ClinVar Miner

Submissions for variant NM_000536.4(RAG2):c.104G>T (p.Gly35Val)

dbSNP: rs148508754
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Pediatric Immunology Service, The Chaim Sheba Medical Center at Tel HaShomer RCV000681572 SCV000693920 likely pathogenic Histiocytic medullary reticulosis; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive; Recombinase activating gene 2 deficiency; Inborn error of immunity 2018-03-06 criteria provided, single submitter research
Invitae RCV001219165 SCV001391087 pathogenic Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive 2023-11-06 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 35 of the RAG2 protein (p.Gly35Val). This variant is present in population databases (no rsID available, gnomAD no frequency). This missense change has been observed in individuals with RAG2-related conditions (PMID: 15025726, 30307608). ClinVar contains an entry for this variant (Variation ID: 496618). 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%. Experimental studies have shown that this missense change affects RAG2 function (PMID: 10777560). For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics, part of Exact Sciences RCV003420026 SCV004115636 pathogenic RAG2-related disorder 2023-05-10 criteria provided, single submitter clinical testing The RAG2 c.104G>T variant is predicted to result in the amino acid substitution p.Gly35Val. This variant has been reported in multiple homozygous individuals with severe combined immunodeficiency (Corneo et al. 2000. PubMed ID: 10777560; Tabori et al. 2004. PubMed ID: 15025726; Meshaal et al. 2018. PubMed ID: 30307608). An in vitro experimental study suggests this variant disrupts the V-D-J recombination process for proper immunological function (Corneo et al. 2000. PubMed ID: 10777560). This variant is reported in one out of 251,316 total alleles in gnomAD (http://gnomad.broadinstitute.org/variant/11-36615615-C-A). This variant is interpreted as pathogenic.
Baylor Genetics RCV003471946 SCV004200535 pathogenic Combined immunodeficiency with skin granulomas 2023-12-14 criteria provided, single submitter clinical testing
Natera, Inc. RCV001834860 SCV002087229 pathogenic Histiocytic medullary reticulosis 2021-06-02 no assertion criteria provided clinical testing

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