Submissions for variant NM_000536.4(RAG2):c.25A>G (p.Ser9Gly)

gnomAD frequency: 0.00001  dbSNP: rs1851108332

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	RCV004765359	SCV005375467	uncertain significance	Recombinase activating gene 2 deficiency	2024-05-07	reviewed by expert panel	curation	NM_000536.4(RAG2):c.25A>G is a missense variant predicted to cause substitution of Serine by Glycine at amino acid 9 (p.Ser9Gly).This missense variant is located in the core domain (amino acids 1-383) (PM1_supporting).The highest population minor allele frequency in gnomAD v4 is 0.00003333 (2/60006) in Admixed American population which is lower than the ClinGen SCID VCEP threshold (<0.0000588) for PM2_Supporting, and therefore meets this criterion (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	RCV002047019	SCV002109827	uncertain significance	Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	2022-07-11	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 9 of the RAG2 protein (p.Ser9Gly). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RAG2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1349574). 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. 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.