ClinVar Miner

Submissions for variant NM_000448.3(RAG1):c.2918G>A (p.Arg973His)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Baylor Genetics RCV003472557 SCV004200511 likely pathogenic Combined immunodeficiency due to partial RAG1 deficiency 2023-04-14 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV003779081 SCV004568677 pathogenic Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive 2024-06-22 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 973 of the RAG1 protein (p.Arg973His). This variant is present in population databases (no rsID available, gnomAD 0.004%). This missense change has been observed in individual(s) with Omenn syndrome (PMID: 11313270). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects RAG1 function (PMID: 11313270). 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: 24290284; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics RCV005047610 SCV005683493 likely pathogenic Combined immunodeficiency due to partial RAG1 deficiency; Combined immunodeficiency with skin granulomas; Histiocytic medullary reticulosis; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive 2024-02-29 criteria provided, single submitter clinical testing

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