ClinVar Miner

Submissions for variant NM_000536.4(RAG2):c.303T>A (p.Asn101Lys)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV003017779 SCV003304554 likely pathogenic Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive 2022-01-17 criteria provided, single submitter clinical testing This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 101 of the RAG2 protein (p.Asn101Lys). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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 missense change has been observed in individual(s) with severe combined immunodeficiency (PMID: 33628209; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004700882 SCV005203425 uncertain significance not specified 2024-07-18 criteria provided, single submitter clinical testing Variant summary: RAG2 c.303T>A (p.Asn101Lys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251442 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.303T>A in individuals affected with Severe Combined Immunodeficiency and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 2087156). Based on the evidence outlined above, the variant was classified as uncertain significance.

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