: PMID: 30888838
10x families with a single affected, all missense
5x unknown inheritance
5x inherited from an unaffected parent

1x 2 generational fam with an unaffected obligate carrier, missense variant

variants reported and their counts in gnomad v4:
Ala2013Thr 1091 hets 1 hom
Arg297His 97 hets
Thr585Met 36 hets
Pro942Leu 62 hets
Ala1219Val 44 hets
Arg1241Trp 13 hets
Ser1333Thr absent
Val1964Ile 185 hets
Thr2098Met 358 hets
Val2440Glu absent

PMID: 36103205
2x individual however only 1 has a personal history of R-SCAD
Ala1574Val

Sources: Literature
Spontaneous coronary artery dissection v0.50 LMX1B Ain Roesley Publications for gene: LMX1B were set to 37979122; 29650765
Spontaneous coronary artery dissection v0.49 LMX1B Ain Roesley Classified gene: LMX1B as Amber List (moderate evidence)
Spontaneous coronary artery dissection v0.49 LMX1B Ain Roesley Gene: lmx1b has been classified as Amber List (Moderate Evidence).
Spontaneous coronary artery dissection v0.48 LMX1B Ain Roesley edited their review of gene: LMX1B: Changed rating: AMBER; Changed publications: 29650765; Changed phenotypes: Nail-patella syndrome MIM#161200
Spontaneous coronary artery dissection v0.48 LMX1B Ain Roesley changed review comment from: PMID: 37979122; listed as "likely monogenic disease effect"

However, only a single patient found in literature
PMID: 29650765; 1x individual with SCAD and an NMD fs

this gene is constraint for LoF in gnomad v4 with only 2 hets for an NMD variant.

amber so as to not miss a diagnosis
Sources: Literature; to:
PMID: 29650765; 1x individual with SCAD and an NMD fs

this gene is constraint for LoF in gnomad v4 with only 2 hets for an NMD variant.

amber so as to not miss a diagnosis
Sources: Literature
Spontaneous coronary artery dissection v0.48 LMX1B Ain Roesley changed review comment from: PMID: 37979122; listed as "likely monogenic disease effect"

However, only a single patient found in literature
PMID: 29650765; 1x individual with SCAD and an NMD fs
Sources: Literature; to: PMID: 37979122; listed as "likely monogenic disease effect"

However, only a single patient found in literature
PMID: 29650765; 1x individual with SCAD and an NMD fs

this gene is constraint for LoF in gnomad v4 with only 2 hets for an NMD variant.

amber so as to not miss a diagnosis
Sources: Literature
Spontaneous coronary artery dissection v0.48 YY1AP1 Ain Roesley Publications for gene: YY1AP1 were set to
Spontaneous coronary artery dissection v0.47 YY1AP1 Ain Roesley Classified gene: YY1AP1 as Amber List (moderate evidence)
Spontaneous coronary artery dissection v0.47 YY1AP1 Ain Roesley Gene: yy1ap1 has been classified as Amber List (Moderate Evidence).
Spontaneous coronary artery dissection v0.46 YY1AP1 Ain Roesley edited their review of gene: YY1AP1: Changed rating: AMBER; Changed publications: 33125268
Spontaneous coronary artery dissection v0.46 YY1AP1 Ain Roesley changed review comment from:
PMID: 33125268
1x individual with a canonical splice + 1x protein truncating variant. However, phasing could not be performed

no other literature found
Sources: Literature; to:
PMID: 33125268
1x individual with a canonical splice + 1x protein truncating variant. However, phasing could not be performed

no other literature found

amber so as to not miss a diagnosis
Sources: Literature
Spontaneous coronary artery dissection v0.46 YY1AP1 Ain Roesley changed review comment from: PMID: 37979122; listed as "likely monogenic disease effect"

PMID: 33125268 was cited in paper above.
1x individual with a canonical splice + 1x protein truncating variant. However, phasing could not be performed

no other literature found
Sources: Literature; to:
PMID: 33125268
1x individual with a canonical splice + 1x protein truncating variant. However, phasing could not be performed

no other literature found
Sources: Literature
Spontaneous coronary artery dissection v0.46 PTGIR Ain Roesley Publications for gene: PTGIR were set to 32531060; 37979122
Spontaneous coronary artery dissection v0.45 PTGIR Ain Roesley changed review comment from: PMID: 37979122; listed as "likely monogenic disease effect"

PMID: 32531060; searched for 'rare' LoF variants in individuals with fibromuscular dysplasia.
However, this gene is NOT LoF constraint in gnomad v4.
200 hets for an NMD variant
Sources: Literature; to: PMID: 32531060; searched for 'rare' LoF variants in individuals with fibromuscular dysplasia.
However, this gene is NOT LoF constraint in gnomad v4.
200 hets for an NMD variant

All other papers cited PMID: 32531060
Sources: Literature
Spontaneous coronary artery dissection v0.45 TLN1 Ain Roesley Publications for gene: TLN1 were set to 30888838; 37979122
Spontaneous coronary artery dissection v0.44 TLN1 Ain Roesley edited their review of gene: TLN1: Changed publications: 30888838, 36103205
Spontaneous coronary artery dissection v0.44 TLN1 Ain Roesley changed review comment from: PMID: 37979122; listed as "likely monogenic disease effect"

but AMBER rating
10 unique rare heterozygous missense variants in 11 individuals were identified in a 2 generation SCAD family and 56 unrelated individuals with sporadic SCAD. All variants had a MAF of less than 0.06% and occurred within highly conserved β-integrin, F-actin, or vinculin binding domains. Incomplete penetrance was evident in the familial case and five individuals with unaffected heterozygous parents. No functional assays were conducted.
Sources: Literature; to: PMID: 30888838
10x families with a single affected, all missense
5x unknown inheritance
5x inherited from n unaffected parent

1x 2 generational fam with an unaffected obligate carrier, missense variant

variants reported and their counts in gnomad v4:
Ala2013Thr 1091 hets 1 hom
Arg297His 97 hets
Thr585Met 36 hets
Pro942Leu 62 hets
Ala1219Val 44 hets
Arg1241Trp 13 hets
Ser1333Thr absent
Val1964Ile 185 hets
Thr2098Met 358 hets
Val2440Glu absent

PMID: 36103205
2x individual however only 1 has a personal history of R-SCAD
Ala1574Val

