Submissions for variant NM_000536.4(RAG2):c.644C>T (p.Thr215Ile)

gnomAD frequency: 0.00032  dbSNP: rs35691292

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	RCV003492295	SCV004242272	benign	Recombinase activating gene 2 deficiency	2024-01-23	reviewed by expert panel	curation	The c.644C>T (NM_000536.4) variant in RAG2 is a missense variant predicted to cause substitution of Threonine by Isoleucine at amino acid 215 (p.Thr215Ile). The filtering allele frequency (the lower threshold of the 95% CI of 2177/91084 alleles) of the c.644C>T variant in RAG2 is 0.02308 for South Asian chromosomes by gnomAD v.4, which is higher than the ClinGen SCID VCEP threshold (>0.00872) for BA1, and therefore meets this criterion (BA1). Additionally, 42 homozygous individuals have been described (40 and 2 individuals in South Asian and "Remaining" populations, respectively (BS2_Supporting). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive recombinase activating gene 2 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: BA1 and BS2_Supporting (VCEP specifications version 1.0).
GeneDx	RCV000433357	SCV000514367	benign	not specified	2016-12-23	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Pediatric Immunology Service, The Chaim Sheba Medical Center at Tel HaShomer	RCV000681585	SCV000693933	uncertain significance	Histiocytic medullary reticulosis; 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
Labcorp Genetics (formerly Invitae), Labcorp	RCV001081978	SCV000767448	benign	Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	2024-01-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000433357	SCV000918149	benign	not specified	2018-02-21	criteria provided, single submitter	clinical testing	Variant summary: RAG2 c.644C>T (p.Thr215Ile) results in a non-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. However, these predictions have yet to be functionally assessed. The variant allele was found at a frequency of 0.003 in 277112 control chromosomes in the gnomAD database, including 11 homozygotes. The observed variant frequency is approximately 4.22 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. The variant, c.644C>T, has been reported in the literature in individuals affected with Severe Combined Immunodeficiency Syndrome/Omenn Syndrome (Tabori_2004, Lev_2012, Meshaal_2015). These reports do not provide unequivocal conclusions about association of the variant with Severe Combined Immunodeficiency Syndrome/Omenn Syndrome. A ClinVar Submission from a clinical diagnostic laboratory (evaluation after 2014) classifies the variant as benign. Based on the evidence outlined above, the variant was classified as benign.
Mendelics	RCV000645697	SCV001135029	likely benign	not provided	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001104047	SCV001260874	benign	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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
Illumina Laboratory Services, Illumina	RCV001104048	SCV001260875	benign	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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001104048	SCV002767439	likely benign	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as likely benign. Following criteria are met: 0308 - Population frequency for this variant is out of keeping with known incidence of autosomal recessive B cell-negative severe combined immunodeficiency (MIM#614074). (SB) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000433357	SCV005090889	benign	not specified	2024-07-31	criteria provided, single submitter	clinical testing
OMIM	RCV000014016	SCV000034263	pathogenic	Severe combined immunodeficiency, B cell-negative	2004-04-01	no assertion criteria provided	literature only
Natera, Inc.	RCV001104047	SCV001458520	benign	Histiocytic medullary reticulosis	2020-04-13	no assertion criteria provided	clinical testing