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| Hereditary Neuropathy_CMT - isolated v1.50 | ARPC3 |
Bryony Thompson gene: ARPC3 was added gene: ARPC3 was added to Hereditary Neuropathy_CMT - isolated. Sources: Literature Mode of inheritance for gene: ARPC3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: ARPC3 were set to 36928819; 26166300 Phenotypes for gene: ARPC3 were set to Charcot-Marie-Tooth disease MONDO:0015626 Review for gene: ARPC3 was set to AMBER Added comment: Posterior probability association (PPA) 0.995 for Charcot-Marie Tooth disease under a dominant MOI in the 100,000 Genomes project “Rareservoir” using a Bayesian statistical method - BeviMed. 549 CMT cases and 54,856 controls used in BeviMed analysis. 5 rare variants (missense, splice region, a splice acceptor site) enriched in the CMT cohort (n=14). Additionally, ArpC3 conditional knockout mice fail to ensheath axons causing axon dysfunction. Sources: Literature |
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| Hereditary Neuropathy_CMT - isolated v1.46 | PMP2 | Zornitza Stark Mode of pathogenicity for gene: PMP2 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 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary Neuropathy_CMT - isolated v1.43 | WARS |
Zornitza Stark edited their review of gene: WARS: Added comment: ClinGen curation: In 2017, three families, two Taiwanese and one Belgian, were shown to carry the same heterozygous His257Arg missense variant in WARS1 co-segregating with a juvenile onset distal motor neuropathy phenotype (PMID: 28369220). The authors show evidence of a dominant-negative effect of the His257Arg mutation capable of dimerizing with the wild-type protein and impairing the overall aminoacylation function. When transfected into neuronal-like cells, an effect on neurite length was also observed. Two other WARS1 missense variants have been linked with this consistent juvenile onset HMN phenotype since then (PMID: 31321409). In these two families, significant segregation or de novo inheritance was shown, but functional evidence was absent. The phenotype in all five published WARS1 families is very consistent, a juvenile onset motor neuropathy phenotype affecting both upper and lower limbs without any sensory involvement. The panel concludes that the evidence for the pathogenicity of the His257Arg mutation is sufficient to link WARS1 to the motor neuropathy phenotype. More reports will solidify the gene-disease relationship in the future. Based on the curated evidence, we classify the gene-disease relationship of WARS1 and autosomal dominant motor neuropathy as limited, but with the advice to include it on panels.; Changed rating: AMBER |
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| Hereditary Neuropathy_CMT - isolated v1.42 | RTN2 |
Zornitza Stark gene: RTN2 was added gene: RTN2 was added to Hereditary Neuropathy_CMT - isolated. Sources: Literature Mode of inheritance for gene: RTN2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: RTN2 were set to 38527963 Phenotypes for gene: RTN2 were set to distal hereditary motor neuropathy, MONDO:0018894, RTN2-related Review for gene: RTN2 was set to GREEN Added comment: PMID:38527963 reported the identification of seven novel or ultra-rare homozygous loss-of-function RTN2 variants in 14 individuals from seven unrelated families with distal hereditary motor neuropathy. All affected individuals exhibited weakness in the distal upper and lower limbs, lower limb spasticity, hyperreflexia, with an onset in the first decade of life. Nerve conduction studies revealed axonal motor neuropathy with neurogenic changes in the electromyography. Characterisation of C. elegans RTN2 homolog loss-of-function variants demonstrated morphological and behavioural differences compared to the parental strain, and treatment with an endoplasmic/sarcoplasmic reticulum Ca(2+) re-uptake inhibitor (2,5-di-tert-butylhydroquinone) rescued key phenotypic differences. Sources: Literature |
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| Hereditary Neuropathy_CMT - isolated v1.39 | PMP2 | Sangavi Sivagnanasundram reviewed gene: PMP2: Rating: AMBER; 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: PMID: 28747762, https://search.clinicalgenome.org/CCID:005836; Phenotypes: Charcot-Marie-Tooth disease MONDO:0015626; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary Neuropathy_CMT - isolated v1.39 | BSCL2 | Sangavi Sivagnanasundram edited their review of gene: BSCL2: 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 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary Neuropathy_CMT - isolated v1.39 | DYNC1H1 | Sangavi Sivagnanasundram Deleted their comment | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary Neuropathy_CMT - isolated v1.39 | ATP1A1 | Sangavi Sivagnanasundram commented on gene: ATP1A1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary Neuropathy_CMT - isolated v1.39 | BANF1 |
