Submissions for variant NM_000536.4(RAG2):c.95G>T (p.Gly32Val)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	RCV003991483	SCV004809140	uncertain significance	Recombinase activating gene 2 deficiency	2024-02-20	reviewed by expert panel	curation	NM_000536.4(RAG2):c.95G>T is a missense variant predicted to cause substitution of Glycine by Valine at amino acid 32 (p.Gly32Val).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	RCV002586200	SCV002938398	likely pathogenic	Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	2022-03-24	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 32 of the RAG2 protein (p.Gly32Val). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Gly32 amino acid residue in RAG2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26457731, 33628209). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. 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).