Sources: Literature
Prepair 1000+ v1.141 USP9X Lilian Downie Marked gene: USP9X as ready
Prepair 1000+ v1.141 USP9X Lilian Downie Gene: usp9x has been classified as Green List (High Evidence).
Prepair 1000+ v1.141 USP9X Lilian Downie Phenotypes for gene: USP9X were changed from Mental retardation, X-linked 99, 300919 (3) to Intellectual developmental disorder, X-linked 99, MIM#300919
Prepair 1000+ v1.140 USP9X Lilian Downie Publications for gene: USP9X were set to
Prepair 1000+ v1.139 USP9X Lilian Downie Added comment: Comment on mode of inheritance: X-linked dominant, females can be severely affected
Prepair 1000+ v1.139 USP9X Lilian Downie Mode of inheritance for gene: USP9X was changed from X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Prepair 1000+ v1.138 USP9X Lilian Downie Mode of inheritance for gene: USP9X was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Prepair 1000+ v1.137 VLDLR Lilian Downie Marked gene: VLDLR as ready
Prepair 1000+ v1.137 VLDLR Lilian Downie Gene: vldlr has been classified as Green List (High Evidence).
Prepair 1000+ v1.137 VLDLR Lilian Downie Phenotypes for gene: VLDLR were changed from Cerebellar hypoplasia and mental retardation with or without quadrupedal locomotion 1, 224050 (3) to Cerebellar hypoplasia, impaired intellectual development, and dysequilibrium syndrome MIM#224050
Prepair 1000+ v1.136 VLDLR Lilian Downie Publications for gene: VLDLR were set to
Prepair 1000+ v1.135 WDR45B Lilian Downie Marked gene: WDR45B as ready
Prepair 1000+ v1.135 WDR45B Lilian Downie Gene: wdr45b has been classified as Green List (High Evidence).
Prepair 1000+ v1.135 WDR45B Lilian Downie Publications for gene: WDR45B were set to
Prepair 1000+ v1.134 WNT1 Lilian Downie Marked gene: WNT1 as ready
Prepair 1000+ v1.134 WNT1 Lilian Downie Gene: wnt1 has been classified as Green List (High Evidence).
Prepair 1000+ v1.134 WNT1 Lilian Downie Publications for gene: WNT1 were set to
Prepair 1000+ v1.133 COX20 Lilian Downie Phenotypes for gene: COX20 were changed from Mitochondrial complex IV deficiency, 220110 (3) to Mitochondrial complex IV deficiency, nuclear type 11, MIM#619054
Prepair 1000+ v1.132 COX20 Lilian Downie Marked gene: COX20 as ready
Prepair 1000+ v1.132 COX20 Lilian Downie Gene: cox20 has been classified as Green List (High Evidence).
Prepair 1000+ v1.132 COX20 Lilian Downie Publications for gene: COX20 were set to
Prepair 1000+ v1.131 CPT2 Lilian Downie Marked gene: CPT2 as ready
Prepair 1000+ v1.131 CPT2 Lilian Downie Gene: cpt2 has been classified as Green List (High Evidence).
Prepair 1000+ v1.131 CPT2 Lilian Downie Phenotypes for gene: CPT2 were changed from CPT II deficiency, lethal neonatal, 608836 (3) to CPT II deficiency, infantile MIM#600649; CPT II deficiency, lethal neonatal MIM#608836; CPT II deficiency, myopathic, stress-induced MIM#255110
Prepair 1000+ v1.130 CPT2 Lilian Downie Publications for gene: CPT2 were set to
Prepair 1000+ v1.129 DHODH Lilian Downie Marked gene: DHODH as ready
Prepair 1000+ v1.129 DHODH Lilian Downie Gene: dhodh has been classified as Green List (High Evidence).
Prepair 1000+ v1.129 DHODH Lilian Downie Publications for gene: DHODH were set to
Prepair 1000+ v1.128 ACADM Lilian Downie Marked gene: ACADM as ready
Prepair 1000+ v1.128 ACADM Lilian Downie Gene: acadm has been classified as Green List (High Evidence).
Prepair 1000+ v1.128 ACADM Lilian Downie Publications for gene: ACADM were set to
Prepair 1000+ v1.127 ERCC6L2 Lilian Downie Marked gene: ERCC6L2 as ready
Prepair 1000+ v1.127 ERCC6L2 Lilian Downie Gene: ercc6l2 has been classified as Green List (High Evidence).
Prepair 1000+ v1.127 ERCC6L2 Lilian Downie Publications for gene: ERCC6L2 were set to
Genetic Epilepsy v1.42 Zornitza Stark List of related panels changed from Seizure; HP:0001250 to Seizure; HP:0001250; Epileptic encephalopathy; HP:0200134
Prepair 1000+ v1.126 ADAT3 Lilian Downie Marked gene: ADAT3 as ready
Prepair 1000+ v1.126 ADAT3 Lilian Downie Gene: adat3 has been classified as Green List (High Evidence).
Prepair 1000+ v1.126 ADAT3 Lilian Downie Phenotypes for gene: ADAT3 were changed from Mental retardation, autosomal recessive 36, 615286 (3) to Neurodevelopmental disorder with brain abnormalities, poor growth, and dysmorphic facies, MIM#615286
Prepair 1000+ v1.125 ADAT3 Lilian Downie Publications for gene: ADAT3 were set to
Prepair 1000+ v1.124 CYP11A1 Lilian Downie Marked gene: CYP11A1 as ready
Prepair 1000+ v1.124 CYP11A1 Lilian Downie Gene: cyp11a1 has been classified as Green List (High Evidence).
Prepair 1000+ v1.124 CYP11A1 Lilian Downie Publications for gene: CYP11A1 were set to
Prepair 1000+ v1.123 ARMC4 Lilian Downie Marked gene: ARMC4 as ready
Prepair 1000+ v1.123 ARMC4 Lilian Downie Added comment: Comment when marking as ready: Primary ciliary dyskinesia-23 is an autosomal recessive disorder resulting from defective ciliary motility. Affected individuals have respiratory distress and recurrent upper and lower airway infections, and they often develop bronchiectasis. About 50% of patients have situs inversus or laterality defects. Ultrastructural analysis of respiratory cilia shows defects in the outer dynein arm
Prepair 1000+ v1.123 ARMC4 Lilian Downie Gene: armc4 has been classified as Green List (High Evidence).
Prepair 1000+ v1.123 ARMC4 Lilian Downie Publications for gene: ARMC4 were set to
Prepair 1000+ v1.122 ARV1 Lilian Downie Marked gene: ARV1 as ready
Prepair 1000+ v1.122 ARV1 Lilian Downie Added comment: Comment when marking as ready: Developmental and epileptic encephalopathy-38 (DEE38) is an autosomal recessive neurologic and neurodegenerative disorder characterized by the onset of various type of seizures usually between about 4 and 7 months of age. Prior to the onset of seizures, most infants show severely impaired global development, hypotonia with poor head control, and visual inattention with roving eye movements and nystagmus. Seizures are usually refractory to treatment and associated with status epilepticus. Patients have little or no development with inability to walk or speak, spasticity or abnormal movements, and often cortical blindness. There is failure to thrive, and many require tube-feeding. Death in early childhood due to aspiration or intractable epilepsy may occur.
Prepair 1000+ v1.122 ARV1 Lilian Downie Gene: arv1 has been classified as Green List (High Evidence).
Prepair 1000+ v1.122 BUB1B Zornitza Stark Marked gene: BUB1B as ready
Prepair 1000+ v1.122 BUB1B Zornitza Stark Gene: bub1b has been classified as Green List (High Evidence).
Prepair 1000+ v1.122 BUB1B Zornitza Stark Phenotypes for gene: BUB1B were changed from Mosaic variegated aneuploidy syndrome 1, 257300 (3) to Mosaic variegated aneuploidy syndrome 1, MIM# 257300
Prepair 1000+ v1.121 BUB1B Zornitza Stark Publications for gene: BUB1B were set to
Prepair 1000+ v1.120 C12orf57 Zornitza Stark Marked gene: C12orf57 as ready
Prepair 1000+ v1.120 C12orf57 Zornitza Stark Gene: c12orf57 has been classified as Green List (High Evidence).
Prepair 1000+ v1.120 C12orf57 Zornitza Stark Phenotypes for gene: C12orf57 were changed from Temtamy syndrome, 218340 (3) to Temtamy syndrome, MIM # 218340
Prepair 1000+ v1.119 C12orf57 Zornitza Stark Publications for gene: C12orf57 were set to
Prepair 1000+ v1.118 C12orf57 Zornitza Stark Tag founder tag was added to gene: C12orf57.
Prepair 1000+ v1.118 CHST3 Zornitza Stark Marked gene: CHST3 as ready
Prepair 1000+ v1.118 CHST3 Zornitza Stark Gene: chst3 has been classified as Green List (High Evidence).
Prepair 1000+ v1.118 CHST3 Zornitza Stark Publications for gene: CHST3 were set to
Prepair 1000+ v1.117 CNTNAP1 Zornitza Stark Marked gene: CNTNAP1 as ready
Prepair 1000+ v1.117 CNTNAP1 Zornitza Stark Gene: cntnap1 has been classified as Green List (High Evidence).
Prepair 1000+ v1.117 CNTNAP1 Zornitza Stark Phenotypes for gene: CNTNAP1 were changed from Lethal congenital contracture syndrome 7, 616286 (3) to Lethal congenital contracture syndrome 7, MIM # 616286; Hypomyelinating neuropathy, congenital, 3, MIM # 618186
Prepair 1000+ v1.116 CNTNAP1 Zornitza Stark Publications for gene: CNTNAP1 were set to
Prepair 1000+ v1.115 COG7 Zornitza Stark Marked gene: COG7 as ready
Prepair 1000+ v1.115 COG7 Zornitza Stark Gene: cog7 has been classified as Green List (High Evidence).
Prepair 1000+ v1.115 COG7 Zornitza Stark Phenotypes for gene: COG7 were changed from Congenital disorder of glycosylation, type IIe, 608779 (3) to Congenital disorder of glycosylation, type IIe, MIM # 608779
Prepair 1000+ v1.114 COG7 Zornitza Stark Publications for gene: COG7 were set to
Prepair 1000+ v1.113 CYP17A1 Zornitza Stark Marked gene: CYP17A1 as ready
Prepair 1000+ v1.113 CYP17A1 Zornitza Stark Gene: cyp17a1 has been classified as Green List (High Evidence).
Prepair 1000+ v1.113 CYP17A1 Zornitza Stark Phenotypes for gene: CYP17A1 were changed from 17,20-lyase deficiency, isolated, 202110 (3) to 17-alpha-hydroxylase/17,20-lyase deficiency MIM#202110
Prepair 1000+ v1.112 CYP17A1 Zornitza Stark Publications for gene: CYP17A1 were set to
Prepair 1000+ v1.111 CYP2U1 Zornitza Stark Marked gene: CYP2U1 as ready
Prepair 1000+ v1.111 CYP2U1 Zornitza Stark Gene: cyp2u1 has been classified as Green List (High Evidence).
Prepair 1000+ v1.111 CYP2U1 Zornitza Stark Phenotypes for gene: CYP2U1 were changed from Spastic paraplegia 56, autosomal recessive, 615030 (3) to Spastic paraplegia 56, autosomal recessive MIM#615030
Prepair 1000+ v1.110 CYP2U1 Zornitza Stark Publications for gene: CYP2U1 were set to
Prepair 1000+ v1.109 DCX Zornitza Stark Marked gene: DCX as ready
Prepair 1000+ v1.109 DCX Zornitza Stark Gene: dcx has been classified as Green List (High Evidence).
Prepair 1000+ v1.109 DCX Zornitza Stark Phenotypes for gene: DCX were changed from Lissencephaly, X-linked, 300067 (3) to Lissencephaly, X-linked MIM#300067; Subcortical laminal heterotopia, X-linked MIM#300067
Prepair 1000+ v1.108 DCX Zornitza Stark Publications for gene: DCX were set to
Prepair 1000+ v1.107 DDX59 Zornitza Stark Marked gene: DDX59 as ready
Prepair 1000+ v1.107 DDX59 Zornitza Stark Gene: ddx59 has been classified as Green List (High Evidence).
Prepair 1000+ v1.107 DDX59 Zornitza Stark Publications for gene: DDX59 were set to
Prepair 1000+ v1.106 EIF2AK3 Zornitza Stark Marked gene: EIF2AK3 as ready
Prepair 1000+ v1.106 EIF2AK3 Zornitza Stark Gene: eif2ak3 has been classified as Green List (High Evidence).
Prepair 1000+ v1.106 EIF2AK3 Zornitza Stark Phenotypes for gene: EIF2AK3 were changed from Wolcott-Rallison syndrome, 226980 (3) to Wolcott-Rallison syndrome MIM#226980
Prepair 1000+ v1.105 EIF2AK3 Zornitza Stark Publications for gene: EIF2AK3 were set to
Prepair 1000+ v1.104 ASPM Zornitza Stark Marked gene: ASPM as ready
Prepair 1000+ v1.104 ASPM Zornitza Stark Gene: aspm has been classified as Green List (High Evidence).
Prepair 1000+ v1.104 ASPM Zornitza Stark Phenotypes for gene: ASPM were changed from Microcephaly 5, primary, autosomal recessive, 608716 (3) to Microcephaly 5, primary, autosomal recessive (MIM#608716)
Prepair 1000+ v1.103 ASPM Zornitza Stark Publications for gene: ASPM were set to
Prepair 1000+ v1.102 ATP7A Zornitza Stark Marked gene: ATP7A as ready
Prepair 1000+ v1.102 ATP7A Zornitza Stark Gene: atp7a has been classified as Green List (High Evidence).
Prepair 1000+ v1.102 ATP7A Zornitza Stark Phenotypes for gene: ATP7A were changed from Menkes disease, 309400 (3) to Menkes disease(MIM#309400); Occipital horn syndrome(MIM#304150)
Prepair 1000+ v1.101 ATP7A Zornitza Stark Publications for gene: ATP7A were set to
Prepair 1000+ v1.100 ADAMTS2 Zornitza Stark Marked gene: ADAMTS2 as ready
Prepair 1000+ v1.100 ADAMTS2 Zornitza Stark Gene: adamts2 has been classified as Green List (High Evidence).
Prepair 1000+ v1.100 ADAMTS2 Zornitza Stark Phenotypes for gene: ADAMTS2 were changed from Ehlers-Danlos syndrome, type VIIC, 225410 (3) to Ehlers-Danlos syndrome, dermatosparaxis type (MIM# 225410)
Prepair 1000+ v1.99 ADAMTS2 Zornitza Stark Publications for gene: ADAMTS2 were set to
Prepair 1000+ v1.98 ADAMTS2 Zornitza Stark changed review comment from: Congenital onset, severe CTD.; to: Congenital onset, marked joint hyper mobility, skin abnormalities, risk of organ rupture.
Prepair 1000+ v1.98 ADAMTS2 Zornitza Stark reviewed gene: ADAMTS2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Ehlers-Danlos syndrome, dermatosparaxis type (MIM# 225410); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.98 AGRN Zornitza Stark Marked gene: AGRN as ready
Prepair 1000+ v1.98 AGRN Zornitza Stark Gene: agrn has been classified as Green List (High Evidence).
Prepair 1000+ v1.98 AGRN Zornitza Stark Publications for gene: AGRN were set to
Prepair 1000+ v1.97 ARSA Zornitza Stark Marked gene: ARSA as ready
Prepair 1000+ v1.97 ARSA Zornitza Stark Gene: arsa has been classified as Green List (High Evidence).
Prepair 1000+ v1.97 ARSA Zornitza Stark Publications for gene: ARSA were set to
Prepair 1000+ v1.96 ATAD1 Zornitza Stark Marked gene: ATAD1 as ready
Prepair 1000+ v1.96 ATAD1 Zornitza Stark Gene: atad1 has been classified as Green List (High Evidence).
Prepair 1000+ v1.96 ATAD1 Zornitza Stark Phenotypes for gene: ATAD1 were changed from Hyperekplexia 4, 618011 (3), Autosomal recessive to Hyperekplexia 4, MIM#618011
Prepair 1000+ v1.95 ATAD1 Zornitza Stark Publications for gene: ATAD1 were set to
Prepair 1000+ v1.94 ATR Zornitza Stark Marked gene: ATR as ready
Prepair 1000+ v1.94 ATR Zornitza Stark Gene: atr has been classified as Green List (High Evidence).
Prepair 1000+ v1.94 ATR Zornitza Stark Phenotypes for gene: ATR were changed from Seckel syndrome 1, 210600 (3) to Seckel syndrome 1(MIM#210600)
Prepair 1000+ v1.93 ATR Zornitza Stark Publications for gene: ATR were set to
Prepair 1000+ v1.92 ATP8A2 Zornitza Stark Marked gene: ATP8A2 as ready
Prepair 1000+ v1.92 ATP8A2 Zornitza Stark Gene: atp8a2 has been classified as Green List (High Evidence).
Prepair 1000+ v1.92 ATP8A2 Zornitza Stark Phenotypes for gene: ATP8A2 were changed from ?Cerebellar ataxia, mental retardation, and dysequilibrium syndrome 4 to Cerebellar ataxia, impaired intellectual development, and dysequilibrium syndrome 4 (MIM#615268)
Prepair 1000+ v1.91 ATP8A2 Zornitza Stark Publications for gene: ATP8A2 were set to
Prepair 1000+ v1.90 ABCA3 Zornitza Stark Marked gene: ABCA3 as ready
Prepair 1000+ v1.90 ABCA3 Zornitza Stark Gene: abca3 has been classified as Green List (High Evidence).
Prepair 1000+ v1.90 ABCA3 Zornitza Stark Publications for gene: ABCA3 were set to
Prepair 1000+ v1.89 ADAR Zornitza Stark Marked gene: ADAR as ready
Prepair 1000+ v1.89 ADAR Zornitza Stark Gene: adar has been classified as Green List (High Evidence).
Prepair 1000+ v1.89 DYNC1I2 Zornitza Stark Marked gene: DYNC1I2 as ready
Prepair 1000+ v1.89 DYNC1I2 Zornitza Stark Added comment: Comment when marking as ready: Ready to be promoted to Green at next version.
Prepair 1000+ v1.89 DYNC1I2 Zornitza Stark Gene: dync1i2 has been classified as Amber List (Moderate Evidence).
Prepair 1000+ v1.89 CTSC Zornitza Stark Marked gene: CTSC as ready
Prepair 1000+ v1.89 CTSC Zornitza Stark Gene: ctsc has been classified as Green List (High Evidence).
Prepair 1000+ v1.89 CTSC Zornitza Stark Phenotypes for gene: CTSC were changed from Papillon-Lefevre syndrome, 245000 (3) to Haim-Munk syndrome MIM#245010; Papillon-Lefevre syndrome MIM#245000
Prepair 1000+ v1.88 CTSC Zornitza Stark reviewed gene: CTSC: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Haim-Munk syndrome MIM#245010, Papillon-Lefevre syndrome MIM#245000; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.88 CERKL Zornitza Stark Marked gene: CERKL as ready
Prepair 1000+ v1.88 CERKL Zornitza Stark Gene: cerkl has been classified as Amber List (Moderate Evidence).
Prepair 1000+ v1.88 CERKL Zornitza Stark Tag for review tag was added to gene: CERKL.
Prepair 1000+ v1.88 RMRP Lilian Downie Marked gene: RMRP as ready
Prepair 1000+ v1.88 RMRP Lilian Downie Added comment: Comment when marking as ready: A range of phenotypes from mild skeletal dysplasia to a severe (anauxetic dysplasia), there is not a clear genotype phenotype correlation, however loss of function variants are more often reported in the severe phenotypes
Prepair 1000+ v1.88 RMRP Lilian Downie Gene: rmrp has been classified as Green List (High Evidence).
Prepair 1000+ v1.88 RMRP Lilian Downie Publications for gene: RMRP were set to
Prepair 1000+ v1.87 CCDC103 Lilian Downie Marked gene: CCDC103 as ready
Prepair 1000+ v1.87 CCDC103 Lilian Downie Gene: ccdc103 has been classified as Green List (High Evidence).
Prepair 1000+ v1.87 CCDC103 Lilian Downie Publications for gene: CCDC103 were set to
Prepair 1000+ v1.86 AKR1D1 Lilian Downie Marked gene: AKR1D1 as ready
Prepair 1000+ v1.86 AKR1D1 Lilian Downie Gene: akr1d1 has been classified as Green List (High Evidence).
Prepair 1000+ v1.86 AKR1D1 Lilian Downie Publications for gene: AKR1D1 were set to
Prepair 1000+ v1.85 AMT Lilian Downie Marked gene: AMT as ready
Prepair 1000+ v1.85 AMT Lilian Downie Gene: amt has been classified as Green List (High Evidence).
Prepair 1000+ v1.85 AMT Lilian Downie Publications for gene: AMT were set to
Prepair 1000+ v1.84 AMT Lilian Downie reviewed gene: AMT: Rating: ; Mode of pathogenicity: None; Publications: PMID: 16450403,; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.6120 ZSCAN10 Zornitza Stark reviewed gene: ZSCAN10: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Otofacial neurodevelopmental syndrome, MIM# 620910; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Deafness_IsolatedAndComplex v1.195 ZSCAN10 Zornitza Stark Phenotypes for gene: ZSCAN10 were changed from Syndromic disease MONDO:0002254 to Otofacial neurodevelopmental syndrome, MIM# 620910
Deafness_IsolatedAndComplex v1.194 ZSCAN10 Zornitza Stark reviewed gene: ZSCAN10: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Otofacial neurodevelopmental syndrome, MIM# 620910; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1947 ZSCAN10 Zornitza Stark Phenotypes for gene: ZSCAN10 were changed from syndromic disease MONDO:0002254 to Otofacial neurodevelopmental syndrome, MIM# 620910
Mendeliome v1.1946 ZSCAN10 Zornitza Stark reviewed gene: ZSCAN10: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Otofacial neurodevelopmental syndrome, MIM# 620910; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.84 ALG9 Lilian Downie Marked gene: ALG9 as ready
Prepair 1000+ v1.84 ALG9 Lilian Downie Gene: alg9 has been classified as Green List (High Evidence).
Prepair 1000+ v1.84 ALG9 Lilian Downie Publications for gene: ALG9 were set to
Prepair 1000+ v1.83 ATOH7 Lilian Downie Marked gene: ATOH7 as ready
Prepair 1000+ v1.83 ATOH7 Lilian Downie Gene: atoh7 has been classified as Green List (High Evidence).
Prepair 1000+ v1.83 ATOH7 Lilian Downie Publications for gene: ATOH7 were set to
Spontaneous coronary artery dissection v0.44 TGFBR2 Ain Roesley Publications for gene: TGFBR2 were set to 30071989; 27879313
Spontaneous coronary artery dissection v0.43 TGFBR2 Ain Roesley edited their review of gene: TGFBR2: Changed publications: 32897753, 35092149, 36103205; Changed phenotypes: Loeys-Dietz syndrome 2 MIM#610168
Spontaneous coronary artery dissection v0.43 TGFBR2 Ain Roesley changed review comment from: "Definitive" by ClinGen Aortopathy working group.

