Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000657873 | SCV000779634 | likely pathogenic | not provided | 2018-05-17 | criteria provided, single submitter | clinical testing | The W340R variant has previously been reported in association with Fabry disease (Whybra et al., 2001). Functional analysis of W340R found that it is associated with no detectable residual enzyme activity (Benjamin et al., 2017). The W340R variant is not observed in large population cohorts (Lek et al., 2016). The W340R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. In summary, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. |
| Labcorp Genetics |
RCV001244524 | SCV001417750 | pathogenic | Fabry disease | 2020-02-13 | criteria provided, single submitter | clinical testing | This variant has been observed in an individual affected with Fabry disease (Invitae). ClinVar contains an entry for this variant (Variation ID: 546086). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Trp340 amino acid residue in GLA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 27896102). 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 missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant is not present in population databases (ExAC no frequency). This sequence change replaces tryptophan with arginine at codon 340 of the GLA protein (p.Trp340Arg). The tryptophan residue is highly conserved and there is a moderate physicochemical difference between tryptophan and arginine. |
| Genome- |
RCV001244524 | SCV002054386 | likely pathogenic | Fabry disease | 2021-07-15 | criteria provided, single submitter | clinical testing |