ClinVar Miner

Submissions for variant NM_000169.2(GLA):c.1018T>C (p.Trp340Arg) (rs1555984869)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx 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.
Invitae RCV001244524 SCV001417750 pathogenic Fabry disease 2019-10-18 criteria provided, single submitter clinical testing 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. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with Fabry disease (Invitae). ClinVar contains an entry for this variant (Variation ID: 546086). 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 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. For these reasons, this variant has been classified as Pathogenic.

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