ClinVar Miner

Submissions for variant NM_000536.4(RAG2):c.13A>T (p.Met5Leu)

dbSNP: rs1851109238
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen RCV004765365 SCV005375453 uncertain significance Recombinase activating gene 2 deficiency 2024-04-29 reviewed by expert panel curation NM_000536.4(RAG2):c.13A>T is a missense variant predicted to cause substitution of Methionine by Leucine at amino acid 5 (p.Met5Leu).This missense variant is located in the core domain (amino acids 1-383) (PM1_supporting). The variant is absent in gnomAD v4 (PM2_supporting). To our knowledge, this variant has not been reported in the literature in individuals affected with RAG2 related conditions or in functional studies. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to RAG2 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM1_supporting, PM2_supporting (VCEP specifications version 1).
Labcorp Genetics (formerly Invitae), Labcorp RCV002023203 SCV002303712 uncertain significance Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive 2022-08-09 criteria provided, single submitter clinical testing 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RAG2 protein function. ClinVar contains an entry for this variant (Variation ID: 1512780). This variant has not been reported in the literature in individuals affected with RAG2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 5 of the RAG2 protein (p.Met5Leu).

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