Submissions for variant NM_000536.4(RAG2):c.193G>T (p.Asp65Tyr)

dbSNP: rs909264507

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	RCV003403136	SCV004102792	likely pathogenic	Recombinase activating gene 2 deficiency	2023-11-14	reviewed by expert panel	curation	The NM_000536.4:c.193G>T variant in RAG2 is a missense variant predicted to cause substitution of aspartic acid by tyrosine at amino acid 65 (p.Asp74Tyr). The variant has been reported in one individual with SCID. The individual was homozygous of this variant (PM3_Supporting, PMID 21624848). The individual had a T-B-NK+ lymphocyte profile and showed reduced T-cell proliferation under PHA stimulation, which supports a diagnosis of leaky/atypical SCID (PP4, PMID 21624848). The highest population minor allele frequency of this variant in gnomAD v2.1.1 is 0.000008791 (1/113758 alleles) in the European (non-Finnish) population, which is lower than the SCID-VCEP threshold (<0.0000588) for PM2_Supporting. No homozygous individual has been observed in the gnomAD v2.1.1 (PM2_Supporting). This variant resides within the core domain (amino acids 1-383) of RAG2, defined as a critical functional domain by the ClinGen SCID VCEP. (PM1_Supporting). An in vitro recombination activity assay shows that the relevant activity of the p.D65Y variant compared to wildtype RAG2 is 6.8%, which is below the threshold (<25%) established by the SCID VCEP for PS3_Moderate (PS3_Moderate, PMID 29772310). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive recombinase activating gene 2 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PP4, PM3_Supporting, PM2_Supporting, PM1_Supporting, and PS3_Moderate (VCEP specifications version 1.0).
GeneDx	RCV000489480	SCV000577637	pathogenic	not provided	2020-01-20	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect with a recombination activity of 6.8% of WT hRAG2(Tirosh 2018); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 21624848, 29772310)
Pediatric Immunology Service, The Chaim Sheba Medical Center at Tel HaShomer	RCV000681576	SCV000693924	likely pathogenic	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
Fulgent Genetics, Fulgent Genetics	RCV002496885	SCV002802552	likely pathogenic	Combined immunodeficiency with skin granulomas; Histiocytic medullary reticulosis; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	2021-11-12	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002526041	SCV003439691	uncertain significance	Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	2021-12-28	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 65 of the RAG2 protein (p.Asp65Tyr). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with severe combined immunodeficiency (PMID: 21624848). ClinVar contains an entry for this variant (Variation ID: 427020). 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. Experimental studies have shown that this missense change affects RAG2 function (PMID: 29772310). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003226307	SCV003922723	likely pathogenic	Severe combined immunodeficiency disease	2023-03-14	criteria provided, single submitter	clinical testing	Variant summary: RAG2 c.193G>T (p.Asp65Tyr) results in a non-conservative amino acid change in 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 4e-06 in 251474 control chromosomes (gnomAD). c.193G>T has been reported in the literature in an individual homozygous for the variant affected with Severe Combined Immunodeficiency (Dalal_2011). These data indicate that the variant may be associated with disease. At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated severely decreased recombinase activity (Tirosh_2019). Four submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as pathogenic (n=1), likely pathogenic (n=2), or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.