Zornitza Stark gene: BANF1 was added gene: BANF1 was added to Hereditary Neuropathy_CMT - isolated. Sources: Literature Mode of inheritance for gene: BANF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: BANF1 were set to 36980188 Phenotypes for gene: BANF1 were set to Hereditary peripheral neuropathy, MONDO:0020127, BANF1-related Review for gene: BANF1 was set to RED Added comment: Single individual reported with de novo variant, Gly16Arg, and a neuropathy. Sources: Literature |
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| Hereditary Neuropathy_CMT - isolated v1.37 | MYO9B |
Melanie Marty gene: MYO9B was added gene: MYO9B was added to Hereditary Neuropathy_CMT - isolated. Sources: Literature Mode of inheritance for gene: MYO9B was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MYO9B were set to PMID: 36260368 Phenotypes for gene: MYO9B were set to Charcot-Marie-Tooth disease type 2 (MONDO:0018993), MYO9B-related Review for gene: MYO9B was set to AMBER Added comment: PMID: 36260368 2 x families with CMT2 neuropathy (1st family: 2 siblings with hom missense variants + 2nd family: 2 siblings with chet missense and in frame del). 1 patient with isolated optic atrophy with 2 x chet missense variants. Western blot analysis in patient fibroblasts (CMT2 patient with hom missense) showed that MYO9B expression levels were significantly decreased. Myo9b-null mouse model: analysis of sciatic nerve, spinal cord, and optic nerve. A few degenerated myelinated axons and clusters of regenerated axons in sciatic nerves (at 12 months) but the other nerves looked normal. Ultrastructural analysis of optic nerves revealed loss of myelinated fibers, and occasional enlarged axons that contained accumulations of organelles. Sources: Literature |
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| Hereditary Neuropathy_CMT - isolated v1.37 | MME | Bryony Thompson Mode of inheritance for gene: MME was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary Neuropathy_CMT - isolated v1.36 | MME | Bryony Thompson Deleted their review | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary Neuropathy_CMT - isolated v1.36 | MME | Bryony Thompson commented on gene: MME | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary Neuropathy_CMT - isolated v1.36 | MME | Bryony Thompson Deleted their review | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary Neuropathy_CMT - isolated v1.34 | SLC12A6 |
Sangavi Sivagnanasundram gene: SLC12A6 was added gene: SLC12A6 was added to Hereditary Neuropathy_CMT - isolated. Sources: Other Mode of inheritance for gene: SLC12A6 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: SLC12A6 were set to 31439721; 27485015; 33323309 Phenotypes for gene: SLC12A6 were set to Charcot-Marie-Tooth disease, axonal, type 2II (MIM#620068) Review for gene: SLC12A6 was set to GREEN Added comment: Well established gene-disease association. >3 unrelated individuals with variants in SLC12A6 and a clinical diagnosis of hereditary neuropathy. Age of onset of disease is variable (typically within the first 4 decades of life). 31439721; 27485015 In vitro functional studies were conducted that showed a reduced in protein activity in the presence of a mutation in SLC12A6 relevant to neuropathy PMID: 27485015 10yr with progressive axonal peripheral neuropathy and the presence of T991A missense variant. In vitro functional assay using fibroblast and HEK293 cells showed that in the presence of the mutation there was a reduction in protein function. PMID: 33323309 31M with progressive muscle weakness from the age of 27. Nerve conduction studies confirmed sensorimotor neuropathy indicating intermediate CMT and a genetic finding of R207H heterozygous variant in SLC12A6. Sources: Other |
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| Hereditary Neuropathy_CMT - isolated v1.30 | DHX9 |
Zornitza Stark gene: DHX9 was added gene: DHX9 was added to Hereditary Neuropathy_CMT - isolated. Sources: Literature Mode of inheritance for gene: DHX9 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: DHX9 were set to 37467750 Phenotypes for gene: DHX9 were set to Charcot-Marie-Tooth disease, MONDO:0015626, DHX9-related Review for gene: DHX9 was set to GREEN Added comment: PMID:37467750 - 17 unrelated individuals were identified with de novo, ultra-rare, heterozygous missense or loss-of-function DHX9 variants, of which 14 individuals were reported with a neurodevelopmental disorder (NDD) and three were reported with Charcot-Marie-Tooth disease (CMT). All 14 cases with NDD had developmental delay, of which eight were reported with intellectual disability (4 severe, 1 moderate, 3 mild). Two cases did not have ID, one had borderline ID and three cases were too young (0-5 years old). The three cases with CMT presented with adult-onset axonal neuropathy. LoF variants caused mild NDD phenotypes and nuclear localization signal (NLS) missense variants caused severe NDD. CMT2-associated missense variants caused aberrant nucleolar DHX9 accumulation, a phenomenon previously associated with cellular stress. Sources: Literature |
