ClinVar Miner

Submissions for variant NM_000377.3(WAS):c.1266_1267insG (rs1557007312)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000590506 SCV000696639 pathogenic Wiskott-Aldrich syndrome 2017-08-10 criteria provided, single submitter clinical testing Variant summary: The WAS c.1271dupG (p.Leu425Profs) variant results in a premature termination codon, predicted to cause a truncated or absent WAS protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as likely pathogenic by our laboratory (e.g. c.1352delC, p.Pro451fs). MutationTaster predicts a damaging outcome for this variant. Functional studies showed absent or very low WASP protein levels in PBMCs and T lymphocytes derived from Wiskott-Aldrich syndrome patients (Qasim_2001, Wada_2003). This variant was not found in the large control database ExAC in 30090 control chromosomes and was found in several male patients with Wiskott-Aldrich syndrome (Qasim_2001, Wada_2003, Kolluri_1995, Simon_2014). Taken together, this variant is classified as pathogenic.
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics RCV001009627 SCV001161677 pathogenic X-linked thrombocytopenia with normal platelets 2020-02-11 criteria provided, single submitter clinical testing A hemizygous single base pair deletion in exon 10 of the WAS gene that results in a frameshift and premature truncation of the protein 70 amino acids downstream to codon 425 was detected. The observed variant c.1266_1267insG (p.Leu425ProfsTer) has not been reported in the 1000 Genomes and ExAC databases. The in silico prediction of the variant is damaging by MutationTaster2. The observed variant has previously been reported in patients affected with thrombocytopenia (Kolluri et al 1995) and has been reported as pathogenic in ClinVar database. The reference codon is conserved across primates. In summary, the variant meets our criteria to be classified as pathogenic.
Invitae RCV001056670 SCV001221124 pathogenic X-linked severe congenital neutropenia; X-linked thrombocytopenia with normal platelets; Wiskott-Aldrich syndrome 2019-03-22 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the WAS gene (p.Leu425Profs*70). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 78 amino acids of the WAS protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals and families affected with Wiskott-Aldrich syndrome (PMID: 8528198, 11442475, 12727931, 24210885). This variant is also known as G insertion after G13O5, 1271insG, and 1305insG in the literature. ClinVar contains an entry for this variant (Variation ID: 495844). This variant has been reported to affect WAS protein function (PMID: 11442475, 12727931). For these reasons, this variant has been classified as Pathogenic.

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