Submissions for variant NM_000536.4(RAG2):c.3G>A (p.Met1Ile)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	RCV003991484	SCV004809145	likely pathogenic	Recombinase activating gene 2 deficiency	2024-03-04	reviewed by expert panel	curation	NM_000536.4(RAG2):c.3G>A is a missense variant predicted to cause substitution of Methionine by Isoleucine at amino acid 1 (p.Met1Ile).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). This variant was found in trans with p.Arg229Gln (classified as pathogenic by SCID VCEP) (1 pt.) (PM3) (Invitae proband; internal lab communication).Patient with SCID (0.5 pt.), SCID gene panel conducted (0.5 pt.),T- B- NK+ by flow cytometry (0.5 pt.); total :1.5 pts (PP4) (Invitae proband; internal lab communication). 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: PVS1_Supporting,PM1_supporting,PM2_supporting,PM3,PP4 (VCEP specifications version 1).
Labcorp Genetics (formerly Invitae), Labcorp	RCV002847102	SCV003223490	pathogenic	Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	2022-07-24	criteria provided, single submitter	clinical testing	This sequence change affects the initiator methionine of the RAG2 mRNA. The next in-frame methionine is located at codon 5. For these reasons, this variant has been classified as Pathogenic. 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. This variant is not present in population databases (gnomAD no frequency).