ClinVar Miner

Submissions for variant NM_000169.2(GLA):c.770C>T (p.Ala257Val) (rs1569303218)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000781428 SCV000919446 likely pathogenic Fabry disease 2018-10-01 criteria provided, single submitter clinical testing Variant summary: GLA c.770C>T (p.Ala257Val) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 178780 control chromosomes (gnomAD). c.770C>T has been reported in the literature in female individuals with a confirmed diagnosis of Fabry Disease ascertained at a single institution (Echevarria 2015). These data indicate that the variant is likely to be associated with disease. This publication also reported experimental evidence evaluating an impact on protein function. The most pronounced variant effect resulted in activities ranging from as low as 17% of normal activity to 129% of normal activity with a median activity in the range of 45-63% of normal. The results of enzyme activity were influenced by the degree of X-chromosome inactivation ranging from random, skewed towards mutant or the wild-type alleles. 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 RCV000781428 SCV001223813 pathogenic Fabry disease 2019-03-25 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 257 of the GLA protein (p.Ala257Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with Fabry disease (PMID: 25974833). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). For these reasons, this variant has been classified as Pathogenic.

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