ClinVar Miner

Submissions for variant NM_000169.2(GLA):c.991C>T (p.Leu331Phe) (rs730880437)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000157874 SCV000207805 likely benign not specified 2014-03-28 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.
CSER _CC_NCGL, University of Washington RCV000590949 SCV000700119 uncertain significance Fabry disease 2016-10-01 criteria provided, single submitter research Found in patient having exome sequencing for an unrelated indication. No known history of Fabry disease. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review.
Color RCV000590949 SCV001342145 uncertain significance Fabry disease 2019-11-26 criteria provided, single submitter clinical testing
Broad Institute Rare Disease Group,Broad Institute RCV000590949 SCV001422925 uncertain significance Fabry disease 2020-01-22 no assertion criteria provided curation The p.Leu331Phe variant in GLA has not been previosuly reported in individuals with Fabry disease, but it has been identified in 0.0037% (3/81926) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs730880437). 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 been reported in ClinVar as likely benign by GeneDx and a VUS by the University of Washington Medical Center (ID: 180828). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. This variant was detected in 1 unaffected individual in ClinVar, suggesting that this variant is not pathogenic for Fabry disease. In summary, the clinical significance of the p.Leu331Phe is uncertain. CMG/AMP Criteria applied: PM2_supporting, BS2_supporting (Richards 2015).

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