ClinVar Miner

Submissions for variant NM_000448.3(RAG1):c.2326C>T (p.Arg776Trp)

gnomAD frequency: 0.00001  dbSNP: rs121918572
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000801211 SCV000940977 pathogenic Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive 2022-08-23 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 776 of the RAG1 protein (p.Arg776Trp). This variant is present in population databases (rs121918572, gnomAD 0.0009%). This missense change has been observed in individuals with severe combined immunodeficiency (SCID) (PMID: 18701881, 32445296). It has also been observed to segregate with disease in related individuals. This variant is also known as C2438T. ClinVar contains an entry for this variant (Variation ID: 13161). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RAG1 protein function. Experimental studies have shown that this missense change affects RAG1 function (PMID: 18701881). This variant disrupts the p.Arg776 amino acid residue in RAG1. Other variant(s) that disrupt this residue have been observed in individuals with RAG1-related conditions (PMID: 17572155, 19458910), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV003473098 SCV004200515 pathogenic Combined immunodeficiency due to partial RAG1 deficiency 2023-02-25 criteria provided, single submitter clinical testing
OMIM RCV000014047 SCV000034294 pathogenic Severe combined immunodeficiency, B cell-negative 2009-02-01 no assertion criteria provided literature only

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