ClinVar Miner

Submissions for variant NM_000377.2(WAS):c.257G>A (p.Arg86His) (rs132630268)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000414284 SCV000490878 pathogenic not provided 2015-11-19 criteria provided, single submitter clinical testing The R86H missense variant in the WAS gene has been reported previously in association with Wiskott-Aldrich syndrome (Derry et al., 1994). This alteration is located in the WH1 domain and is expected to disrupt normal binding function between the WAS and WIP (WASP-interacting) proteins (Rajmohan et al., 2009; Worth et al., 2013). Therefore, we interpert R86H as a pathogenic variant.
Integrated Genetics/Laboratory Corporation of America RCV000011864 SCV000918355 pathogenic Wiskott-Aldrich syndrome 2018-11-20 criteria provided, single submitter clinical testing Variant summary: WAS c.257G>A (p.Arg86His) results in a non-conservative amino acid change located in the EVH1 domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 195436 control chromosomes (gnomAD). c.257G>A has been reported in the literature in multiple individuals from different ethnicities who were affected with Wiskott-Aldrich Syndrome (e.g. Derry 1994, Kolluri 1995, Park 2007, Alapi 2006, Gulacsy 2011). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, demonstrating a disrupted interaction with WIP and a severe decrease in protein level (with normal mRNA levels) in T cells from a patient (Stewart 1999, de La Fuente 2007). Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000633305 SCV000754522 pathogenic Severe congenital neutropenia X-linked; Thrombocytopenia, X-linked; Wiskott-Aldrich syndrome 2017-12-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 86 of the WAS protein (p.Arg86His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in many individuals affected with Wiskott-Aldrich syndrome (PMID: 23033889, 12969986, 22523910, 9326235, 15284122). This variant has also been reported to segregate with X-linked thrombocytopenia in a family (PMID: 20959042). This variant is also known as c.291G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 11115). Experimental studies have shown that this missense change disrupts the activity of WAS protein via reducing the binding ability to WASP-interacting protein and the protein stability (PMID: 10202051, 17213309, 19817875). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000011864 SCV000032097 pathogenic Wiskott-Aldrich syndrome 1996-07-01 no assertion criteria provided literature only

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