ClinVar Miner

Submissions for variant NM_000161.3(GCH1):c.539A>G (p.Gln180Arg)

dbSNP: rs1566660298
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000699765 SCV000828490 pathogenic Dystonia 5; GTP cyclohydrolase I deficiency 2023-07-03 criteria provided, single submitter clinical testing This missense change has been observed in individuals with autosomal dominant GCH1-related conditions (PMID: 10825351; Invitae). It has also been observed to segregate with disease in related individuals. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gln180 amino acid residue in GCH1. Other variant(s) that disrupt this residue have been observed in individuals with GCH1-related conditions (PMID: 19491146), which suggests that this may be a clinically significant amino acid residue. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 577096). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 180 of the GCH1 protein (p.Gln180Arg).
GeneDx RCV002259363 SCV002538911 likely pathogenic not provided 2022-06-10 criteria provided, single submitter clinical testing Previously reported in two siblings with dopa-responsive dystonia in the published literature (Tassin et al., 2000); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26206375, 10825351)

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