ClinVar Miner

Submissions for variant NM_000536.4(RAG2):c.1352G>C (p.Gly451Ala) (rs121918575)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000521152 SCV000616851 pathogenic not provided 2017-07-26 criteria provided, single submitter clinical testing The G451A variant has been reported previously in association with a RAG2-related disorder (Schuetz et al., 2008). It has also been observed in numerous individuals referred to GeneDx for testing. The variant is observed in 5/66740 (0.007%) alleles from individuals of European background in the ExAC dataset (Lek et al., 2016). This substitution occurs at a position within the PHD domain that is conserved across species; this domain has been shown to be critical for proper protein localization and stabilization as well as histone binding (Couëdel et al., 2010). Functional studies have shown G451A has a detrimental effect on V(D)J recombination activity (Schuetz et al., 2008). In summary, we consider this variant to be pathogenic.
Pediatric Immunology Service,The Chaim Sheba Medical Center at Tel HaShomer RCV000681597 SCV000693945 uncertain significance Combined immunodeficiency with skin granulomas; Recombinase activating gene 2 deficiency; Primary immunodeficiency 2018-03-06 criteria provided, single submitter research
Invitae RCV000821298 SCV000962052 uncertain significance Combined cellular and humoral immune defects with granulomas; Severe immunodeficiency, autosomal recessive, T-cell negative, B-cell negative, NK cell-positive 2019-01-02 criteria provided, single submitter clinical testing This sequence change replaces glycine with alanine at codon 451 of the RAG2 protein (p.Gly451Ala). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and alanine. This variant is present in population databases (rs121918575, ExAC 0.007%). This variant has been observed in several individuals affected with RAG2-related conditions (PMID: 18463379, 26457731). ClinVar contains an entry for this variant (Variation ID: 13138). This variant has been reported to affect RAG2 protein function (PMID: 18463379, 24331380). 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.
OMIM RCV000014020 SCV000034267 pathogenic Combined cellular and humoral immune defects with granulomas 2008-05-08 no assertion criteria provided literature only

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