Submissions for variant NM_000169.3(GLA):c.782G>A (p.Gly261Asp)

dbSNP: rs869312401

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001255564	SCV001432044	pathogenic	Fabry disease	2020-08-04	criteria provided, single submitter	clinical testing	Variant summary: GLA c.782G>A (p.Gly261Asp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183472 control chromosomes. c.782G>A has been reported in the literature in individuals affected with Classic/severe/renal manifestations of Fabry Disease and subsequently cited by others (example, Takata_1997, Altarescu_2001, Ashley_2001, Branton_2002, Garman_2002). These data indicate that the variant is likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity and no response to the pharmacological chaperone 1- deoxygalactonojirimycin (DGJ) (example, Takata_1997, Shin_2008). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, however the Fabry disease database cites at-least six records of this variant in patients (http://fabry-database.org/mutants/) citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001255564	SCV002235157	pathogenic	Fabry disease	2022-03-10	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 261 of the GLA protein (p.Gly261Asp). ClinVar contains an entry for this variant (Variation ID: 977728). This missense change has been observed in individual(s) with Fabry disease (PMID: 9105656, 11322659, 11531969, 32797665). 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly261 amino acid residue in GLA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23935525, 29491734; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site.