ClinVar Miner

Submissions for variant NM_000536.4(RAG2):c.644C>T (p.Thr215Ile) (rs35691292)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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 immunodeficiency, autosomal recessive, T-cell negative, B-cell negative, NK cell-positive; Recombinase activating gene 2 deficiency; Primary immunodeficiency 2018-03-06 criteria provided, single submitter research
Invitae RCV000645697 SCV000767448 benign Combined cellular and humoral immune defects with granulomas; Severe immunodeficiency, autosomal recessive, T-cell negative, B-cell negative, NK cell-positive 2017-10-25 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America 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.
OMIM RCV000014016 SCV000034263 pathogenic Severe combined immunodeficiency, B cell-negative 2004-04-01 no assertion criteria provided literature only

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