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| Hereditary Neuropathy_CMT - isolated v1.21 | ITPR3 | Zornitza Stark edited their review of gene: ITPR3: Added comment: Additional family with 3 individuals in 2 generations reported in PMID 24627108.; Changed rating: GREEN; Changed publications: 32949214, 24627108; Changed phenotypes: Charcot-Marie-Tooth disease, demyelinating, type 1J, MIM# 620111 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary Neuropathy_CMT - isolated v1.20 | FICD |
Alison Yeung gene: FICD was added gene: FICD was added to Hereditary Neuropathy_CMT - isolated. Sources: Literature Mode of inheritance for gene: FICD was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: FICD were set to 36136088 Phenotypes for gene: FICD were set to Hereditary motor neurone disease, FICD-related, MONDO:0024257 Review for gene: FICD was set to GREEN Added comment: Three unrelated families with recurrent homozygous missense variant: p.Arg374His One further family with Chet variants: p.Arg 374His and p.Gly370GlufsTer53 Fibroblasts from patients with FICD variants have abnormally increased levels of AMPylated and thus inactivated BiP. Onset of symptoms in childhood with progressive course. Presentation with severe lower limb spasticity and mild upper limb spascticity, nerve conduction test shows motor neuropathy. Sources: Literature |
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| Hereditary Neuropathy_CMT - isolated v1.19 | SARS | Seb Lunke Added comment: Comment when marking as ready: potentially specific to the aminoacylation domain | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary Neuropathy_CMT - isolated v1.18 | SARS |
Ee Ming Wong gene: SARS was added gene: SARS was added to Hereditary Neuropathy_CMT - isolated. Sources: Literature Mode of inheritance for gene: SARS was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: SARS were set to 36088542 Phenotypes for gene: SARS were set to Genetic peripheral neuropathy MONDO#0020127, SARS1-related Review for gene: SARS was set to GREEN gene: SARS was marked as current diagnostic Added comment: -Two missense variants within the aminoacylation domain identified in 16 affected individuals from 3 distinct CMT families -Mutant SerRS proteins exhibited reduced aminoacylation activity and abnormal SerRS dimerization, which suggests the impairment of total protein synthesis and induction of eIF2α phosphorylation Sources: Literature |
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| Hereditary Neuropathy_CMT - isolated v1.17 | NRG1 |
Zornitza Stark gene: NRG1 was added gene: NRG1 was added to Hereditary Neuropathy_CMT - isolated. Sources: Expert Review Mode of inheritance for gene: NRG1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NRG1 were set to 35485770 Phenotypes for gene: NRG1 were set to Peripheral neuropathy MONDO:0005244 Review for gene: NRG1 was set to RED Added comment: 1 female with consanguineous parents with distal muscle weakness starting age 20, progressively worsening, described as a peripheral neuropathy. Has a homozygous missense, 23 hets in gnomad. Proband has a sister who is also mildly affected, cramps and numbness in legs and feet. She is also homozygous for the variant. All 8 healthy family members that were tested were either only het or were hom for the WT allele. 13 other hom variants were identified in the proband, 11 were ruled out based on homs in gnomad, genes associated with off phenotype conditions, or non-segregation within the family. 2 variants in ZFHX4 and DMTN did cosegregate with disease. These 2 gene have limited reports/functional studies for off phenotype conditions so the NRG1 variant was thought to be the best match. In a homozygous null NGR1 zebrafish, the variant identified in this individual was not able to rescue the phenotype compared to WT. Sources: Expert Review |
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| Hereditary Neuropathy_CMT - isolated v1.13 | SCO2 | Bryony Thompson edited their review of gene: SCO2: Added comment: Now 6 individuals from 4 families with compound heterozygous or homozygous missense variants (p.Glu140Lys and p.Pro169Thr; p.Arg171Gln and p.Asp135Gly; p.Arg255Trp; p.Gly121Arg) and an axonal CMT phenotype without the fatal infantile cardioencephalomyopathy phenotype also associated with SCO2 deficiency.; Changed rating: GREEN; Changed publications: 29351582, 31844624, 35112411; Changed phenotypes: autosomal recessive axonal charcot-marie-tooth disease due to copper metabolism defect MONDO:0033850 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary Neuropathy_CMT - isolated v1.10 | JAG1 |
