Submissions for variant NM_000536.4(RAG2):c.53G>T (p.Gly18Val)

gnomAD frequency: 0.00001  dbSNP: rs1851106893

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	RCV004765346	SCV005375463	uncertain significance	Recombinase activating gene 2 deficiency	2024-05-01	reviewed by expert panel	curation	NM_000536.4(RAG2):c.53G>T is a missense variant predicted to cause substitution of Glycine by Valine at amino acid 18 (p.Gly18Val).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 0.00002415(1/41408 alleles) in African/African American population, which is lower than the ClinGen SCID VCEP threshold (<0.0000588) for PM2_Supporting, meeting 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	RCV001063225	SCV001228062	pathogenic	Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	2023-09-08	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 18 of the RAG2 protein (p.Gly18Val). For these reasons, this variant has been classified as Pathogenic. 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 expected to disrupt RAG2 protein function. ClinVar contains an entry for this variant (Variation ID: 857533). This missense change has been observed in individual(s) with clinical features of severe combined immunodeficency (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).