ClinVar Miner

Submissions for variant NM_000536.4(RAG2):c.1A>G (p.Met1Val)

dbSNP: rs1564997814
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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 RCV004765337 SCV005375459 uncertain significance Recombinase activating gene 2 deficiency 2024-06-14 reviewed by expert panel curation NM_000536.4(RAG2):c.1A>G is a missense variant predicted to cause substitution of Methionine by Valine at amino acid 1 (p.Met1Val). This sequence change affects the initiator methionine of the RAG2 mRNA. The next possible initiation codon is at codon 5. This region does not contain known pathogenic/likely pathogenic variants (PVS1_Supporting). This missense variant is located in the core domain (amino acids 1-383) (PM1_supporting). The variant is absent in gnomAD v4 (PM2_supporting). Female with SCID (0.5 pt.), genome sequencing conducted (0.5 pt.)& T-B-NK+ lymphocyte subset profile (0.5 pt.) (Total :1.5 pts) (PP4 met) (PMID: 31031743). The patient was found compound heterozygous for c.1A>G; p.M1V and c.1403_1406delATCT (not evaluated by SCID VCEP yet) (PMID: 31031743) (PM3 not evaluated). 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: PVS1_Supporting,PM1_supporting, PM2_supporting,PP4 met(VCEP specifications version 1).
Labcorp Genetics (formerly Invitae), Labcorp RCV003768299 SCV004585492 pathogenic Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive 2023-03-18 criteria provided, single submitter clinical testing Disruption of the initiator codon has been observed in individual(s) with severe combined immunodeficiency (PMID: 31031743; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. For these reasons, this variant has been classified as Pathogenic. This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the RAG2 mRNA. The next in-frame methionine is located at codon 5.

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