Zornitza Stark changed review comment from: Two unrelated families reported with CMT type 2. Affected individuals in both families exhibited severe vocal fold paresis, a rare feature of peripheral nerve disease that can be life-threatening. Studies of mutant protein posttranslational modification and localization indicated that the mutations (p.Ser577Arg, p.Ser650Pro) impair protein glycosylation and reduce JAG1 cell surface expression. Mice harboring heterozygous CMT2-associated mutations exhibited mild peripheral neuropathy, and homozygous expression resulted in embryonic lethality by midgestation. Pre-existing rat model. Sources: Literature; to: Two unrelated families reported with CMT type 2, 9 affected individuals. Affected individuals in both families exhibited severe vocal fold paresis, a rare feature of peripheral nerve disease that can be life-threatening. Studies of mutant protein posttranslational modification and localization indicated that the mutations (p.Ser577Arg, p.Ser650Pro) impair protein glycosylation and reduce JAG1 cell surface expression. Mice harboring heterozygous CMT2-associated mutations exhibited mild peripheral neuropathy, and homozygous expression resulted in embryonic lethality by midgestation. Pre-existing rat model. Sources: Literature |
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| Hereditary Neuropathy_CMT - isolated v1.8 | COX20 |
Hazel Phillimore changed review comment from: Eight unrelated families carried the Chinese Han founder variant c.41A>G., p.(Lys14Arg) in either homozygous or compound heterozygous state with another variant. (This variant is predicted to cause aberrant splicing by abolishing the donor splice site of exon 1). Three homozygous for p.(Lys14Arg), two compound heterozygous with p.(Trp74Cys), the others with p.(Ser33Leu), c.157+7A>G, or p.(Gln87*) All patients displayed sensory ataxia, with early to juvenile age of onset from 1 to 17 years. The clinical presentations of these patients showed some overlaps in central and peripheral nervous systems. However, our patients presented predominant proprioceptive sensory loss and sensory ataxia rather than a multisystem neurological impairment. Initial symptoms: difficulty walking, bilateral foot deformity. Patient’s fibroblasts and transfected cell lines showed reduction of COX20 protein consistent with a loss-of-function mechanism, and reduced complex IV assembly, enzyme activity and oxygen consumption rate which is consistent with mitochondrial dysfunction.. Sources: Literature; to: Eight unrelated families carried the Chinese Han founder variant c.41A>G., p.(Lys14Arg) in either homozygous or compound heterozygous state with another variant. (This variant is predicted to cause aberrant splicing by abolishing the donor splice site of exon 1). Three homozygous for p.(Lys14Arg), two compound heterozygous with p.(Trp74Cys), the others with p.(Ser33Leu), c.157+7A>G, or p.(Gln87*) All patients displayed sensory ataxia, with early to juvenile age of onset from 1 to 17 years. The clinical presentations of these patients showed some overlap in central and peripheral nervous systems. They presented with predominant proprioceptive sensory loss and sensory ataxia rather than a multisystem neurological impairment. Initial symptoms: difficulty walking, bilateral foot deformity. Patient’s fibroblasts and transfected cell lines showed reduction of COX20 protein consistent with a loss-of-function mechanism, and reduced complex IV assembly, enzyme activity and oxygen consumption rate which is consistent with mitochondrial dysfunction.. Sources: Literature |
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| Hereditary Neuropathy_CMT - isolated v1.8 | COX20 |
Hazel Phillimore gene: COX20 was added gene: COX20 was added to Hereditary Neuropathy_CMT - isolated. Sources: Literature Mode of inheritance for gene: COX20 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: COX20 were set to PMID: 33751098 Phenotypes for gene: COX20 were set to sensory neuronopathy; sensory neuron disease; ganglionopathy Review for gene: COX20 was set to GREEN Added comment: Eight unrelated families carried the Chinese Han founder variant c.41A>G., p.(Lys14Arg) in either homozygous or compound heterozygous state with another variant. (This variant is predicted to cause aberrant splicing by abolishing the donor splice site of exon 1). Three homozygous for p.(Lys14Arg), two compound heterozygous with p.(Trp74Cys), the others with p.(Ser33Leu), c.157+7A>G, or p.(Gln87*) All patients displayed sensory ataxia, with early to juvenile age of onset from 1 to 17 years. The clinical presentations of these patients showed some overlaps in central and peripheral nervous systems. However, our patients presented predominant proprioceptive sensory loss and sensory ataxia rather than a multisystem neurological impairment. Initial symptoms: difficulty walking, bilateral foot deformity. Patient’s fibroblasts and transfected cell lines showed reduction of COX20 protein consistent with a loss-of-function mechanism, and reduced complex IV assembly, enzyme activity and oxygen consumption rate which is consistent with mitochondrial dysfunction.. Sources: Literature |
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| Hereditary Neuropathy_CMT - isolated v1.2 | IQGAP3 |
Zornitza Stark gene: IQGAP3 was added gene: IQGAP3 was added to Hereditary Neuropathy_CMT - isolated. Sources: Literature Mode of inheritance for gene: IQGAP3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: IQGAP3 were set to 32341455 Phenotypes for gene: IQGAP3 were set to Hereditary neuropathy Review for gene: IQGAP3 was set to RED Added comment: Single multiplex family reported with intronic variant and limited functional data. Sources: Literature |
