Submissions for variant NM_000169.3(GLA):c.197A>G (p.Glu66Gly)

dbSNP: rs869312264

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Revvity Omics, Revvity	RCV003487869	SCV004235156	uncertain significance	not provided	2023-06-07	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV003779245	SCV004685139	likely pathogenic	Fabry disease	2023-11-22	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 66 of the GLA protein (p.Glu66Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Fabry disease (PMID: 16773563). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects GLA function (PMID: 16773563). This variant disrupts the p.Glu66 amino acid residue in GLA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15861341, 23935525). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003779245	SCV005185274	likely pathogenic	Fabry disease	2024-05-09	criteria provided, single submitter	clinical testing	Variant summary: GLA c.197A>G (p.Glu66Gly) 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. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 182566 control chromosomes. c.197A>G has been reported in the literature in individuals affected with Fabry Disease (e.g. Spada_2006, Sanders_2020). These data indicate that the variant is likely to be be associated with disease. In vitro studies in COS-7 and HEK cells showed that this variant results in 29-39% activity compared to wild-type (e.g. Spada_2006, .Oommen_2019). The following publications have been ascertained in the context of this evaluation (PMID: 31036492, 32802993, 16773563). ClinVar contains an entry for this variant (Variation ID: 2689132). Based on the evidence outlined above, the variant was classified as likely pathogenic.