Reviewed in PMID 27879313 (265 cases with variants in TGFBR2).
Sources: Literature; to: PMID: 32897753
3x individuals with 2x missense and 1x +5G splice
both missense variants are absent in gnomad v4
reported SCADs: circumflex coronary artery, right descending posterior coronary artery and cervico-cephalic aneurysm and arterial dissection

PMID: 35092149
2x individuals from a SCAD cohort, however both without variant information

PMID: 36103205
3x SCAD individuals with 2x missense variants
p.Val387Leu has 569 hets + 1 hom in gnomad v4
p.Ala531Thr has 3 hets


Sources: Literature
Spontaneous coronary artery dissection v0.43 TGFBR1 Ain Roesley Publications for gene: TGFBR1 were set to 36584339; 30071989; 27879313
Spontaneous coronary artery dissection v0.42 TGFBR1 Ain Roesley Classified gene: TGFBR1 as Amber List (moderate evidence)
Spontaneous coronary artery dissection v0.42 TGFBR1 Ain Roesley Gene: tgfbr1 has been classified as Amber List (Moderate Evidence).
Spontaneous coronary artery dissection v0.41 TGFBR1 Ain Roesley edited their review of gene: TGFBR1: Changed rating: AMBER; Changed publications: 35092149, 36103205; Changed phenotypes: Loeys-Dietz syndrome 1 MIM#609192
Spontaneous coronary artery dissection v0.41 TGFBR1 Ain Roesley changed review comment from: "Definitive" by ClinGen Aortopathy working group.

Reviewed in PMID 27879313 (176 cases with variants in TGFBR1).

AMBER for AR disease: PMID 36584339
Biallelic variants reported in a single family with two sibs. Presented with severe dilatation of aorta, diaphragmatic hernia, skin translucency, and profound joint laxity at birth
Sources: Radboud University Medical Center, Nijmegen; to: PMID: 35092149
1x individual with SCAD, the missense has 3 hets in gnomad v4

PMID: 36103205
1x individual with R-SCAD and fhx, however the missense has 60 hets in gnomad v4

Amber so as to not miss a diagnosis
Spontaneous coronary artery dissection v0.41 TGFB3 Ain Roesley Publications for gene: TGFB3 were set to 30071989; 25835445
Spontaneous coronary artery dissection v0.40 TGFB3 Ain Roesley edited their review of gene: TGFB3: Changed publications: 32897753
Spontaneous coronary artery dissection v0.40 TGFB3 Ain Roesley changed review comment from: Uncertain for isolated aneurysm, but causes broader connective tissue disorder phenotype. 43 patients from 11 reported with significant cardiovascular involvement, including thoracic/abdominal aortic aneurysm and dissection, and mitral valve disease. Other systemic features overlapped clinically with Loeys-Dietz, Shprintzen-Goldberg, and Marfan syndromes, including cleft palate, bifid uvula, skeletal overgrowth, cervical spine instability and clubfoot deformity
Sources: Literature; to: PMID: 32897753
4x individuals with missense, however only 3x with personal history of SCAD


Sources: Literature
Spontaneous coronary artery dissection v0.40 TGFB2 Ain Roesley Publications for gene: TGFB2 were set to 30071989; 22772371
Spontaneous coronary artery dissection v0.39 TGFB2 Ain Roesley edited their review of gene: TGFB2: Changed publications: 33125268, 36103205; Changed phenotypes: Loeys-Dietz syndrome 4 MIM#614816
Spontaneous coronary artery dissection v0.39 TGFB2 Ain Roesley changed review comment from:
PMID: 33125268:
2x missense in SCAD individuals

PMID: 36103205
3x individuals with missense, however no personal history of SCAD, only fam history

borderline amber/green

Sources: Literature; to:
PMID: 33125268:
2x missense in SCAD individuals

PMID: 36103205
1x individual with missense and peripartum SCAD


Sources: Literature
Spontaneous coronary artery dissection v0.39 TGFB2 Ain Roesley changed review comment from: "Definitive" by ClinGen Aortopathy Working Group.