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| Hereditary Neuropathy_CMT - isolated v1.0 | CADM3 |
Teresa Zhao gene: CADM3 was added gene: CADM3 was added to Hereditary Neuropathy_CMT - isolated. Sources: Literature Mode of inheritance for gene: CADM3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: CADM3 were set to PMID: 33889941 Phenotypes for gene: CADM3 were set to Charcot-Marie-Tooth disease Penetrance for gene: CADM3 were set to unknown Review for gene: CADM3 was set to AMBER Added comment: Three families reported with the same missense variant in CADM3, p.Tyr172Cys (one family de novo), with mice work to show reduced expression of the mutant protein in axons and abnormal axonal organization. Sources: Literature |
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| Hereditary Neuropathy_CMT - isolated v0.204 | PRX | Zornitza Stark changed review comment from: Both mono-allelic and bi-allelic variants are associated with neuropathy.; to: Predominantly bi-allelic variants are associated with neuropathy, rare reports of mono-allelic variants. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary Neuropathy_CMT - isolated v0.190 | LMNA |
Zornitza Stark changed review comment from: Founder variant p.Arg298Cys (c.892C>T) reported in 3 families, supportive functional data, plus another case reported as part of a large CMT cohort.; to: Founder variant p.Arg298Cys (c.892C>T) reported in 3 families, supportive functional data, plus another case reported as part of a large CMT cohort Note mono allelic variants in this gene cause a range of phenotypes. |
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| Hereditary Neuropathy_CMT - isolated v0.170 | SEPT9 | Zornitza Stark Added comment: Comment when marking as ready: New HGNC approved name is SEPTIN9. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary Neuropathy_CMT - isolated v0.165 | DHTKD1 | Zornitza Stark changed review comment from: Comment on list classification: Two unrelated families and animal model.; to: Comment on list classification: Two unrelated families and animal model. Note bi-allelic variants are associated with a metabolic disorder. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary Neuropathy_CMT - isolated v0.126 | MME | Zornitza Stark Marked gene: MME as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary Neuropathy_CMT - isolated v0.126 | MME | Zornitza Stark Gene: mme has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary Neuropathy_CMT - isolated v0.126 | MME | Zornitza Stark Phenotypes for gene: MME were changed from HMSN; Charcot-Marie-Tooth disease, axonal, type 2T, 617017 to Charcot-Marie-Tooth disease, axonal, type 2T, MIM# 617017; MONDO:0014866 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary Neuropathy_CMT - isolated v0.125 | MME | Zornitza Stark Publications for gene: MME were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary Neuropathy_CMT - isolated v0.124 | MME | Zornitza Stark Mode of inheritance for gene: MME was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary Neuropathy_CMT - isolated v0.123 | MME | Zornitza Stark reviewed gene: MME: Rating: GREEN; Mode of pathogenicity: None; Publications: 26991897, 27588448, 33144514, 31429185; Phenotypes: Charcot-Marie-Tooth disease, axonal, type 2T, MIM# 617017, MONDO:0014866; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary Neuropathy_CMT - isolated v0.112 | INF2 |
Zornitza Stark changed review comment from: Autosomal dominant intermediate Charcot-Marie-Tooth disease E with focal segmental glomerulonephritis is characterized by the neurologic features of CMT, including distal muscle weakness and atrophy and distal sensory loss, and the features of FSGS, including proteinuria, progression to end-stage renal disease, and a characteristic histologic pattern on renal biopsy. Nine variants reported in 12 individuals. All were located in exons 2 and 3, which encode the diaphanous inhibitory domain (DID), and most of them were between nucleotides 300 and 500 in the second and third armadillo repeats. These variants were located in distinct areas from those associated with isolated FSGS5.; to: Autosomal dominant intermediate Charcot-Marie-Tooth disease E with focal segmental glomerulonephritis is characterized by the neurologic features of CMT, including distal muscle weakness and atrophy and distal sensory loss, and the features of FSGS, including proteinuria, progression to end-stage renal disease, and a characteristic histologic pattern on renal biopsy. Nine variants reported in 12 individuals in the initial publication PMID 22187985. All were located in exons 2 and 3, which encode the diaphanous inhibitory domain (DID), and most of them were between nucleotides 300 and 500 in the second and third armadillo repeats. These variants were located in distinct areas from those associated with isolated FSGS5. |
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| Hereditary Neuropathy_CMT - isolated v0.99 | HARS |
