ClinVar Miner

Submissions for variant NM_000536.4(RAG2):c.475C>T (p.Arg159Cys)

gnomAD frequency: 0.00004  dbSNP: rs764485070
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genomics Facility, Ludwig-Maximilians-Universität München RCV001824243 SCV002073880 pathogenic Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive 2021-12-28 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001869833 SCV002228861 pathogenic Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive 2024-02-24 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 159 of the RAG2 protein (p.Arg159Cys). This variant is present in population databases (rs764485070, gnomAD 0.007%). This missense change has been observed in individual(s) with Omenn syndrome and/or severe combined immunodeficiency (PMID: 24144642, 28747913, 32445296, 32655540). ClinVar contains an entry for this variant (Variation ID: 1339534). 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 RAG2 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics RCV002503333 SCV002812636 likely pathogenic Combined immunodeficiency with skin granulomas; Histiocytic medullary reticulosis; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive 2021-11-24 criteria provided, single submitter clinical testing
Baylor Genetics RCV003475102 SCV004200547 pathogenic Combined immunodeficiency with skin granulomas 2023-06-10 criteria provided, single submitter clinical testing
GeneDx RCV004720949 SCV005327889 likely pathogenic not provided 2024-02-08 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34426522, 26996199, 27825771, 32445296, 32655540, 24144642, 35482138, 28747913)

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