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

Total submissions: 2

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.