PMID: 22772371: 4 families
Sources: Literature; to:
PMID: 33125268:
2x missense in SCAD individuals

PMID: 36103205
3x individuals with missense, however no personal history of SCAD, only fam history

borderline amber/green

Sources: Literature
Intellectual disability syndromic and non-syndromic v0.6120 COQ8A Zornitza Stark Marked gene: COQ8A as ready
Intellectual disability syndromic and non-syndromic v0.6120 COQ8A Zornitza Stark Gene: coq8a has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.6120 COQ8A Zornitza Stark Phenotypes for gene: COQ8A were changed from to coenzyme Q10 deficiency MONDO:0018151
Intellectual disability syndromic and non-syndromic v0.6119 COQ8A Zornitza Stark Publications for gene: COQ8A were set to
Intellectual disability syndromic and non-syndromic v0.6118 COQ8A Zornitza Stark Mode of inheritance for gene: COQ8A was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.6117 CTDP1 Zornitza Stark Marked gene: CTDP1 as ready
Intellectual disability syndromic and non-syndromic v0.6117 CTDP1 Zornitza Stark Gene: ctdp1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.6117 CTDP1 Zornitza Stark Phenotypes for gene: CTDP1 were changed from to congenital cataracts-facial dysmorphism-neuropathy syndrome MONDO:0011402
Intellectual disability syndromic and non-syndromic v0.6116 CTDP1 Zornitza Stark Publications for gene: CTDP1 were set to
Intellectual disability syndromic and non-syndromic v0.6115 CTDP1 Zornitza Stark Mode of inheritance for gene: CTDP1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.6114 CTSA Zornitza Stark Marked gene: CTSA as ready
Intellectual disability syndromic and non-syndromic v0.6114 CTSA Zornitza Stark Gene: ctsa has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.6114 CTSA Zornitza Stark Phenotypes for gene: CTSA were changed from to Galactosialidosis MONDO:0009737
Intellectual disability syndromic and non-syndromic v0.6113 CTSA Zornitza Stark Publications for gene: CTSA were set to
Intellectual disability syndromic and non-syndromic v0.6112 CTSA Zornitza Stark Mode of inheritance for gene: CTSA was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.6111 CTSD Zornitza Stark Marked gene: CTSD as ready
Intellectual disability syndromic and non-syndromic v0.6111 CTSD Zornitza Stark Gene: ctsd has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.6111 CTSD Zornitza Stark Phenotypes for gene: CTSD were changed from to neuronal ceroid lipofuscinosis MONDO:0016295
Intellectual disability syndromic and non-syndromic v0.6110 CTSD Zornitza Stark Mode of inheritance for gene: CTSD was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.6109 CYB5R3 Zornitza Stark Marked gene: CYB5R3 as ready
Intellectual disability syndromic and non-syndromic v0.6109 CYB5R3 Zornitza Stark Gene: cyb5r3 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.6109 CYB5R3 Zornitza Stark Phenotypes for gene: CYB5R3 were changed from to Methemoglobinemia MONDO:0001117
Intellectual disability syndromic and non-syndromic v0.6108 CYB5R3 Zornitza Stark Publications for gene: CYB5R3 were set to
Intellectual disability syndromic and non-syndromic v0.6107 CYB5R3 Zornitza Stark Mode of inheritance for gene: CYB5R3 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.6106 SOX9 Zornitza Stark Marked gene: SOX9 as ready
Intellectual disability syndromic and non-syndromic v0.6106 SOX9 Zornitza Stark Gene: sox9 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.6106 SOX9 Zornitza Stark Phenotypes for gene: SOX9 were changed from to campomelic dysplasia MONDO:0007251
Intellectual disability syndromic and non-syndromic v0.6105 SOX9 Zornitza Stark Publications for gene: SOX9 were set to
Intellectual disability syndromic and non-syndromic v0.6104 SOX9 Zornitza Stark Mode of inheritance for gene: SOX9 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.6103 SOX9 Zornitza Stark Classified gene: SOX9 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.6103 SOX9 Zornitza Stark Gene: sox9 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.6102 SOX9 Zornitza Stark changed review comment from: Agree ID typically not part of the phenotype. Note reports of milder cases and DD/ID reported in some survivors, therefore downgraded to Amber.; to: Agree ID typically not part of the phenotype. Note reports of milder cases and DD/ID reported in some survivors (this publication suggests >80%), therefore downgraded to Amber.
Intellectual disability syndromic and non-syndromic v0.6102 SOX9 Zornitza Stark reviewed gene: SOX9: Rating: AMBER; Mode of pathogenicity: None; Publications: 21373255; Phenotypes: campomelic dysplasia MONDO:0007251; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.6102 SOX9 Zornitza Stark Classified gene: SOX9 as Red List (low evidence)
Intellectual disability syndromic and non-syndromic v0.6102 SOX9 Zornitza Stark Gene: sox9 has been classified as Red List (Low Evidence).
Miscellaneous Metabolic Disorders v1.47 GLS Zornitza Stark Mode of inheritance for gene: GLS was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.6101 GLS Zornitza Stark Phenotypes for gene: GLS were changed from Global developmental delay, progressive ataxia, and elevated glutamine, MIM# 618412 to Epileptic encephalopathy, early infantile, 71, MIM# 618328; Global developmental delay, progressive ataxia, and elevated glutamine, MIM# 618412
Intellectual disability syndromic and non-syndromic v0.6100 GLS Zornitza Stark Mode of inheritance for gene: GLS was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Genetic Epilepsy v1.41 GLS Zornitza Stark Phenotypes for gene: GLS were changed from Epileptic encephalopathy, early infantile, 71, MIM# 618328; Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development MONDO:0032685 to Epileptic encephalopathy, early infantile, 71, MIM# 618328; Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development MONDO:0032685
Genetic Epilepsy v1.40 GLS Zornitza Stark Phenotypes for gene: GLS were changed from Epileptic encephalopathy, early infantile, 71, MIM# 618328 to Epileptic encephalopathy, early infantile, 71, MIM# 618328; Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development MONDO:0032685
Genetic Epilepsy v1.39 GLS Zornitza Stark Publications for gene: GLS were set to 30575854
Genetic Epilepsy v1.38 GLS Zornitza Stark Mode of inheritance for gene: GLS was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Genetic Epilepsy v1.37 GLS Zornitza Stark Classified gene: GLS as Green List (high evidence)
Genetic Epilepsy v1.37 GLS Zornitza Stark Gene: gls has been classified as Green List (High Evidence).
Genetic Epilepsy v1.36 GLS Zornitza Stark edited their review of gene: GLS: Added comment: PMID 38622440: additional individual reported with bi-allelic variants.

Note GoF variants also postulated to cause a neurodevelopmental phenotype, including seizures, though evidence is more limited, PMID 37151363. Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development MONDO:0032685; Changed rating: GREEN; Changed publications: 30575854, 38622440, 37151363; Changed phenotypes: Epileptic encephalopathy, early infantile, 71, MIM# 618328, Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development MONDO:0032685; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Cataract v0.368 GLS Zornitza Stark Phenotypes for gene: GLS were changed from Infantile cataracts to Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development MONDO:0032685
Cataract v0.367 GLS Zornitza Stark Mode of pathogenicity for gene: GLS was changed from None to Other
Cataract v0.367 GLS Zornitza Stark Mode of inheritance for gene: GLS was changed from BIALLELIC, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Cataract v0.366 GLS Zornitza Stark edited their review of gene: GLS: Changed phenotypes: Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development MONDO:0032685; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Aminoacidopathy v1.132 GLS Zornitza Stark Publications for gene: GLS were set to 29468182; 30575854; 30970188; 16641247; 30239721, 37151363
Aminoacidopathy v1.131 GLS Zornitza Stark Phenotypes for gene: GLS were changed from glutaminase deficiency MONDO:0600001 to Glutaminase deficiency MONDO:0600001; Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development MONDO:0032685
Aminoacidopathy v1.130 GLS Zornitza Stark Publications for gene: GLS were set to 29468182, 30575854, 30970188; 16641247
Aminoacidopathy v1.129 GLS Zornitza Stark Mode of inheritance for gene: GLS was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Aminoacidopathy v1.128 GLS Zornitza Stark reviewed gene: GLS: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Glutaminase deficiency MONDO:0600001, Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development MONDO:0032685; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1946 ACOX2 Zornitza Stark Publications for gene: ACOX2 were set to 27647924; 27884763
Peroxisomal Disorders v0.54 ACOX2 Zornitza Stark Publications for gene: ACOX2 were set to 27647924; 27884763; 29287774
Pancreatitis v1.6 CLDN2 Zornitza Stark Classified gene: CLDN2 as Red List (low evidence)
Pancreatitis v1.6 CLDN2 Zornitza Stark Gene: cldn2 has been classified as Red List (Low Evidence).
Pancreatitis v1.5 CLDN2 Zornitza Stark edited their review of gene: CLDN2: Changed rating: RED
Mendeliome v1.1945 CLDN2 Zornitza Stark Classified gene: CLDN2 as Red List (low evidence)
Mendeliome v1.1945 CLDN2 Zornitza Stark Gene: cldn2 has been classified as Red List (Low Evidence).
Mendeliome v1.1944 CLDN2 Zornitza Stark changed review comment from: Azoospermia and nephrolithiasis: single multigenerational family reported.; to: Azoospermia and nephrolithiasis: single multigenerational family reported.

