ClinVar Miner

Submissions for variant NM_000377.2(WAS):c.91G>A (p.Glu31Lys) (rs1557006239)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000657918 SCV000779685 likely pathogenic not provided 2018-05-17 criteria provided, single submitter clinical testing The E31K variant has been published previously in association with Wiskott-Aldrich syndrome (Kolluri et al., 1995; Ariga et al., 1997). The variant is not observed in large population cohorts (Lek et al., 2016). E31K 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. Additionally, functional studies have shown E31K damages the ability of the WAS protein to bind WIP (Rajmohan et al., 2009). In summary, this variant is likely pathogenic.
Invitae RCV000633307 SCV000754524 pathogenic Severe congenital neutropenia X-linked; Thrombocytopenia, X-linked; Wiskott-Aldrich syndrome 2018-12-27 criteria provided, single submitter clinical testing This sequence change replaces glutamate with lysine at codon 31 of the WAS protein (p.Glu31Lys). The glutamate residue is highly conserved and there is a small physicochemical difference between glutamate and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in many individuals affected with Wiskott-Aldrich syndrome, and at least one of them has been found be de novo (PMID: 8528198, 11442475, 8682510, 15284122, 21185603, 28623282, 22523910, 25792466, 25476427). This variant is also known as c.125G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 528222). Experimental studies have shown that this missense change disrupts the activity of WAS protein via altering the binding ability to WASP-interacting protein and the normal subcellular localization (PMID: 19817875). For these reasons, this variant has been classified as Pathogenic.

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