Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000589425 | SCV000695745 | pathogenic | Fabry disease | 2016-07-04 | criteria provided, single submitter | clinical testing | Variant summary: The GLA c.790G>T (p.Asp264Tyr) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. Aspartate-264 is on the beta 7-strand of the beta/alfa-barrel and has its side-chain in the active site. A change to tyrosine would constrict the active site and remove the negative charge that assists in orientating the substrate (Shabbeer_2006). Multiple functional studies show that this variant leads to defective protein (Shabbeer_2006, Spada_2006, Lukas_2013). This variant is absent from approximately 87755 control chromosomes from ExAc. The variant has been reported in multiple FAB patients in literature and by a clinical diagnostic center in ClinVar. Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Another missense variant at the same codon, p.Asp264Val has also been found in FAB patients and reported to be pathogenic in literature and databases, suggesting that this codon is likely to be a mutational hot-spot. Taken together, this variant is classified as Pathogenic. |
| Revvity Omics, |
RCV003137795 | SCV003818190 | pathogenic | not provided | 2022-09-01 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV000589425 | SCV005842296 | pathogenic | Fabry disease | 2024-09-02 | criteria provided, single submitter | clinical testing | This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 264 of the GLA protein (p.Asp264Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Fabry disease (PMID: 15712228, 23935525, 26333625). ClinVar contains an entry for this variant (Variation ID: 222393). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt GLA protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects GLA function (PMID: 16773563). This variant disrupts the p.Asp264 amino acid residue in GLA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7504405, 9116979, 19387866, 21598360; internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |