ClinVar Miner

Submissions for variant NM_000161.3(GCH1):c.541+1G>T (rs1555358599)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000579215 SCV000681336 pathogenic not provided 2018-01-08 criteria provided, single submitter clinical testing The c.541+1G>T variant in the GCH1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This splice site variant destroys the canonical splice donor site in intron 4. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. The c.541+1G>T variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.541+1G>T as a pathogenic variant.
Invitae RCV001059581 SCV001224208 pathogenic Dystonia 5; GTP cyclohydrolase I deficiency 2019-01-14 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 4 of the GCH1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). Disruption of this splice site has been observed in individuals affected with dopa-responsive dystonia (PMID: 11113234, 15753436, Invitae). ClinVar contains an entry for this variant (Variation ID: 489338). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in GCH1 are known to be pathogenic (PMID: 19491146). For these reasons, this variant has been classified as Pathogenic.

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