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Prepair 1000+ v1.592 GCH1 Lilian Downie Added comment: Comment when marking as ready: Biallelic variants in GCH1 typically result in severe deficiency of GTPCH activity, and result in hyperphenylalaninemia due to secondary PAH deficiency. This can be identified by newborn screening. However, patients with phenotypes that are intermediate between the classic DRD and severe GTPCH deficiency symptoms have been described, such those with severe DRD and additional neurological features but without hyperphenylalaninemia (for review, see Table in Brüggemann et al 2012, PMID 22473768). Because the mechanism of disease in both the monoallelic and biallelic cases is loss of function of GTPCH, and there is a range of GTPCH activity that can cause disease, the decision was made to curate GCH1 for GTPCH deficiency with semi-dominant inheritance. Note that heterozygous parents of biallelic individuals are usually reported as unaffected, although there are some exceptions (Furukawa et al, 1998, PMID 9667588; Bodzioch et al, 2010, PMID 20842687). Reduced penetrance has been reported for individuals with monoallelic GCH1 variants, with penetrance varying according to age and diagnostic criteria. In addition, some variants (e.g. p.Arg184His and p.Lys224Arg) have been reported in monallelic and biallelic individuals. This data was presented to the ClinGen Lumping and Splitting Working Group on November 3, 2020 and there was agreement that GTPCH deficiency should be curated as a semi-dominant trait, including individuals with monoallelic and biallelic GCH1 variants.
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+ v1.45 ARG1 Zornitza Stark Marked gene: ARG1 as ready
Prepair 1000+ v1.45 ARG1 Zornitza Stark Gene: arg1 has been classified as Green List (High Evidence).
Prepair 1000+ v1.45 ARG1 Zornitza Stark Phenotypes for gene: ARG1 were changed from Argininemia, 207800 (3) to Argininemia MIM# 207800
Prepair 1000+ v1.44 ARG1 Zornitza Stark Publications for gene: ARG1 were set to
Prepair 1000+ v1.9 ARG1 Kate Scarff reviewed gene: ARG1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 26467175, 2365823, 1598908, 29726057; Phenotypes: Argininemia MIM# 207800; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Prepair 1000+ v1.3 ARG1 Seb Lunke Added phenotypes Argininemia, 207800 (3) for gene: ARG1
Prepair 1000+ v0.0 ARG1 Zornitza Stark gene: ARG1 was added
gene: ARG1 was added to Reproductive Carrier Screen_VCGS. Sources: Mackenzie's Mission,Expert Review Green
Mode of inheritance for gene: ARG1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: ARG1 were set to Argininemia, 207800 (3)