ClinVar Miner

Submissions for variant NM_000169.2(GLA):c.640-1G>A

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000733701 SCV000861794 pathogenic not provided 2018-06-08 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781421 SCV000919439 likely pathogenic Fabry disease 2018-05-04 criteria provided, single submitter clinical testing Variant summary: GLA c.640-1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3 acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 178678 control chromosomes (gnomAD). The variant, c.640-1G>A, has been reported in the literature in an individual a Japanese woman with Fabry disease who presented with ischemic stroke, aseptic meningitis, and psychiatric symptoms (Sawada_2015) and an individual presenting with classic Fabry disease (Shabbeer_2006). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae RCV000781421 SCV000962384 pathogenic Fabry disease 2018-08-20 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 4 of the GLA 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). This variant has been observed in individuals affected with Fabry disease, being de novo in one of them (PMID: 16595074, 26631895). 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 GLA are known to be pathogenic (PMID: 10666480, 12175777). For these reasons, this variant has been classified as Pathogenic.

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