ClinVar Miner

Submissions for variant NM_000536.4(RAG2):c.104G>C (p.Gly35Ala) (rs148508754)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000030395 SCV000053064 likely pathogenic Severe combined immunodeficiency disease 2011-08-18 criteria provided, single submitter curation Converted during submission to Likely pathogenic.
Pediatric Immunology Service,The Chaim Sheba Medical Center at Tel HaShomer RCV000681571 SCV000693919 uncertain significance Atypical severe combined immunodeficiency due to complete RAG1/2 deficiency; Recombinase activating gene 2 deficiency; Primary immunodeficiency 2018-03-06 criteria provided, single submitter research
Invitae RCV000819784 SCV000960465 uncertain significance Combined cellular and humoral immune defects with granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive 2018-12-18 criteria provided, single submitter clinical testing This sequence change replaces glycine with alanine at codon 35 of the RAG2 protein (p.Gly35Ala). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and alanine. This variant is present in population databases (rs148508754, ExAC 0.001%). This variant has been observed in several individuals affected with combined immunodeficiency, hyper IgM syndrome and recurrent infections (PMID: 24174341, 28769923, 26457731). ClinVar contains an entry for this variant (Variation ID: 36716). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Gly35 amino acid residue in RAG2. Other variant(s) that disrupt this residue have been observed in individuals with RAG2-related conditions (PMID: 15025726), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. 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.

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