Submissions for variant NM_000536.4(RAG2):c.1504A>G (p.Met502Val)

gnomAD frequency: 0.00149  dbSNP: rs145614809

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001653875	SCV000605000	uncertain significance	not provided	2020-05-15	criteria provided, single submitter	clinical testing
Pediatric Immunology Service, The Chaim Sheba Medical Center at Tel HaShomer	RCV000681604	SCV000693952	benign	Histiocytic medullary reticulosis; Recombinase activating gene 2 deficiency; Inborn error of immunity	2018-03-06	criteria provided, single submitter	research
Invitae	RCV000645688	SCV000767439	likely benign	Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	2024-01-30	criteria provided, single submitter	clinical testing
Counsyl	RCV000669183	SCV000793910	uncertain significance	Combined immunodeficiency with skin granulomas; Histiocytic medullary reticulosis; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	2017-09-12	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001103958	SCV001260780	uncertain significance	Histiocytic medullary reticulosis	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001103959	SCV001260781	uncertain significance	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Genome-Nilou Lab	RCV001103959	SCV001712293	uncertain significance	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	2021-05-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001103958	SCV001806130	uncertain significance	Histiocytic medullary reticulosis	2021-07-22	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001579122	SCV001806531	uncertain significance	Combined immunodeficiency with skin granulomas	2021-07-22	criteria provided, single submitter	clinical testing
GeneDx	RCV001653875	SCV001864081	benign	not provided	2019-01-16	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 17572155, 19178939, 26457731, 29772310, 16960852)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002282190	SCV002570639	likely benign	not specified	2022-07-07	criteria provided, single submitter	clinical testing	Variant summary: RAG2 c.1504A>G (p.Met502Val) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0019 in 251354 control chromosomes in the gnomAD database, including 3 homozygotes. The observed variant frequency is approximately 3-fold of the estimated maximal expected allele frequency for a pathogenic variant in RAG2 causing Severe Combined Immunodeficiency Syndrome/Omenn Syndrome phenotype (0.00071), strongly suggesting that the variant is benign. c.1504A>G has been reported in the literature in individuals affected with Severe Combined Immunodeficiency Syndrome/Omenn Syndrome (e.g. Sobacchi_2006, Sheehan_2009, Walter_2015). In at least two of these individuals, co-occurrence of the variant in cis with a RAG1 pathogenic variant was reported (RAG1 c.1303A>G, p.Met435Val; Sheehan_2009, Walter_2015), providing supporting evidence for a benign role. Experimental evidence evaluating an impact on protein function demonstrated the variant to have wild-type levels of recombination activity (Tirosh_2019). Three ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign and five ClinVar submitters (evaluation after 2014) cite it as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV003925510	SCV004745089	likely benign	RAG2-related condition	2020-05-29	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).