Zornitza Stark changed review comment from: Four unrelated families reported.; to: Four unrelated families reported. New HGNC approved name is HARS1. |
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| Hereditary Neuropathy_CMT - isolated v0.71 | VWA1 |
Melanie Marty gene: VWA1 was added gene: VWA1 was added to Hereditary Neuropathy_CMT - isolated. Sources: Literature Mode of inheritance for gene: VWA1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: VWA1 were set to 33459760; 33693694; 33559681 Phenotypes for gene: VWA1 were set to Hereditary motor neuropathy Added comment: Six different truncating variants identified in 15 affected individuals from six families (biallelic inheritance). Disease manifested in childhood or adulthood with proximal and distal muscle weakness predominantly of the lower limbs. Myopathological and neurophysiological findings were indicative of combined neurogenic and myopathic pathology. Early childhood foot deformity was frequent, but no sensory signs were observed. An additional 17 individuals from 15 families with hereditary motor neuropathy were identified. A 10-bp repeat expansion at the end of exon 1 was observed in 14 families and was homozygous in 10 of them. This mutation, c.62_71dup [p.Gly25Argfs*74], leads to a frameshift that results in a reduction in VWA1 transcript levels via nonsense-mediated decay. Sources: Literature |
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| Hereditary Neuropathy_CMT - isolated v0.68 | SPTAN1 |
Melanie Marty gene: SPTAN1 was added gene: SPTAN1 was added to Hereditary Neuropathy_CMT - isolated. Sources: Literature Mode of inheritance for gene: SPTAN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: SPTAN1 were set to 33578420; 31332438 Phenotypes for gene: SPTAN1 were set to Distal hereditary motor neuropathy Penetrance for gene: SPTAN1 were set to Incomplete Review for gene: SPTAN1 was set to GREEN Added comment: 13 affected individuals from 4 families reported (nonsense variants) with AD distal hereditary motor neuropathy. Variable penetrance was noted and phenotype severity differs greatly between patients. Functional studies show NMD and reduced protein levels in patient cells. Sources: Literature |
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| Hereditary Neuropathy_CMT - isolated v0.60 | ITPR3 |
Zornitza Stark gene: ITPR3 was added gene: ITPR3 was added to Hereditary Neuropathy_CMT - isolated. Sources: Literature Mode of inheritance for gene: ITPR3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: ITPR3 were set to 32949214 Phenotypes for gene: ITPR3 were set to Charcot-Marie-Tooth disease Mode of pathogenicity for gene: ITPR3 was set to Other Review for gene: ITPR3 was set to AMBER Added comment: Two unrelated families reported: variant segregated in four affected individuals in one family and was de novo in the second family where there was a single affected person. Some evidence for dominant-negative effect. Sources: Literature |
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| Hereditary Neuropathy_CMT - isolated v0.59 | SYT2 | Zornitza Stark changed review comment from: Mono-allelic disease, PMID 25192047: dominant missense variants in SYT2 reported as a rare cause of distal motor neuropathy and myasthenic syndrome, manifesting with stable or slowly progressive distal weakness of variable severity along with presynaptic NMJ impairment in three families. These variants are thought to have a dominant-negative effect on synaptic vesicle exocytosis, although the precise pathomechanism remains to be elucidated. Supportive functional data from Drosophila.; to: Dominant missense variants in SYT2 reported as a rare cause of distal motor neuropathy and myasthenic syndrome, manifesting with stable or slowly progressive distal weakness of variable severity along with presynaptic NMJ impairment in three families. These variants are thought to have a dominant-negative effect on synaptic vesicle exocytosis, although the precise pathomechanism remains to be elucidated. Supportive functional data from Drosophila. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary Neuropathy_CMT - isolated v0.59 | SYT2 | Zornitza Stark changed review comment from: Mono-allelic disease, PMID 25192047: dominant missense variants in SYT2 reported as a rare cause of distal motor neuropathy and myasthenic syndrome, manifesting with stable or slowly progressive distal weakness of variable severity along with presynaptic NMJ impairment in two families. These variants are thought to have a dominant-negative effect on synaptic vesicle exocytosis, although the precise pathomechanism remains to be elucidated. Supportive functional data from Drosophila.; to: Mono-allelic disease, PMID 25192047: dominant missense variants in SYT2 reported as a rare cause of distal motor neuropathy and myasthenic syndrome, manifesting with stable or slowly progressive distal weakness of variable severity along with presynaptic NMJ impairment in three families. These variants are thought to have a dominant-negative effect on synaptic vesicle exocytosis, although the precise pathomechanism remains to be elucidated. Supportive functional data from Drosophila. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary Neuropathy_CMT - isolated v0.59 | GARS | Zornitza Stark Added comment: Comment when marking as ready: New HGNC approved name is GARS1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary Neuropathy_CMT - isolated v0.54 | GBF1 |