LIMITED by ClinGen.
Mendeliome v1.1944 CLDN2 Zornitza Stark changed review comment from: Pancreatitis: Numerous publications linking common variants at this locus with susceptibility to pancreatitis. KO mice do not have a pancreatic phenotype. Likely polygenic susceptibility rather than Mendelian disorder.; to: Pancreatitis: Numerous publications linking common variants at this locus with susceptibility to pancreatitis. KO mice do not have a pancreatic phenotype; have calciuria. Likely polygenic susceptibility rather than Mendelian disorder.
Mendeliome v1.1944 CLDN2 Zornitza Stark changed review comment from: Azoospermia: single multigenerational family reported.; to: Azoospermia and nephrolithiasis: single multigenerational family reported.
Mendeliome v1.1944 CLDN2 Zornitza Stark edited their review of gene: CLDN2: Changed rating: RED
Prepair 1000+ v1.82 ADAR Lisa Norbart reviewed gene: ADAR: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Aicardi-Goutieres syndrome 6, MIM#615010; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.82 ABCA3 Lisa Norbart reviewed gene: ABCA3: Rating: GREEN; Mode of pathogenicity: None; Publications: 15044640; Phenotypes: Surfactant metabolism dysfunction, pulmonary, 3, MIM#610921; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.82 ATP8A2 Ee Ming Wong reviewed gene: ATP8A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 22892528, 31612321; Phenotypes: Cerebellar ataxia, impaired intellectual development, and dysequilibrium syndrome 4 (MIM#615268); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Prepair 1000+ v1.82 ATR Karina Sandoval reviewed gene: ATR: Rating: GREEN; Mode of pathogenicity: None; Publications: 12640452, 19620979, 30199583, 23111928, 23111928; Phenotypes: Seckel syndrome 1(MIM#210600); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.82 ATOH7 Ee Ming Wong reviewed gene: ATOH7: Rating: GREEN; Mode of pathogenicity: None; Publications: 22068589, 22645276, 31696227, 11493566, 11493566; Phenotypes: Persistent hyperplastic primary vitreous, autosomal recessive, MIM# 221900, microphthalmia, cataract, glaucoma, congenital retinal nonattachment; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Prepair 1000+ v1.82 ALG9 Cassandra Muller reviewed gene: ALG9: Rating: GREEN; Mode of pathogenicity: None; Publications: 28932688, 25966638, 26453364, 30676690, 36326140; Phenotypes: Congenital disorder of glycosylation, type Il, MIM#608776, Gillessen-Kaesbach-Nishimura syndrome, MIM# 263210; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.82 ATAD1 Ee Ming Wong reviewed gene: ATAD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28180185, 29390050, 29659736; Phenotypes: Hyperekplexia 4, MIM#618011; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Prepair 1000+ v1.82 ARSA Ee Ming Wong reviewed gene: ARSA: Rating: GREEN; Mode of pathogenicity: None; Publications: 25987178, 23348427, 33195324; Phenotypes: Metachromatic leukodystrophy, MIM# 250100; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Prepair 1000+ v1.82 AKR1D1 Ee Ming Wong changed review comment from: Well established gene-disease association.
Inborn error of bile acid metabolism. At least 6 cases (with 5 variants) in 5 families reported.
Severe condition with congenital onset, leads to liver failure.; to: Well established gene-disease association.
Inborn error of bile acid metabolism. At least 6 cases (with 5 variants) in 5 families reported.
Severe condition with congenital onset, leads to liver failure.
Prepair 1000+ v1.82 AKR1D1 Ee Ming Wong reviewed gene: AKR1D1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 12970144, 20522910, 30373615; Phenotypes: Bile acid synthesis defect, congenital, 2, MIM# 235555; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Prepair 1000+ v1.82 AGRN Cassandra Muller reviewed gene: AGRN: Rating: GREEN; Mode of pathogenicity: None; Publications: 19631309, 22205389, 32221959; Phenotypes: Myasthenic syndrome, congenital, 8, with pre- and postsynaptic defects, MIM# 615120; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.82 ADAMTS2 Ee Ming Wong reviewed gene: ADAMTS2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 30071989, 26765342, 28306229; Phenotypes: Ehlers-Danlos syndrome, dermatosparaxis type (MIM# 225410); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Spontaneous coronary artery dissection v0.39 SMAD3 Ain Roesley changed review comment from: Missense variants within the MH2 domain have been suggested to exert dominant negative mechanism by disprupting the formation of homo-oligomers (PMID: 30661052) Loss-of-function proven for PTCs (PMID: 30661052)

"Definitive" by ClinGen Aortopathy working group.
Sources: Literature; to: PMID: 32897753
1x individual with SCAD, canonical splice variant

PMID: 29650765
1x individual with SCAD, missense D258H absent in gnomad v4

PMID: 33125268
2x individuals with SCAD, 1x start loss and 1x fs

PMID: 33190788
1x individual with another variant in MYH11

Sources: Literature
Spontaneous coronary artery dissection v0.39 SMAD2 Ain Roesley Publications for gene: SMAD2 were set to 29967133
Spontaneous coronary artery dissection v0.38 SMAD2 Ain Roesley edited their review of gene: SMAD2: Changed publications: 32897753, 30448172
Spontaneous coronary artery dissection v0.38 SMAD2 Ain Roesley edited their review of gene: SMAD2: Changed publications: PMID: 32897753, 30448172
Spontaneous coronary artery dissection v0.38 SMAD2 Ain Roesley changed review comment from: 9 individuals from 5 families with wide spectrum of autosomal dominant aortic and arterial aneurysmal disease combined with connective tissue disease similar to Marfan syndrome and Loeys-Dietz syndrome.
Sources: Literature; to: PMID: 32897753
3x individuals with SCAD, all missense and absent/1 het in gnomad v4

PMID: 30448172
1x individual with a missense, absent in gnomad v4

Sources: Literature
Spontaneous coronary artery dissection v0.38 MYLK Ain Roesley Publications for gene: MYLK were set to 30071989; 27586135; 21055718; 25907466
Spontaneous coronary artery dissection v0.37 MYLK Ain Roesley Classified gene: MYLK as Amber List (moderate evidence)
Spontaneous coronary artery dissection v0.37 MYLK Ain Roesley Gene: mylk has been classified as Amber List (Moderate Evidence).
Spontaneous coronary artery dissection v0.36 MYLK Ain Roesley edited their review of gene: MYLK: Changed rating: AMBER; Changed publications: 33125268; Changed phenotypes: Aortic aneurysm, familial thoracic 7 MIM#613780
Spontaneous coronary artery dissection v0.36 MYLK Ain Roesley changed review comment from: Association between variants in this gene and aortic dissection established in multiple individuals and a 5-generation family (PMID 27586135;21055718;25907466).

"Definitive" by Clingen Aortopathy Working Group.
Sources: Literature; to: PMID: 33125268
1x SCAD individual with a stop gain

1x indiv from google search (https://medwinpublishers.com/CRIJ/unraveling-the-genetic-complexity-a-case-report-of-mylk-gene-mutation-in-a-patient-with-scad.pdf)
however, the specific variant was not provided - Authors said 'a VUS was identified'

Other papers from Google cite PMID: 33125268

Red/Amber rating, amber so as to not miss a diagnosis

Sources: Literature
Spontaneous coronary artery dissection v0.36 LOX Ain Roesley Publications for gene: LOX were set to 30071989; 26838787; 30675029.
Spontaneous coronary artery dissection v0.35 LOX Ain Roesley Classified gene: LOX as Amber List (moderate evidence)
Spontaneous coronary artery dissection v0.35 LOX Ain Roesley Gene: lox has been classified as Amber List (Moderate Evidence).
Spontaneous coronary artery dissection v0.34 LOX Ain Roesley edited their review of gene: LOX: Changed rating: AMBER; Changed publications: 32897753, 36103205; Changed phenotypes: Aortic aneurysm, familial thoracic 10 MIM#617168
Spontaneous coronary artery dissection v0.34 LOX Ain Roesley changed review comment from: Reviewed as having 'strong' gene-disease association by the HTAAD working group, based on ClinGen framework (PMID: 30071989).

Missense and nonsense variants described in six unrelated families with HTAAD and functional studies of three missense variants demonstrated a reduction in LOX activity (Guo et.al. (2016); PMID: 26838787).

Two further individuals with negative family history: one individual has pathogenic nonsense variant and second individual has VUS missense variant (Renner et al. (2019); PMID: 30675029).
Sources: Literature; to: PMID: 32897753
1x with circumflex coronary artery, possibly the same individual reported in PMID: 33125268
Met298Arg is absent in gnomad

PMID: 36103205
1x however, the missense was curated as benign (97 hets in gnomad v4)

Red/Amber rating - amber so as to not miss a diagnosis

Sources: Literature
Prepair 1000+ v1.82 ATP7A Karina Sandoval reviewed gene: ATP7A: Rating: GREEN; Mode of pathogenicity: None; Publications: 20170900, 33137485, 31969342, 31558336, 7842019, 8981948; Phenotypes: Menkes disease(MIM#309400), Occipital horn syndrome(MIM#304150); Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Prepair 1000+ v1.82 ATP13A2 Karina Sandoval reviewed gene: ATP13A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 30868101, 21362476, 31588715, 22388936; Phenotypes: Kufor-Rakeb syndrome (MIM#606693); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.82 ASPM Karina Sandoval reviewed gene: ASPM: Rating: GREEN; Mode of pathogenicity: None; Publications: 18452193, 19332161, 19770472, 27250695, 29243349; Phenotypes: Microcephaly 5, primary, autosomal recessive (MIM#608716); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Spontaneous coronary artery dissection v0.34 FLNA Ain Roesley changed review comment from:

PMID: 32897753
1x individual with left anterior descending coronary artery

Sources: Literature

; to: borderline red/amber but amber so as to not miss a diagnosis

PMID: 32897753
1x individual with left anterior descending coronary artery

Sources: Literature
Spontaneous coronary artery dissection v0.34 FLNA Ain Roesley Phenotypes for gene: FLNA were changed from periventricular heterotopia 1 MIM#300049 to Spontaneous coronary artery dissection
Spontaneous coronary artery dissection v0.33 FLNA Ain Roesley Classified gene: FLNA as Amber List (moderate evidence)
Spontaneous coronary artery dissection v0.33 FLNA Ain Roesley Gene: flna has been classified as Amber List (Moderate Evidence).
Spontaneous coronary artery dissection v0.32 FLNA Ain Roesley edited their review of gene: FLNA: Changed publications: 32897753
Spontaneous coronary artery dissection v0.32 FLNA Ain Roesley changed review comment from: Large review of 114 patients with loss-of-function FLNA mutations with periventricular nodular heterotopia (PVNH), found that most subjects had a cardiac anomaly or vascular abnormality (64.9%). Thoracic aortic aneurysms or dilatation (TAA) were found in 18.4%, and were associated with other structural cardiac malformations in 57.1% of patients (Chen et al. 2018; PMID: 29334594).

PMID: 32897753
1x individual with left anterior descending coronary artery

Sources: Literature

; to:

PMID: 32897753
1x individual with left anterior descending coronary artery

Sources: Literature
Spontaneous coronary artery dissection v0.32 FLNA Ain Roesley edited their review of gene: FLNA: Changed rating: AMBER; Changed publications: 29334594, 32897753; Changed phenotypes: periventricular heterotopia 1 MIM#300049
Spontaneous coronary artery dissection v0.32 FLNA Ain Roesley changed review comment from: Large review of 114 patients with loss-of-function FLNA mutations with periventricular nodular heterotopia (PVNH), found that most subjects had a cardiac anomaly or vascular abnormality (64.9%). Thoracic aortic aneurysms or dilatation (TAA) were found in 18.4%, and were associated with other structural cardiac malformations in 57.1% of patients (Chen et al. 2018; PMID: 29334594).
Sources: Literature; to: Large review of 114 patients with loss-of-function FLNA mutations with periventricular nodular heterotopia (PVNH), found that most subjects had a cardiac anomaly or vascular abnormality (64.9%). Thoracic aortic aneurysms or dilatation (TAA) were found in 18.4%, and were associated with other structural cardiac malformations in 57.1% of patients (Chen et al. 2018; PMID: 29334594).

