ClinVar Miner

Submissions for variant NM_000161.3(GCH1):c.607G>A (p.Gly203Arg) (rs988395114)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000440945 SCV000521171 pathogenic not provided 2018-07-26 criteria provided, single submitter clinical testing The G203R variant in the GCH1 gene has been reported previously in individuals with dopa-responsive dystonia (Bandmann et al., 1996; Wu-Chou et al., 2010; Yu et al., 2013). Overexpression of the mutant enzyme in COS cells resulted in a enzyme activity less than 6% of controls, and co-expression of the mutant and wild type enzyme resulted in a reduction in enzyme activity attributed to an inactivation of the enzyme (Ueno et al., 2000). The G203R variant is not observed in large population cohorts (Lek et al., 2016). The G203R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Multiple missense variants in nearby residues have been reported in the Human Gene Mutation Database in association with dopa-responsive dystonia (Stenson et al., 2014). We interpret G203R as a pathogenic variant.
Invitae RCV000811926 SCV000952218 pathogenic Dystonia 5; GTP cyclohydrolase I deficiency 2018-11-30 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 203 of the GCH1 protein (p.Gly203Arg). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in many individuals affected with dystonia including several individuals in whom the variant was reported to arise de novo (PMID: 20108370, 8852666, 23211702, 11486899, 20491893). This variant has also been observed to segregate with disease with reduced penetrance in families (PMID: 20082337, 19332422). ClinVar contains an entry for this variant (Variation ID: 381665). This variant has been reported to affect GCH1 protein function (PMID: 10984670). For these reasons, this variant has been classified as Pathogenic.

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