ClinVar Miner

Submissions for variant NM_000161.3(GCH1):c.646C>T (p.Arg216Ter)

dbSNP: rs41298440
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Mendelics RCV000989228 SCV001139461 pathogenic GTP cyclohydrolase I deficiency 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV001090535 SCV001246140 pathogenic not provided 2018-01-01 criteria provided, single submitter clinical testing
Invitae RCV001858704 SCV002240163 pathogenic Dystonia 5; GTP cyclohydrolase I deficiency 2023-04-17 criteria provided, single submitter clinical testing ClinVar contains an entry for this variant (Variation ID: 803028). For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the GCH1 protein in which other variant(s) (p.Arg241Gln) have been determined to be pathogenic (PMID: 24993959). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This premature translational stop signal has been observed in individuals with dystonia (PMID: 8852666, 24509643, 29948246, 31213404). This variant is present in population databases (rs41298440, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Arg216*) in the GCH1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 35 amino acid(s) of the GCH1 protein.

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