Paul De Fazio gene: GBF1 was added gene: GBF1 was added to Hereditary Neuropathy_CMT - isolated. Sources: Literature Mode of inheritance for gene: GBF1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: GBF1 were set to 32937143 Phenotypes for gene: GBF1 were set to Axonal Neuropathy Review for gene: GBF1 was set to GREEN gene: GBF1 was marked as current diagnostic Added comment: Four unrelated families with individuals affected by sporadic or dominant Distal hereditary motor neuropathies (HMNs) or axonal Charcot-Marie-Tooth neuropathy (CMT2). 3 missense variants (1 de novo) and 1 nonsense variant (de novo). Age of onset varied from childhood (nonsense variant) to 50s. Authors observed marked increase in Golgi fragmentation in primary fibroblasts derived from all affected individuals. Sources: Literature |
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| Hereditary Neuropathy_CMT - isolated v0.51 | LAS1L |
Zornitza Stark gene: LAS1L was added gene: LAS1L was added to Hereditary Neuropathy_CMT - isolated. Sources: Expert Review Mode of inheritance for gene: LAS1L was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for gene: LAS1L were set to 24647030 Phenotypes for gene: LAS1L were set to congenital lethal motor neuron disease Review for gene: LAS1L was set to RED Added comment: Variants in this gene are generally associated with XL intellectual disability (Wilson-Turner syndrome, MIM# 309585). Single case report of congenital lethal motor neuron disease (SMARD) identified with supportive zebrafish model. Unclear whether this is a distinct phenotype/mechanism at present, await further reports. Sources: Expert Review |
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| Hereditary Neuropathy_CMT - isolated v0.49 | C1orf194 | Zornitza Stark edited their review of gene: C1orf194: Added comment: PMID: 32592472 (2020) - An additional knockout mouse model by same research group, demonstrating defects in motor and sensory functions, myelination abnormalities, peripheral nerve loss and muscle atrophy.; Changed publications: 31199454, 32592472 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary Neuropathy_CMT - isolated v0.47 | IGHMBP2 | Crystle Lee changed review comment from: >5 families reported with CMT2.; to: >5 families reported with CMT2. Complete loss of protein function appears to result in the move severe condition (spinal muscular atrophy with respiratory distress type 1 (SMARD1) [MIM#604320]) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary Neuropathy_CMT - isolated v0.46 | PMP22 | Bryony Thompson Added comment: Comment on list classification: Both SNVs and CNVs cause disease | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary Neuropathy_CMT - isolated v0.43 | SORD |
Seb Lunke gene: SORD was added gene: SORD was added to Hereditary Neuropathy_CMT - isolated. Sources: Literature Mode of inheritance for gene: SORD was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SORD were set to 32367058 Phenotypes for gene: SORD were set to isolated hereditary neuropathy gene: SORD was marked as current diagnostic Added comment: 45 individuals from 38 families across multiple ancestries carrying the nonsense c.757delG (p.Ala253GlnfsTer27) variant in SORD, in either a homozygous or compound heterozygous state Sources: Literature |
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| Hereditary Neuropathy_CMT - isolated v0.34 | JAG1 |
Zornitza Stark gene: JAG1 was added gene: JAG1 was added to Hereditary Neuropathy_CMT - isolated. Sources: Literature Mode of inheritance for gene: JAG1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: JAG1 were set to 32065591; 25707699 Phenotypes for gene: JAG1 were set to Peripheral neuropathy Review for gene: JAG1 was set to GREEN Added comment: Two unrelated families reported with CMT type 2. Affected individuals in both families exhibited severe vocal fold paresis, a rare feature of peripheral nerve disease that can be life-threatening. Studies of mutant protein posttranslational modification and localization indicated that the mutations (p.Ser577Arg, p.Ser650Pro) impair protein glycosylation and reduce JAG1 cell surface expression. Mice harboring heterozygous CMT2-associated mutations exhibited mild peripheral neuropathy, and homozygous expression resulted in embryonic lethality by midgestation. Pre-existing rat model. Sources: Literature |
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| Hereditary Neuropathy_CMT - isolated v0.32 | C1orf194 |
