Submissions for variant NM_000448.3(RAG1):c.3016A>G (p.Met1006Val)

gnomAD frequency: 0.00148  dbSNP: rs139113046

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000645690	SCV000767441	likely benign	Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	2025-02-03	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001108724	SCV001265993	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	RCV001108725	SCV001265994	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.
GeneDx	RCV001544721	SCV001763904	likely benign	not provided	2020-08-11	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 19178939, 24290284, 22001740, 31388879, 25976673, 22039266, 24472623, 21625022)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001805777	SCV002051356	likely benign	not specified	2021-12-24	criteria provided, single submitter	clinical testing	Variant summary: RAG1 c.3016A>G (p.Met1006Val) 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 250170 control chromosomes in the gnomAD database, including 2 homozygotes. The observed variant frequency is approximately 2.7 fold of the estimated maximal expected allele frequency for a pathogenic variant in RAG1 causing Severe Combined Immunodeficiency Syndrome/Omenn Syndrome phenotype (0.00071), strongly suggesting that the variant is benign. c.3016A>G has been reported in the literature in individuals affected with Severe Combined Immunodeficiency Syndrome/Omenn Syndrome but without unequivocal conclusions regarding causation (example Sheehan_2009). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign, n=2; VUS, n=1). Based on the evidence outlined above, the variant was classified as likely benign.
CeGaT Center for Human Genetics Tuebingen	RCV001544721	SCV004130010	likely benign	not provided	2024-01-01	criteria provided, single submitter	clinical testing	RAG1: BS2
PreventionGenetics, part of Exact Sciences	RCV004533380	SCV004729356	likely benign	RAG1-related disorder	2020-05-22	no assertion criteria provided	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).