PMID: 32897753
1x individual with left anterior descending coronary artery

Sources: Literature
Spontaneous coronary artery dissection v0.32 FBN1 Ain Roesley edited their review of gene: FBN1: Changed publications: 29357934, 34842564, 35092149; Changed phenotypes: Marfan syndrome MIM#154700, familial thoracic aortic aneurysm and aortic dissection MONDO:0019625, FBN1-related
Spontaneous coronary artery dissection v0.32 FBN1 Ain Roesley changed review comment from: Dominant-negative and LoF (haploinsufficiency) have been reported as disease mechanisms (OMIM). PTV are associated with more severe MFS and with aortic events. Missense are associated with a milder MFS and less often result in aortic events (PMID: 29357934 ).

definitive by clingen curation
Sources: Literature; to: Dominant-negative and LoF (haploinsufficiency) have been reported as disease mechanisms (OMIM). PTV are associated with more severe MFS and with aortic events. Missense are associated with a milder MFS and less often result in aortic events (PMID: 29357934 ).

definitive by clingen curation

at least 3x individuals with Marfan + FBN1 variant have been reported with SCAD
PMID: 34842564, 35092149

Sources: Literature
Spontaneous coronary artery dissection v0.32 COL5A1 Ain Roesley edited their review of gene: COL5A1: Changed publications: 32938213, 35234813; Changed phenotypes: Ehlers-Danlos syndrome, classic type, 1 MIM#130000, Fibromuscular dysplasia, multifocal MIM#619329
Spontaneous coronary artery dissection v0.32 COL5A1 Ain Roesley changed review comment from: GeneReviews: 75-78% of classical EDS is caused by pathogenic variants in COL5A1. Haploinsufficiency is the more common disease mechanism whoeever, missense variants in the triple helical domain of the α1(V) or α2(V) chains are likely to have dominant-negative activity.
(https://www.ncbi.nlm.nih.gov/books/NBK1244/)

Multifocal fibromuscular dysplasia (FMDMF) is characterized histologically by medial fibroplasia and angiographically by multiple arterial stenoses with intervening mural dilations. Arterial tortuosity, macroaneurysms, dissections, and rupture may occur.

4 unrelated individuals reported, but all had the same variant, p.Gly514Ser, and haplotype analysis was consistent with founder effect. Further rare missense variants were identified in a cohort, although limited information available.
Sources: Literature; to: GeneReviews: 75-78% of classical EDS is caused by pathogenic variants in COL5A1. Haploinsufficiency is the more common disease mechanism whoeever, missense variants in the triple helical domain of the α1(V) or α2(V) chains are likely to have dominant-negative activity.
(https://www.ncbi.nlm.nih.gov/books/NBK1244/)

SCAD individuals with variants in COL5A1 have been reported
PMID: 35234813

Sources: Literature
Prepair 1000+ v1.82 EIF2AK3 Andrew Coventry reviewed gene: EIF2AK3: Rating: GREEN; Mode of pathogenicity: None; Publications: 10932183 12960215 16813601 11997520 20202148 11430819; Phenotypes: Wolcott-Rallison syndrome MIM#226980; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.82 DDX59 Andrew Coventry reviewed gene: DDX59: Rating: GREEN; Mode of pathogenicity: None; Publications: 28711741 29127725 23972372 28289185; Phenotypes: Orofaciodigital syndrome V MIM#174300; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Spontaneous coronary artery dissection v0.32 COL3A1 Ain Roesley edited their review of gene: COL3A1: Changed publications: 30071989, 32897753, 35234813
Spontaneous coronary artery dissection v0.32 COL3A1 Ain Roesley changed review comment from: Classified as Definitive by Clingen for heritable thoracic aortic aneurysm and dissection; Ehlers-Danlos syndrome, vascular type.
Sources: Literature; to: Classified as Definitive by Clingen for heritable thoracic aortic aneurysm and dissection; Ehlers-Danlos syndrome, vascular type.

Several individuals with SCAD have also been reported with variants in COL3A1
PMID: 32897753
PMID: 36103205
PMID: 35234813


Sources: Literature
Prepair 1000+ v1.82 DCX Andrew Coventry reviewed gene: DCX: Rating: GREEN; Mode of pathogenicity: None; Publications: 10915612 9489699 12552055 20301364 14625554; Phenotypes: Lissencephaly, X-linked MIM#300067, Subcortical laminal heterotopia, X-linked MIM#300067; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Spontaneous coronary artery dissection v0.32 COL3A1 Ain Roesley edited their review of gene: COL3A1: Changed publications: 30071989, 32897753; Changed phenotypes: Ehlers-Danlos syndrome, vascular type MIM#130050
Prepair 1000+ v1.82 CYP2U1 Andrew Coventry reviewed gene: CYP2U1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23176821 32006740 29034544 26914923 24337409 28725025; Phenotypes: Spastic paraplegia 56, autosomal recessive MIM#615030; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.82 CYP17A1 Andrew Coventry changed review comment from: Established gene-disease association. Congenital onset. More than 100 families reported. Mechanism impacts hormone production in gonads and adrenal glands. Phenotype typically includes hypertension, low blood potassium, and abnormal development of sexual characteristics including genitalia (disorder of sexual development) in both males and females. Phenotypic spectrum for those affected is variable.; to: Established gene-disease association. Congenital onset. More than 100 families reported. Mechanism impacts hormone production in gonads and adrenal glands. Phenotype typically includes hypertension, low blood potassium, and abnormal development of sexual characteristics including genitalia (disorder of sexual development) in both males and females. Phenotypic spectrum of severity for those affected is variable.
Prepair 1000+ v1.82 CYP17A1 Andrew Coventry reviewed gene: CYP17A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 2843762 14671162 2026124 35178494 35043964; Phenotypes: 17-alpha-hydroxylase/17,20-lyase deficiency MIM#202110; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.82 COG7 Kate Scarff reviewed gene: COG7: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 15107842, 17356545, 28883096, 17395513, 16151902; Phenotypes: Congenital disorder of glycosylation, type IIe, MIM # 608779; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.82 CNTNAP1 Kate Scarff reviewed gene: CNTNAP1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 28374019, 29511323, 29882456, 27668699; Phenotypes: Lethal congenital contracture syndrome 7, MIM # 616286, Hypomyelinating neuropathy, congenital, 3, MIM # 618186; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.82 CHST3 Kate Scarff reviewed gene: CHST3: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 18513679; Phenotypes: Spondyloepiphyseal dysplasia with congenital joint dislocations, MIM # 143095; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.82 CCDC103 Kate Scarff reviewed gene: CCDC103: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 22581229, 32447765, 31858719, 28790179; Phenotypes: Primary ciliary dyskinesia-17, MIM # 614679; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.82 C12orf57 Kate Scarff reviewed gene: C12orf57: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 23453666, 29383837, 31853307; Phenotypes: Temtamy syndrome, MIM # 218340; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.82 CNNM4 Lilian Downie Marked gene: CNNM4 as ready
Prepair 1000+ v1.82 CNNM4 Lilian Downie Gene: cnnm4 has been classified as Green List (High Evidence).
Prepair 1000+ v1.82 CNNM4 Lilian Downie Publications for gene: CNNM4 were set to
Prepair 1000+ v1.81 CNGB3 Lilian Downie Marked gene: CNGB3 as ready
Prepair 1000+ v1.81 CNGB3 Lilian Downie Gene: cngb3 has been classified as Green List (High Evidence).
Prepair 1000+ v1.81 CNGB3 Lilian Downie Publications for gene: CNGB3 were set to
Prepair 1000+ v1.80 CNGB3 Lilian Downie Tag SV/CNV tag was added to gene: CNGB3.
Prepair 1000+ v1.80 CLP1 Lilian Downie Marked gene: CLP1 as ready
Prepair 1000+ v1.80 CLP1 Lilian Downie Gene: clp1 has been classified as Green List (High Evidence).
Prepair 1000+ v1.80 CLP1 Lilian Downie Publications for gene: CLP1 were set to
Prepair 1000+ v1.79 B3GAT3 Lilian Downie Marked gene: B3GAT3 as ready
Prepair 1000+ v1.79 B3GAT3 Lilian Downie Gene: b3gat3 has been classified as Green List (High Evidence).
Prepair 1000+ v1.79 B3GAT3 Lilian Downie Publications for gene: B3GAT3 were set to
Prepair 1000+ v1.78 CLN6 Lilian Downie Marked gene: CLN6 as ready
Prepair 1000+ v1.78 CLN6 Lilian Downie Gene: cln6 has been classified as Green List (High Evidence).
Prepair 1000+ v1.78 CLN6 Lilian Downie Publications for gene: CLN6 were set to
Prepair 1000+ v1.77 CLDN1 Lilian Downie Marked gene: CLDN1 as ready
Prepair 1000+ v1.77 CLDN1 Lilian Downie Gene: cldn1 has been classified as Green List (High Evidence).
Prepair 1000+ v1.77 CLDN1 Lilian Downie Publications for gene: CLDN1 were set to
Prepair 1000+ v1.76 CLCNKB Lilian Downie Tag for review tag was added to gene: CLCNKB.
Prepair 1000+ v1.76 BUB1B Kate Scarff reviewed gene: BUB1B: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 18548531; Phenotypes: Mosaic variegated aneuploidy syndrome 1, MIM# 257300; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.76 CLCNKB Lilian Downie Marked gene: CLCNKB as ready
Prepair 1000+ v1.76 CLCNKB Lilian Downie Added comment: Comment when marking as ready: The digenic inheritance is not clearly proven, patients with variants in both genes also had biallelic variants in this gene which is just as likely to have been the cause. Not enough evidence to report in carrier screening as a digenic condition. PMID: 18310267
Prepair 1000+ v1.76 CLCNKB Lilian Downie Gene: clcnkb has been classified as Green List (High Evidence).
Spontaneous coronary artery dissection v0.32 TLN1 Ain Roesley changed review comment from: PMID: 37979122; listed as "likely monogenic disease effect"

but AMBER rating
10 unique rare heterozygous missense variants in 11 individuals were identified in a 2 generation SCAD family and 56 unrelated individuals with sporadic SCAD. All variants had a MAF of less than 0.06% and occurred within highly conserved β-integrin, F-actin, or vinculin binding domains. Incomplete penetrance was evident in the familial case and five individuals with sporadic SCAD from whom parental DNA was available. No functional assays were conducted.
Sources: Literature; to: PMID: 37979122; listed as "likely monogenic disease effect"

