Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001218570 | SCV001390458 | uncertain significance | X-linked severe congenital neutropenia; Thrombocytopenia 1; Wiskott-Aldrich syndrome | 2020-01-30 | criteria provided, single submitter | clinical testing | This variant has not been reported in the literature in individuals with WAS-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with proline at codon 55 of the WAS protein (p.Leu55Pro). The leucine residue is moderately conserved and there is a moderate physicochemical difference between leucine and proline. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001824936 | SCV002074438 | uncertain significance | not specified | 2022-01-26 | criteria provided, single submitter | clinical testing | Variant summary: WAS c.164T>C (p.Leu55Pro) results in a non-conservative amino acid change located in the WH1/EVH1 domain (IPR000697) of the encoded protein sequence. Most missense mutations identified in Wiskott-Aldrich Syndrome patients are found in the EVH1/WH1 domain and some have been shown to decrease the affinity of WASp to WIP [WASp-interacting protein (WIP)], leading to dissociation of the complex and degradation of WASp (Massaad_2013). Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 182969 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.164T>C in individuals affected with Wiskott-Aldrich Syndrome and no experimental evidence demonstrating its impact on protein function have been published. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. |