ClinVar Miner

Submissions for variant NM_000448.2(RAG1):c.1210C>T (p.Arg404Trp) (rs764981110)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics RCV000788766 SCV000928002 likely pathogenic not provided 2018-10-18 criteria provided, single submitter clinical testing
Invitae RCV000817183 SCV000957730 pathogenic Combined cellular and humoral immune defects with granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive 2019-12-18 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 404 of the RAG1 protein (p.Arg404Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs764981110, ExAC 0.002%). This variant has been observed in individuals affected with Omenn syndrome and with clinical features of severe combined immunodeficiency (PMID: 11313270, 26829731, Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. This variant has been reported to affect RAG1 protein function (PMID: 11313270). This variant disrupts the p.Arg404 amino acid residue in RAG1. Other variant(s) that disrupt this residue have been observed in individuals with RAG1-related conditions (PMID: 12200379, 16960852, 24290284, 24985406), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.

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