ClinVar Miner

Submissions for variant NM_000448.3(RAG1):c.2923C>T (p.Arg975Trp)

gnomAD frequency: 0.00001  dbSNP: rs121918570
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000820053 SCV000960746 likely pathogenic Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive 2023-06-15 criteria provided, single submitter clinical testing ClinVar contains an entry for this variant (Variation ID: 13159). This missense change has been observed in individual(s) with granulomatous disease and Omenn syndrome (PMID: 18463379, 19064334, 24290284). This variant is present in population databases (rs121918570, gnomAD 0.004%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 975 of the RAG1 protein (p.Arg975Trp). 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. 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. This variant disrupts the p.Arg975 amino acid residue in RAG1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11133745, 24290284, 27484032). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects RAG1 function (PMID: 24290284).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003330387 SCV004039264 pathogenic Severe combined immunodeficiency disease 2023-08-24 criteria provided, single submitter clinical testing Variant summary: RAG1 c.2923C>T (p.Arg975Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 250554 control chromosomes (gnomAD). c.2923C>T has been reported in the literature as a biallelic genotype in multiple individuals affected with Severe Combined Immunodeficiency Syndrome/Omenn Syndrome (e.g. Schuetz_2008, Schonberger_2009, Shen_2019, Vignesh_2021, Tanita_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 recombination efficiency in vitro and found that the variant has approximately 3% of the wildtype activity (e.g. Schuetz_2008). Additionally, another variant affecting the same amino acid, c.2924G>A (p.Arg975Gln), has been classified as pathogenic, suggesting p.Arg975 is important for proper protein function. The following publications have been ascertained in the context of this evaluation (PMID: 19064334, 18463379, 31632441, 35281013, 33628209). One submitter has provided a clinical-significance assessment for this variant to ClinVar after 2014 and has classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics RCV003473096 SCV004200500 pathogenic Combined immunodeficiency due to partial RAG1 deficiency 2023-06-01 criteria provided, single submitter clinical testing
OMIM RCV000014045 SCV000034292 pathogenic Combined immunodeficiency with skin granulomas 2008-05-08 no assertion criteria provided literature only

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