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
Invitae RCV000633307 SCV000754524 pathogenic X-linked severe congenital neutropenia; X-linked thrombocytopenia with normal platelets; 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.
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.

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