ClinVar Miner

Submissions for variant NM_000161.3(GCH1):c.626+1G>A

dbSNP: rs1555358507
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000634835 SCV000756179 pathogenic Dystonia 5; GTP cyclohydrolase I deficiency 2024-09-23 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 5 of the GCH1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely disrupts the C-terminus of the protein. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with dystonia (PMID: 9749603, 17101830, 19491146). ClinVar contains an entry for this variant (Variation ID: 529415). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that disruption of this splice site results in skipping of exon 5 and introduces a new termination codon (PMID: 9749603). However the mRNA is not expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen RCV001090536 SCV001246141 pathogenic not provided 2018-02-01 criteria provided, single submitter clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV001090536 SCV001447630 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV001090536 SCV002018416 likely pathogenic not provided 2022-05-18 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV001090536 SCV003802776 pathogenic not provided 2022-09-27 criteria provided, single submitter clinical testing The GCH1 c.626+1G>A variant, also referred to as IVS5+1G>A, results in the substitution of a guanine within the consensus splice donor site with an adenine, which may result in splicing defects. Across a selection of the available literature, the c.626+1G>A variant has been identified in a heterozygous state in at least six individuals with dopa-responsive dystonia (PMID: 11486899; PMID: 19491146; PMID: 20937667; PMID: 28958832; PMID: 33875303). The c.626+1G>A variant was also found the asymptomatic father and sister. At least one additional variant, c.626+1G>C, has been reported at the same position in affected individuals (PMID: 24993959; PMID: 35041927). The c.626+1G>A variant is not found in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Analysis of cDNA using electrophoresis and additional sequencing demonstrated that this splice variant was associated with skipping exon 5 and a truncated protein product (PMID: 11486899). Based on the available evidence, the c.626+1G>A variant is classified as pathogenic for GTP cyclohydrolase I deficiency.
OMIM RCV001836648 SCV000030093 pathogenic Dystonia 5 2001-06-01 no assertion criteria provided literature only

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