Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001379650 | SCV001577487 | pathogenic | Fabry disease | 2023-10-03 | criteria provided, single submitter | clinical testing | This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 56 of the GLA protein (p.Cys56Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Fabry disease (PMID: 8875188, 23935525; Invitae). ClinVar contains an entry for this variant (Variation ID: 222186). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GLA protein function. Experimental studies have shown that this missense change affects GLA function (PMID: 26415523). For these reasons, this variant has been classified as Pathogenic. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001379650 | SCV002571897 | pathogenic | Fabry disease | 2022-08-09 | criteria provided, single submitter | clinical testing | Variant summary: GLA c.167G>A (p.Cys56Tyr) 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 183298 control chromosomes. c.167G>A has been reported in the literature in individuals affected with Fabry Disease, and was presumed de novo in at least one case (eg. Davies_1996, Rodrguez-Mari_2003, etc). The variant was reported to have completely absent enzyme activity and was non-responsive to DGJ (Lukas_2016). Additionally, other variants at the same codon have been reported in association with Fabry disease in HGMD (C56S, C56F, C56G, C56R). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |