ClinVar Miner

Submissions for variant NM_000448.3(RAG1):c.2917C>T (p.Arg973Cys)

gnomAD frequency: 0.00001  dbSNP: rs1389614116
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001060735 SCV001225442 likely pathogenic Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive 2023-08-19 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 973 of the RAG1 protein (p.Arg973Cys). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with severe combined immunodeficiency and with combined immunodeficiency and autoimmunity (PMID: 24290284, 32888943; Invitae). ClinVar contains an entry for this variant (Variation ID: 855458). 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: 24290284). This variant disrupts the p.Arg973 amino acid residue in RAG1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11313270, 28747913, 30307608). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center RCV001706717 SCV001934394 uncertain significance Combined immunodeficiency with skin granulomas 2021-01-15 criteria provided, single submitter clinical testing
Baylor Genetics RCV003473673 SCV004200480 likely pathogenic Combined immunodeficiency due to partial RAG1 deficiency 2023-12-02 criteria provided, single submitter clinical testing

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