Zornitza Stark gene: C1orf194 was added gene: C1orf194 was added to Hereditary Neuropathy_CMT - isolated. Sources: Literature Mode of inheritance for gene: C1orf194 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: C1orf194 were set to 31199454 Phenotypes for gene: C1orf194 were set to Charcot-Marie-Tooth disease, intermediate or demyelinating Review for gene: C1orf194 was set to AMBER Added comment: Two unrelated families with missense variants, one with intermediate CMT, the other with demyelinating CMT. Different phenotypic manifestations may relate to different mechanism, but this remains to be fully elucidated. Supportive mouse model. Sources: Literature |
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| Hereditary Neuropathy_CMT - isolated v0.28 | UBA5 |
Zornitza Stark gene: UBA5 was added gene: UBA5 was added to Hereditary Neuropathy_CMT - isolated. Sources: Literature Mode of inheritance for gene: UBA5 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: UBA5 were set to 32179706; 26872069 Phenotypes for gene: UBA5 were set to Hypomyelinating neuropathy Review for gene: UBA5 was set to AMBER Added comment: UBA5 variants have been associated with a range of neurological phenotypes, primarily epilepsy, ID and ataxia. Note these two reports of demyelinating peripheral neuropathy: 26872069 pair of sibs with mild ataxia, one with neuropathy; 32179706 five individuals from a consanguineous family presenting in infancy with severe fatal neuropathy. Some functional data. Due to early mortality, uncertain at present whether additional features would have developed. Sources: Literature |
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| Hereditary Neuropathy_CMT - isolated v0.9 | ARHGEF10 | Zornitza Stark changed review comment from: Single family reported in 2003 with slowed nerve conduction velocities but no other clinical findings. Another individual reported in a large cohort.; to: Single family reported in 2003 with slowed nerve conduction velocities but no other clinical findings. Two others in CMT cohorts, plus functional data. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary Neuropathy_CMT - isolated v0.6 | UBA1 | Bryony Thompson Deleted their comment | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary Neuropathy_CMT - isolated v0.6 | UBA1 | Bryony Thompson edited their review of gene: UBA1: Added comment: Five families reported. Children with XL-SMA usually die from respiratory failure by age two years; however, the age at death ranges from the neonatal period to adolescence, the latter in those exceptional cases in which extensive respiratory and medical support are provided (genereviews).; Changed rating: GREEN; Changed publications: 18179898; Changed phenotypes: Spinal muscular atrophy, X-linked 2, infantile MIM#301830; Changed mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary Neuropathy_CMT - isolated v0.5 | RBM7 |
Bryony Thompson gene: RBM7 was added gene: RBM7 was added to Hereditary Neuropathy - isolated_RMH. Sources: Expert list Mode of inheritance for gene: RBM7 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: RBM7 were set to 27193168 Phenotypes for gene: RBM7 were set to SMA-like spinal motor neuropathy; dHMN/dSMA Review for gene: RBM7 was set to AMBER Added comment: Single case with a homozygote variant, with functional assays in patient fibroblasts. Also, supporting zebrafish model. Sources: Expert list |
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| Hereditary Neuropathy_CMT - isolated v0.3 | PDK3 |
Bryony Thompson gene: PDK3 was added gene: PDK3 was added to Hereditary Neuropathy - isolated_RMH. Sources: Expert list Mode of inheritance for gene: PDK3 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: PDK3 were set to 23297365; 26801680; 27388934; 28902413 Phenotypes for gene: PDK3 were set to Charcot-Marie-Tooth disease, X-linked dominant, 6 MIM#300905; HMSN Review for gene: PDK3 was set to GREEN Added comment: Two unrelated families with the same variant and a single CMT case with another variant, and functional analyses conducted in patient fibroblasts and cell lines. Sources: Expert list |
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| Hereditary Neuropathy_CMT - isolated v0.1 | MED25 |
Bryony Thompson gene: MED25 was added gene: MED25 was added to Hereditary Neuropathy - isolated_RMH. Sources: Expert list Mode of inheritance for gene: MED25 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MED25 were set to 19290556; 30039206 Phenotypes for gene: MED25 were set to Charcot-Marie-Tooth disease, type 2B2 MIM#605589 Review for gene: MED25 was set to RED Added comment: Alternate cause for CMT2B2 identified in the original Costa Rican family (PMID: 19290556) in PNKP (PMID: 30039206). Sources: Expert list |
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| Hereditary Neuropathy_CMT - isolated v0.0 | UBA1 | Bryony Thompson commented on gene: UBA1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary Neuropathy_CMT - isolated v0.0 | MME |
Bryony Thompson gene: MME was added gene: MME was added to Hereditary Neuropathy - isolated_RMH. Sources: Royal Melbourne Hospital,Expert Review Green Mode of inheritance for gene: MME was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: MME were set to HMSN; Charcot-Marie-Tooth disease, axonal, type 2T, 617017 |
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