ClinVar Miner

Submissions for variant NM_000161.2(GCH1):c.323G>A (p.Gly108Asp) (rs104894435)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000634833 SCV000756177 likely pathogenic Dystonia 5, Dopa-responsive type; GTP cyclohydrolase I deficiency 2018-01-25 criteria provided, single submitter clinical testing This sequence change replaces glycine with aspartic acid at codon 108 of the GCH1 protein (p.Gly108Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with dystonia (PMID: 9667588, 15753436, Invitae). ClinVar contains an entry for this variant (Variation ID: 9282). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Different missense substitutions at this codon (p.Gly108Val and p.Gly108Ser) have been reported in individuals affected with dopa-responsive dystonia (PMID: 16917893, 17898029). This suggests that the glycine residue is critical for GCH1 protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
OMIM RCV000009864 SCV000030085 pathogenic Dystonia, dopa-responsive, with or without hyperphenylalaninemia, autosomal recessive 1998-07-01 no assertion criteria provided literature only

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