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

gnomAD frequency: 0.00001  dbSNP: rs1389614116

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001060735	SCV001225442	pathogenic	Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	2024-04-05	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 Omenn syndrome and/or severe combined immunodeficiency and with combined immunodeficiency and autoimmunity (PMID: 24290284, 32888943, 35503492, 36279417; 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects RAG1 function (PMID: 24290284, 36279417). 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. For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001706717	SCV001934394	likely pathogenic	Combined immunodeficiency with skin granulomas	2024-10-01	criteria provided, single submitter	clinical testing	Criteria applied: PS3_MOD,PM3,PM2_SUP,PP3
Baylor Genetics	RCV003473673	SCV004200480	likely pathogenic	Combined immunodeficiency due to partial RAG1 deficiency	2023-12-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004702616	SCV005203034	pathogenic	Severe combined immunodeficiency disease	2024-07-22	criteria provided, single submitter	clinical testing	Variant summary: RAG1 c.2917C>T (p.Arg973Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250542 control chromosomes (gnomAD). c.2917C>T has been reported in the literature in multiple individuals affected with Severe Combined Immunodeficiency (e.g. Lee_2014, Platt_2021, Barreiros_2022). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant results in a complete loss of recombination activity (Lee_2014). The following publications have been ascertained in the context of this evaluation (PMID: 24290284, 32888943, 35503492). ClinVar contains an entry for this variant (Variation ID: 855458). Based on the evidence outlined above, the variant was classified as pathogenic.