Submissions for variant NM_000536.4(RAG2):c.302A>G (p.Asn101Ser)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	RCV004765377	SCV005375455	uncertain significance	Recombinase activating gene 2 deficiency	2024-05-13	reviewed by expert panel	curation	The c.302A>G (NM_000536.4) variant in RAG2 is a missense variant predicted to cause the substitution of Asparagine by Serine at amino acid 101 (p.Asn101Ser). The filtering allele frequency (the upper threshold of the 95% CI of 2/1112008 alleles) of the c.302A>G variant in RAG2 is 0.0000003 for European (non-Finnish) chromosomes by gnomAD v4, which is lower than the ClinGen SCID threshold (<0.0000588) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). This variant is located in the core domain, amino acids 1-383 of RAG2, which is defined as a critical functional domain by the ClinGen SCID VCEP (PMID: 26996199); PM1_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 recombinase activating gene 2 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_Supporting and PM1_Supporting (VCEP specifications version 1).
Labcorp Genetics (formerly Invitae), Labcorp	RCV003073406	SCV003476592	likely pathogenic	Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	2023-10-07	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 101 of the RAG2 protein (p.Asn101Ser). 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: 2163677). 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 disrupts the p.Asn101 amino acid residue in RAG2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 33628209; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Ambry Genetics	RCV003092447	SCV003755590	uncertain significance	Inborn genetic diseases	2021-10-06	criteria provided, single submitter	clinical testing	The c.302A>G (p.N101S) alteration is located in exon 2 (coding exon 1) of the RAG2 gene. This alteration results from a A to G substitution at nucleotide position 302, causing the asparagine (N) at amino acid position 101 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.