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

gnomAD frequency: 0.00003  dbSNP: rs36001797

Total submissions: 7

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	2023-10-26	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