but AMBER rating
10 unique rare heterozygous missense variants in 11 individuals were identified in a 2 generation SCAD family and 56 unrelated individuals with sporadic SCAD. All variants had a MAF of less than 0.06% and occurred within highly conserved β-integrin, F-actin, or vinculin binding domains. Incomplete penetrance was evident in the familial case and five individuals with unaffected heterozygous parents. No functional assays were conducted.
Sources: Literature
Prepair 1000+ v1.76 ARV1 Marta Cifuentes Ochoa reviewed gene: ARV1: Rating: GREEN; Mode of pathogenicity: None; Publications: 35227294, 27270415, 25558065, 34017911, 34296759; Phenotypes: Developmental and epileptic encephalopathy 38 MIM#617020 MONDO:0014868; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.76 ARMC4 Marta Cifuentes Ochoa reviewed gene: ARMC4: Rating: GREEN; Mode of pathogenicity: None; Publications: 31765523, 23849778; Phenotypes: Ciliary dyskinesia, primary, 23, MIM# 615451 primary ciliary dyskinesia 23 MONDO:0014193; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.76 AMT Marta Cifuentes Ochoa reviewed gene: AMT: Rating: GREEN; Mode of pathogenicity: None; Publications: 27362913, 16450403, 30350008, 26179960, 20301531, 25231368, 35646099; Phenotypes: Nonketotic Hyperglycinemia, Glycine encephalopathy MIM#620398; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1944 EMILIN1 Zornitza Stark Phenotypes for gene: EMILIN1 were changed from Neuronopathy, distal hereditary motor, type X, MIM# 620080; Aortic aneurysm, MONDO:0005160, EMILIN2-related to Neuronopathy, distal hereditary motor, type X, MIM# 620080; Arterial tortuosity-bone fragility syndrome, MIM# 620908
Aortopathy_Connective Tissue Disorders v1.86 EMILIN1 Zornitza Stark Phenotypes for gene: EMILIN1 were changed from Neuronopathy, distal hereditary motor, type X, MIM# 620080 Aortic aneurysm, MONDO:0005160, EMILIN2-related to Neuronopathy, distal hereditary motor, type X, MIM# 620080; Arterial tortuosity-bone fragility syndrome, MIM# 620908
Aortopathy_Connective Tissue Disorders v1.85 EMILIN1 Zornitza Stark edited their review of gene: EMILIN1: Changed phenotypes: Neuronopathy, distal hereditary motor, type X, MIM# 620080, Peripheral neuropathy
Aortopathy_Connective Tissue Disorders v1.85 EMILIN1 Zornitza Stark edited their review of gene: EMILIN1: Changed phenotypes: Neuronopathy, distal hereditary motor, type X, MIM# 620080, Peripheral neuropathy, Arterial tortuosity-bone fragility syndrome, MIM# 620908
Peroxisomal Disorders v0.53 ACOX2 Sangavi Sivagnanasundram reviewed gene: ACOX2: Rating: GREEN; Mode of pathogenicity: None; Publications: 27647924, 27884763, 35395098; Phenotypes: congenital bile acid synthesis defect 6 MONDO:0015015; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1943 ACOX2 Sangavi Sivagnanasundram reviewed gene: ACOX2: Rating: GREEN; Mode of pathogenicity: None; Publications: 27647924, 27884763, 35395098; Phenotypes: congenital bile acid synthesis defect 6 MONDO:0015015; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Aminoacidopathy v1.128 GLS Sangavi Sivagnanasundram edited their review of gene: GLS: Added comment: Classified as Moderate by ClinGen Aminoacidopathy GCEP on 26/07/2024 - https://search.clinicalgenome.org/CCID:004966

Two unrelated probands have been reported with an increased glutamate production level. Two missense variants have been reported (Ser482Cys and His461Leu - both absent from gnomAD v4.1). A zebrafish model partially recapitulated the disease.; Changed rating: AMBER; Changed mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Changed publications: 30239721, 37151363; Changed phenotypes: infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development MONDO:0032685; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1943 PRPF4 Sangavi Sivagnanasundram reviewed gene: PRPF4: Rating: GREEN; Mode of pathogenicity: None; Publications: 24419317; Phenotypes: inherited retinal dystrophy MONDO:0019118; Mode of inheritance: None
Retinitis pigmentosa_Autosomal Dominant v0.57 PRPF4 Sangavi Sivagnanasundram reviewed gene: PRPF4: Rating: GREEN; Mode of pathogenicity: None; Publications: 24419317; Phenotypes: inherited retinal dystrophy MONDO:0019118; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Prepair 1000+ v1.76 CYP11A1 Andrew Coventry reviewed gene: CYP11A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 12161514 16705068 18182448 28425981; Phenotypes: Adrenal insufficiency, congenital, with 46XY sex reversal, partial or complete MIM#613743; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.76 CNNM4 Andrew Coventry reviewed gene: CNNM4: Rating: ; Mode of pathogenicity: None; Publications: 30705057 29421294 19200527 19200525; Phenotypes: Jalili syndrome MIM#217080; Mode of inheritance: None
Prepair 1000+ v1.76 CNGB3 Andrew Coventry reviewed gene: CNGB3: Rating: GREEN; Mode of pathogenicity: None; Publications: 17265047 28795510 12140185 28795510; Phenotypes: Achromatopsia 3 MIM#262300; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.76 CLP1 Andrew Coventry reviewed gene: CLP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24766809 24766810 23474986 29307788; Phenotypes: Pontocerebellar hypoplasia, type 10 MIM#615803; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.6099 HDAC3 Zornitza Stark Marked gene: HDAC3 as ready
Intellectual disability syndromic and non-syndromic v0.6099 HDAC3 Zornitza Stark Gene: hdac3 has been classified as Green List (High Evidence).
Hydrops fetalis v0.317 ANGPT2 Zornitza Stark Marked gene: ANGPT2 as ready
Hydrops fetalis v0.317 ANGPT2 Zornitza Stark Gene: angpt2 has been classified as Green List (High Evidence).
Hydrops fetalis v0.317 ANGPT2 Zornitza Stark Classified gene: ANGPT2 as Green List (high evidence)
Hydrops fetalis v0.317 ANGPT2 Zornitza Stark Gene: angpt2 has been classified as Green List (High Evidence).
Hydrops fetalis v0.316 ANGPT2 Zornitza Stark gene: ANGPT2 was added
gene: ANGPT2 was added to Hydrops fetalis. Sources: Expert list
Mode of inheritance for gene: ANGPT2 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Publications for gene: ANGPT2 were set to 32908006; 34876502
Phenotypes for gene: ANGPT2 were set to Lymphatic malformation-10, MIM#619369; Primary lymphoedema Hydrops
Review for gene: ANGPT2 was set to GREEN
Added comment: Mono-allelic disease: association with lymphoedema in 5 unrelated individuals PMID 32908006

Bi-allelic disease PMID 34876502: single family reported with four fetuses with hydrops fetalis homozygous for ANGPT2 NM_001147.2:c.557A>G. The consanguineous parents and surviving sibblings (a girl and a boy), were heterozygous for this variant. This variant is predicted to create a cryptic exonic splice site, resulting in a r.557_566del and nonsense-mediated mRNA decay. This prediction was supported by the lack of a transcript from this allele in the parents.
Sources: Expert list
Mendeliome v1.1943 FZD6 Zornitza Stark Phenotypes for gene: FZD6 were changed from Nail disorder, nonsyndromic congenital, 1, MIM# 161050 to Nail disorder, nonsyndromic congenital, 1, MIM# 161050; Hydrops fetalis, MONDO:0015193, FZD6-related
Mendeliome v1.1942 FZD6 Zornitza Stark Publications for gene: FZD6 were set to 21665003; 23374899
Mendeliome v1.1941 FZD6 Zornitza Stark changed review comment from: PMIDs 33082562; 26036949; 28425981. Three FZD6 variants have been associated with two unrelated cases of fetal hyrdrops.; to: PMIDs 33082562; 26036949; 28425981. Three FZD6 variants have been associated with two unrelated cases of fetal hyrdrops. AMBER for this indication.
Mendeliome v1.1941 FZD6 Zornitza Stark edited their review of gene: FZD6: Changed phenotypes: Nail disorder, nonsyndromic congenital, 1, MIM# 161050, Hydrops fetalis, MONDO:0015193, FZD6-related
Mendeliome v1.1941 FZD6 Zornitza Stark edited their review of gene: FZD6: Added comment: PMIDs 33082562; 26036949; 28425981. Three FZD6 variants have been associated with two unrelated cases of fetal hyrdrops.; Changed publications: 21665003, 23374899, 33082562, 26036949, 28425981
Hydrops fetalis v0.315 FZD6 Zornitza Stark Marked gene: FZD6 as ready
Hydrops fetalis v0.315 FZD6 Zornitza Stark Gene: fzd6 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.263 FZD6 Zornitza Stark Marked gene: FZD6 as ready
Fetal anomalies v1.263 FZD6 Zornitza Stark Gene: fzd6 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.263 FZD6 Zornitza Stark Classified gene: FZD6 as Amber List (moderate evidence)
Fetal anomalies v1.263 FZD6 Zornitza Stark Gene: fzd6 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.262 FZD6 Zornitza Stark gene: FZD6 was added
gene: FZD6 was added to Fetal anomalies. Sources: Expert list
Mode of inheritance for gene: FZD6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FZD6 were set to 33082562; 26036949; 28425981
Phenotypes for gene: FZD6 were set to Hydrops fetalis, MONDO:0015193, FZD6-related
Review for gene: FZD6 was set to AMBER
Added comment: Three FZD6 variants have been associated with two unrelated cases of fetal hyrdrops.
Sources: Expert list
Hydrops fetalis v0.315 FZD6 Zornitza Stark Classified gene: FZD6 as Amber List (moderate evidence)
Hydrops fetalis v0.315 FZD6 Zornitza Stark Gene: fzd6 has been classified as Amber List (Moderate Evidence).
Hydrops fetalis v0.314 FZD6 Zornitza Stark gene: FZD6 was added
gene: FZD6 was added to Hydrops fetalis. Sources: Literature
Mode of inheritance for gene: FZD6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FZD6 were set to 33082562; 26036949; 28425981
Phenotypes for gene: FZD6 were set to Hydrops fetalis, MONDO:0015193, FZD6-related
Review for gene: FZD6 was set to AMBER
Added comment: Three FZD6 variants have been associated with two unrelated cases of fetal hyrdrops
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.6099 SOX9 Ken Lee Wan reviewed gene: SOX9: Rating: RED; Mode of pathogenicity: None; Publications: 20301724, 26663529; Phenotypes: campomelic dysplasia MONDO:0007251; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Fetal anomalies v1.261 TBC1D7 Zornitza Stark Classified gene: TBC1D7 as Amber List (moderate evidence)
Fetal anomalies v1.261 TBC1D7 Zornitza Stark Gene: tbc1d7 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.260 TBC1D7 Zornitza Stark Publications for gene: TBC1D7 were set to 23687350; 24515783
Fetal anomalies v1.259 TBC1D7 Zornitza Stark Classified gene: TBC1D7 as Green List (high evidence)
Fetal anomalies v1.259 TBC1D7 Zornitza Stark Gene: tbc1d7 has been classified as Green List (High Evidence).
Fetal anomalies v1.258 TBC1D7 Zornitza Stark reviewed gene: TBC1D7: Rating: GREEN; Mode of pathogenicity: None; Publications: 36669495; Phenotypes: Macrocephaly/megalencephaly syndrome, autosomal recessive - MIM#248000; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Macrocephaly_Megalencephaly v0.142 TBC1D7 Zornitza Stark Publications for gene: TBC1D7 were set to 24515783; 23687350; 36669495
Macrocephaly_Megalencephaly v0.142 TBC1D7 Zornitza Stark Publications for gene: TBC1D7 were set to 24515783; 23687350
Intellectual disability syndromic and non-syndromic v0.6099 TBC1D7 Zornitza Stark Publications for gene: TBC1D7 were set to 24515783; 23687350
Intellectual disability syndromic and non-syndromic v0.6098 TBC1D7 Zornitza Stark Classified gene: TBC1D7 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.6098 TBC1D7 Zornitza Stark Gene: tbc1d7 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.6097 TBC1D7 Zornitza Stark edited their review of gene: TBC1D7: Added comment: PMID: 36669495 reports additional individuals with compound het variants identified via trio RNASeq.; Changed rating: GREEN; Changed publications: 24515783, 23687350, 36669495
Macrocephaly_Megalencephaly v0.141 TBC1D7 Zornitza Stark Classified gene: TBC1D7 as Green List (high evidence)
Macrocephaly_Megalencephaly v0.141 TBC1D7 Zornitza Stark Gene: tbc1d7 has been classified as Green List (High Evidence).
Macrocephaly_Megalencephaly v0.140 TBC1D7 Zornitza Stark edited their review of gene: TBC1D7: Added comment: PMID: 36669495 reports additional individuals with compound het variants identified via trio RNASeq.; Changed rating: GREEN; Changed publications: 24515783, 23687350, 36669495
Mendeliome v1.1941 TBC1D7 Zornitza Stark Publications for gene: TBC1D7 were set to 24515783; 23687350
Mendeliome v1.1940 TBC1D7 Zornitza Stark Classified gene: TBC1D7 as Green List (high evidence)
Mendeliome v1.1940 TBC1D7 Zornitza Stark Gene: tbc1d7 has been classified as Green List (High Evidence).
Mendeliome v1.1939 TBC1D7 Zornitza Stark edited their review of gene: TBC1D7: Changed rating: GREEN
Mendeliome v1.1939 TBC1D7 Zornitza Stark edited their review of gene: TBC1D7: Added comment: PMID: 36669495 reports additional individuals with compound het variants identified via trio RNASeq.; Changed publications: 24515783, 23687350, 36669495
Fetal anomalies v1.258 GLIS2 Zornitza Stark Classified gene: GLIS2 as Green List (high evidence)
Fetal anomalies v1.258 GLIS2 Zornitza Stark Gene: glis2 has been classified as Green List (High Evidence).
Fetal anomalies v1.257 GLIS2 Zornitza Stark edited their review of gene: GLIS2: Added comment: Five individuals from three unrelated families reported, albeit with homozygous variants. Functional data.; Changed rating: GREEN; Changed publications: 31676329, 17618285, 23559409
Ciliopathies v1.56 GLIS2 Zornitza Stark Classified gene: GLIS2 as Green List (high evidence)
Ciliopathies v1.56 GLIS2 Zornitza Stark Gene: glis2 has been classified as Green List (High Evidence).
Ciliopathies v1.55 GLIS2 Zornitza Stark changed review comment from: Two families reported.; to: Three families (5 individuals) reported, albeit with homozygous variants. Functional data.
Ciliopathies v1.55 GLIS2 Zornitza Stark edited their review of gene: GLIS2: Changed rating: GREEN
Mendeliome v1.1939 GLIS2 Zornitza Stark Classified gene: GLIS2 as Green List (high evidence)
Mendeliome v1.1939 GLIS2 Zornitza Stark Gene: glis2 has been classified as Green List (High Evidence).
Mendeliome v1.1938 GLIS2 Zornitza Stark changed review comment from: Two families reported.; to: Three families (5 individuals) reported. Functional data.
Mendeliome v1.1938 GLIS2 Zornitza Stark edited their review of gene: GLIS2: Changed rating: GREEN
Renal Ciliopathies and Nephronophthisis v1.23 GLIS2 Zornitza Stark Classified gene: GLIS2 as Green List (high evidence)
Renal Ciliopathies and Nephronophthisis v1.23 GLIS2 Zornitza Stark Gene: glis2 has been classified as Green List (High Evidence).
Renal Ciliopathies and Nephronophthisis v1.22 GLIS2 Zornitza Stark changed review comment from: Good functional data, but limited reports in humans.; to: Good functional data. Three unrelated families reported (5 individuals) but note all had homozygous variants.
Renal Ciliopathies and Nephronophthisis v1.22 GLIS2 Zornitza Stark edited their review of gene: GLIS2: Changed rating: GREEN
Regression v0.557 LNPK Zornitza Stark Marked gene: LNPK as ready
Regression v0.557 LNPK Zornitza Stark Gene: lnpk has been classified as Green List (High Evidence).
Regression v0.557 LNPK Zornitza Stark Classified gene: LNPK as Green List (high evidence)
Regression v0.557 LNPK Zornitza Stark Gene: lnpk has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.6097 MSL2 Zornitza Stark Classified gene: MSL2 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.6097 MSL2 Zornitza Stark Gene: msl2 has been classified as Green List (High Evidence).
Mendeliome v1.1938 C17orf53 Zornitza Stark Phenotypes for gene: C17orf53 were changed from Primary ovarian insufficiency to Ovarian dysgenesis 11, MIM# 620897
Mendeliome v1.1937 C17orf53 Zornitza Stark Classified gene: C17orf53 as Green List (high evidence)
Mendeliome v1.1937 C17orf53 Zornitza Stark Gene: c17orf53 has been classified as Green List (High Evidence).
Mendeliome v1.1936 C17orf53 Zornitza Stark edited their review of gene: C17orf53: Added comment: PMID 38105698: Additional family reported with two sibs and compound het LoF variants.

