ClinVar Miner

Submissions for variant NM_000377.2(WAS):c.223G>A (p.Val75Met) (rs782290433)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000768136 SCV000899091 pathogenic Severe congenital neutropenia X-linked; Thrombocytopenia, X-linked; Wiskott-Aldrich syndrome 2018-02-02 criteria provided, single submitter clinical testing WAS NM_000377.2 exon 2 p.Val75Met (c.223G>A): This variant has been reported in the literature in >10 individuals with X-linked thrombocytopenia (Kolluri 1995 PMID:8528198 (using alternate nomenclature c.257G>A), Albert 2010 PMID:20173115, Leblebisatan 2011 PMID:27264129). This variant is present in 1/12157 African alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs782290433). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population and/or variable expressivity. This variant is present in ClinVar (Variation ID:265289). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In addition, functional studies have shown a deleterious effect of this variant (Albert 2010 PMID:20173115, Sarkar 2015 PMID:26261240). In summary, this variant is classified as pathogenic.
GeneDx RCV000255132 SCV000322003 pathogenic not provided 2016-02-19 criteria provided, single submitter clinical testing The V75M missense variant in the WAS gene has been reported previously in association with WAS-related disorders (Albert et al., 2010; Kolluri et al., 1995). Please note, the Kolluri paper uses alternative cDNA nomenclature and indicates the position of the G>A nucleotide substitution at c.257. The V75M variant was not observed at any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This substitution occurs at a position within the WH1 domain that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Functional studies have shown that V75M causes a severe negative effect on WAS protein function by interfering with WAS SUMOylation (Sarkar et al., 2015). Missense variants in the same codon (V75L) and in nearby residues (C73R/Y, F74S, K76T, D77H/G) have been reported in the Human Gene Mutation Database in association with WAS-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, this variant is pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000589566 SCV000696641 pathogenic Thrombocytopenia, X-linked 2017-05-05 criteria provided, single submitter clinical testing Variant summary: The WAS c.223G>A (p.Val75Met) variant located in the WASP family, EVH1 domain (via InterPro) involves the alteration of a non-conserved nucleotide and 3/4 in silico tools (SNPsandGO not captured here due to low reliability index) predict a damaging outcome. Functional studies, Rajmohan_2009 and Sarkar_2015, indicate that the varaint does impact WAS protein functionality. This variant was found in 1/80511 control chromosomes at a frequency of 0.0000124, which does not exceed the estimated maximal expected allele frequency of a pathogenic WAS variant (0.0035355). The variant of interest has been reported in multiple affected individuals diagnosed with X-linked thrombocytopenia. In addition, a clinical diagnostic laboratory classifies this variant as pathogenic. Furthermore, additional variants affecting the same amino acid, c.223G>T (p.V75L), and surrounding, c.221T>C (p.F74S), c.227A>C (p.K76T), and c.218G>A (p.C73Y), have all been reported and classified as pathogenic, suggesting the variant resides in a mutational hotspot. Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as "pathogenic."
Invitae RCV000768136 SCV000945682 pathogenic Severe congenital neutropenia X-linked; Thrombocytopenia, X-linked; Wiskott-Aldrich syndrome 2018-09-13 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 75 of the WAS protein (p.Val75Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs782290433, ExAC 0.01%). This variant has been observed to segregate with X-linked thrombocytopenia (XLT) in several families (PMID: 27264129, 12969986, 9326235) and has also been reported in several unrelated individuals affected with XLT (PMID: 8528198, 15284122, 28931895, 8528199, 20173115) and Wiskott-Aldrich syndrome (PMID: 11793485, 21185603, 8595430). This variant is also known as c.257G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 265289). Experimental studies have shown that this missense change impairs the function of the WASP protein (PMID: 19817875, 26261240). For these reasons, this variant has been classified as Pathogenic.

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