ClinVar Miner

Submissions for variant NM_000161.3(GCH1):c.631A>G (p.Met211Val)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV003783610 SCV004570782 likely pathogenic Dystonia 5; GTP cyclohydrolase I deficiency 2023-09-24 criteria provided, single submitter clinical testing This missense change has been observed in individual(s) with dopa-responsive dystonia and/or tetrahydrobiopterin (BH4)-deficient hyperphenylalaninemia (PMID: 9778264, 11486899, 18044725). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 211 of the GCH1 protein (p.Met211Val). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GCH1 protein function. This variant disrupts the p.Met211 amino acid residue in GCH1. Other variant(s) that disrupt this residue have been observed in individuals with GCH1-related conditions (PMID: 7869202, 34054692), which suggests that this may be a clinically significant amino acid residue. 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.

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