ClinVar Miner

Submissions for variant NM_000169.3(GLA):c.639+6A>C (rs200096940)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000035306 SCV000058954 uncertain significance not specified 2011-12-13 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The 639+6A>C varian t (GLA) has not been previously reported but has been identified by our laborato ry in 1 individual with HCM who carried another possibly disease causing variant in the MYBPC3 gene. This variant occurs in the 5' splice site consensus sequenc e, but not in the invariant +1 or +2 positions. Computational tools do not predi ct an impact on splicing, though their accuracy is unknown. This variant is less likely disease causing but additional information is needed to confirm this.
GeneDx RCV000035306 SCV000728502 likely benign not specified 2017-05-18 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Illumina Clinical Services Laboratory,Illumina RCV001165639 SCV001327853 likely benign Fabry disease 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Color Health, Inc RCV001165639 SCV001352031 likely benign Fabry disease 2019-03-30 criteria provided, single submitter clinical testing
Broad Institute Rare Disease Group, Broad Institute RCV001165639 SCV001422790 uncertain significance Fabry disease 2020-01-22 no assertion criteria provided curation The c.639+6A>C variant in GLA has been reported in at least 1 individual with Fabry disease (PMID:22805550), and has been identified in 0.005% (1/15710) and 0.006% (4/78727) of European (Finnish) and European (non-Finnish) chromosomes, respectively, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs200096940). Although this variant has been seen in the general population, its frequency is low enough to be consistent with Fabry disease. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported in ClinVar as a VUS by the Laboratory for Molecular Medicine and as likely benign by GeneDx. (ID:42457). Computational prediction tools, including splice predictors, and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. One affected individuals with this variant had an alternative molecular basis for Fabry disease, suggesting that this variant may not be pathogenic. In summary, while the clinical significance of the c.639+6A>C variant is uncertain, these data suggest that it is more likely to be benign. ACMG/AMP Criteria applied: BS2, BP5, BP7, BP4, PM2_supporting (Richards 2015).

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