ClinVar Miner

Submissions for variant NM_000448.3(RAG1):c.2867T>C (p.Ile956Thr)

gnomAD frequency: 0.00001  dbSNP: rs182385524
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001389162 SCV001590428 pathogenic Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive 2023-10-12 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 956 of the RAG1 protein (p.Ile956Thr). This variant is present in population databases (rs182385524, gnomAD 0.01%). This missense change has been observed in individual(s) with Omenn syndrome (PMID: 16960852, 24290284, 28083621). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1075542). 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: 24290284). For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics, part of Exact Sciences RCV004528500 SCV004109324 pathogenic RAG1-related disorder 2023-05-02 criteria provided, single submitter clinical testing The RAG1 c.2867T>C variant is predicted to result in the amino acid substitution p.Ile956Thr. This variant has been reported in the homozygous and compound heterozygous states in individuals with Omenn syndrome or atypical severe combined immunodeficiency (Patient 50, Sobacchi et al. 2006. PubMed ID: 16960852; Patient 1, Szaflarska et al. 2017. PubMed ID: 28083621; Table S1, No 20 and 63, Sharapova et al. 2020. PubMed ID: 32655540). It was also reported in the homozygous state in an individual with a suspected primary immunodeficiency, however additional information was not provided (Patient 332, Platt et al. 2020. PubMed ID: 32888943). Functional studies have shown that this variant leads to a reduction in recombination activity (Table E1, Lee et al. 2014. PubMed ID: 24290284). This variant is reported in 0.010% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-36597721-T-C) and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/1075542/). This variant is interpreted as pathogenic.
Baylor Genetics RCV003473990 SCV004200454 pathogenic Combined immunodeficiency due to partial RAG1 deficiency 2023-12-19 criteria provided, single submitter clinical testing

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