ClinVar Miner

Submissions for variant NM_000448.3(RAG1):c.1420C>T (p.Arg474Cys)

gnomAD frequency: 0.00002  dbSNP: rs199474678
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001235005 SCV001407669 pathogenic Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive 2024-01-04 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 474 of the RAG1 protein (p.Arg474Cys). This variant is present in population databases (rs199474678, gnomAD 0.005%). This missense change has been observed in individual(s) with Omenn syndrome, leaky SCID, and combined T and B cell immunodeficiency (PMID: 18822103, 19064334, 24290284, 24472623, 28216420). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 68683). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RAG1 protein function. Experimental studies have shown that this missense change affects RAG1 function (PMID: 21131235, 21502542, 28216420). This variant disrupts the p.Arg474 amino acid residue in RAG1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11133745, 11313270, 18822103). 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.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein RCV003137602 SCV003806839 pathogenic Combined immunodeficiency with skin granulomas 2022-08-11 criteria provided, single submitter clinical testing ACMG classification criteria: PS3 supporting, PS4 moderated, PM2 moderated, PM3 strong, PM5 moderated, PP3 supporting
Baylor Genetics RCV003474646 SCV004200487 pathogenic Combined immunodeficiency due to partial RAG1 deficiency 2024-03-18 criteria provided, single submitter clinical testing
UniProtKB/Swiss-Prot RCV000059564 SCV000091096 not provided not provided no assertion provided not provided

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