HGNC approved name is HROB.; Changed rating: GREEN; Changed publications: 34707299, 31467087, 38105698; Changed phenotypes: Ovarian dysgenesis 11, MIM# 620897
Primary Ovarian Insufficiency_Premature Ovarian Failure v0.333 C17orf53 Zornitza Stark Marked gene: C17orf53 as ready
Primary Ovarian Insufficiency_Premature Ovarian Failure v0.333 C17orf53 Zornitza Stark Added comment: Comment when marking as ready: HGNC approved name is HROB.
Primary Ovarian Insufficiency_Premature Ovarian Failure v0.333 C17orf53 Zornitza Stark Gene: c17orf53 has been classified as Green List (High Evidence).
Primary Ovarian Insufficiency_Premature Ovarian Failure v0.333 C17orf53 Zornitza Stark Tag new gene name tag was added to gene: C17orf53.
Primary Ovarian Insufficiency_Premature Ovarian Failure v0.333 C17orf53 Zornitza Stark Phenotypes for gene: C17orf53 were changed from Primary ovarian insufficiency to Ovarian dysgenesis 11, MIM# 620897
Primary Ovarian Insufficiency_Premature Ovarian Failure v0.332 C17orf53 Zornitza Stark Publications for gene: C17orf53 were set to PMID: 34707299; PMID: 31467087
Primary Ovarian Insufficiency_Premature Ovarian Failure v0.331 C17orf53 Zornitza Stark Classified gene: C17orf53 as Green List (high evidence)
Primary Ovarian Insufficiency_Premature Ovarian Failure v0.331 C17orf53 Zornitza Stark Gene: c17orf53 has been classified as Green List (High Evidence).
Primary Ovarian Insufficiency_Premature Ovarian Failure v0.330 C17orf53 Zornitza Stark reviewed gene: C17orf53: Rating: GREEN; Mode of pathogenicity: None; Publications: 38105698; Phenotypes: Ovarian dysgenesis 11, MIM# 620897; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1936 CD274 Zornitza Stark Marked gene: CD274 as ready
Mendeliome v1.1936 CD274 Zornitza Stark Gene: cd274 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1936 CD274 Zornitza Stark Classified gene: CD274 as Amber List (moderate evidence)
Mendeliome v1.1936 CD274 Zornitza Stark Gene: cd274 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1935 RINT1 Zornitza Stark Phenotypes for gene: RINT1 were changed from Infantile liver failure syndrome 3, MIM# 618641 to Infantile liver failure syndrome 3, MIM# 618641; Hereditary spastic paraplegia, MONDO:0019064, RINT1-related
Mendeliome v1.1934 RINT1 Zornitza Stark Publications for gene: RINT1 were set to PMID: 31204009
Mendeliome v1.1933 RINT1 Zornitza Stark reviewed gene: RINT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 37463447, 38990652; Phenotypes: Hereditary spastic paraplegia, MONDO:0019064, RINT1-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.6096 CYB5R3 Ken Lee Wan reviewed gene: CYB5R3: Rating: GREEN; Mode of pathogenicity: None; Publications: 38303731; Phenotypes: Methemoglobinemia MONDO:0001117; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Hereditary Spastic Paraplegia - paediatric v1.79 RINT1 Zornitza Stark Phenotypes for gene: RINT1 were changed from Infantile liver failure syndrome 3, MIM# 618641; Hereditary spastic paraplegia, MONDO:0019064, RINT1-related to Hereditary spastic paraplegia, MONDO:0019064, RINT1-related
Hereditary Spastic Paraplegia - paediatric v1.78 RINT1 Zornitza Stark Publications for gene: RINT1 were set to 37463447
Hereditary Spastic Paraplegia - paediatric v1.77 RINT1 Zornitza Stark Classified gene: RINT1 as Green List (high evidence)
Hereditary Spastic Paraplegia - paediatric v1.77 RINT1 Zornitza Stark Gene: rint1 has been classified as Green List (High Evidence).
Hereditary Spastic Paraplegia - paediatric v1.76 RINT1 Zornitza Stark reviewed gene: RINT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 38990652; Phenotypes: Hereditary spastic paraplegia, MONDO:0019064, RINT1-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Genetic Epilepsy v1.36 HDAC3 Zornitza Stark Marked gene: HDAC3 as ready
Genetic Epilepsy v1.36 HDAC3 Zornitza Stark Gene: hdac3 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.6096 CTSD Ken Lee Wan reviewed gene: CTSD: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: neuronal ceroid lipofuscinosis MONDO:0016295; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability syndromic and non-syndromic v0.6096 CTSA Ken Lee Wan reviewed gene: CTSA: Rating: GREEN; Mode of pathogenicity: None; Publications: 23915561, 36713078; Phenotypes: Galactosialidosis MONDO:0009737; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Genetic Epilepsy v1.36 HDAC3 Zornitza Stark Classified gene: HDAC3 as Green List (high evidence)
Genetic Epilepsy v1.36 HDAC3 Zornitza Stark Gene: hdac3 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.6096 CTDP1 Ken Lee Wan reviewed gene: CTDP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301787; Phenotypes: congenital cataracts-facial dysmorphism-neuropathy syndrome MONDO:0011402; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Genetic Epilepsy v1.35 HDAC3 Zornitza Stark Classified gene: HDAC3 as Green List (high evidence)
Genetic Epilepsy v1.35 HDAC3 Zornitza Stark Gene: hdac3 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.6096 HDAC3 Zornitza Stark edited their review of gene: HDAC3: Changed phenotypes: Neurodevelopmental disorder, MONDO:0700092, HDAC3-related
Mendeliome v1.1933 HDAC3 Zornitza Stark Marked gene: HDAC3 as ready
Mendeliome v1.1933 HDAC3 Zornitza Stark Gene: hdac3 has been classified as Green List (High Evidence).
Mendeliome v1.1933 HDAC3 Zornitza Stark Classified gene: HDAC3 as Green List (high evidence)
Mendeliome v1.1933 HDAC3 Zornitza Stark Gene: hdac3 has been classified as Green List (High Evidence).