ClinVar Miner

Submissions for variant NM_000536.4(RAG2):c.283G>A (p.Gly95Arg)

gnomAD frequency: 0.00003  dbSNP: rs36001797
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen RCV003398500 SCV004102756 likely pathogenic Recombinase activating gene 2 deficiency 2023-11-14 reviewed by expert panel curation The NM_000536.4:c.283G>A variant in RAG2 is a missense variant predicted to cause substitution of glycine by arginine at amino acid 95 (p.Gly94Arg). This variant has a population max filtering allele frequency of 0.000007010, which is below the threshold for PM2_Supporting set by the ClinGen SCID VCEP for RAG2 (<0.0000588). This variant is located in the core domain (amino acids 1-383) of RAG2, which is defined as a mutational hotspot/critical functional domain by the ClinGen SCID VCEP (PMID: 26996199) (PM1_Supporting). In experimental studies, this variant demonstrates a mean recombination activity that is 0.3% of wildtype, which is below the threshold outlined by the ClinGen SCID VCEP (< 25% of wildtype activity) for PS3_Moderate. This variant has been reported in several individuals with severe combined immunodeficiency or Omenn syndrome. Two unrelated individuals are homozygous for this variant (PMID: 33599911, 30307608) (0.5p + 0.5p). Three individuals carry this variant along with a second co-occurring RAG2 variant (p.Trp453Arg (phase unknown, 0.25p), p.Glu480* (phase unknown, 0p), p.Arg229Trp (confirmed in trans, 0p)) (PMID: 10891502, 31838659, 15025726). (0.5p + 0.5p +0.25p = 1.25p, PS3). The p.Trp453Arg variant has been classified as Likely Pathogenic, whereas the p.Glu480* and p.Arg229Trp variants have not yet been classified by the ClinGen SCID VCEP. At least one of these reported patients meets PP4 criteria established by the ClinGen SCID VCEP: T-B-NK+ lymphocyte subset profile (0.5p), meets clinical diagnostic criteria for SCID (0.5p), testing via large SCID panel or exome sequencing (0.5p): 1.5p (PMID: 33599911). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive SCID based on the ACMG criteria applied: PM1_Supporting, PM2_Supporting, PS3_Moderate, PP4, and PM3 as specified by the ClinGen SCID VCEP (VCEP specifications version 1).
Counsyl RCV000671154 SCV000796104 likely pathogenic Combined immunodeficiency with skin granulomas; Histiocytic medullary reticulosis; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive 2017-12-01 criteria provided, single submitter clinical testing
Invitae RCV001043887 SCV001207656 pathogenic Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive 2024-01-26 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 95 of the RAG2 protein (p.Gly95Arg). This variant is present in population databases (rs36001797, gnomAD 0.05%). This missense change has been observed in individual(s) with Omenn’s syndrome and primary immunodeficiency (PMID: 10891502, 15025726, 26186701). 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: 13133). 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: 10891502). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000014014 SCV001363006 pathogenic Histiocytic medullary reticulosis 2019-03-11 criteria provided, single submitter clinical testing Variant summary: RAG2 c.283G>A (p.Gly95Arg) results in a non-conservative amino acid change located in the kelch motif in the enzymatically active core (Geier_2015) of 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 3.7e-05 in 246230 control chromosomes (gnomAD). c.283G>A has been reported in the literature in multiple individuals affected with Severe Combined Immunodeficiency Syndrome/Omenn Syndrome (Gomez_2000, Tabori_2004, Galal_2018, Geier_2015, Tirosh_2019). These data indicate that the variant is very likely to be associated with disease. A functional study, Gomez_2000, found the variant to impair the ability to mediate the initial nucleolytic steps of the V(D)J recombination reaction, while Tirosh_2019 found the variant to almost completely abolish recombinase activity. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics RCV003473087 SCV004200534 pathogenic Combined immunodeficiency with skin granulomas 2024-03-14 criteria provided, single submitter clinical testing
OMIM RCV000014014 SCV000034261 pathogenic Histiocytic medullary reticulosis 2000-08-01 no assertion criteria provided literature only
Natera, Inc. RCV000014014 SCV002087185 pathogenic Histiocytic medullary reticulosis 2020-11-16 no assertion criteria provided clinical testing

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