Submissions for variant NM_000536.4(RAG2):c.686G>A (p.Arg229Gln)

dbSNP: rs121917894

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	RCV003398499	SCV004102759	pathogenic	Recombinase activating gene 2 deficiency	2023-11-14	reviewed by expert panel	curation	The c.686G>A (NM_000536.4) variant in RAG2 is a missense variant predicted to cause the substitution of arginine by glycine at amino acid 229 (p.Arg229Gln). The filtering allele frequency (the upper threshold of the 95% CI of 2/113660) of the c.686G>A variant in RAG2 is 0.000002920 for European (non-Finnish) chromosomes by gnomAD v2.1.1, which is lower than the ClinGen SCID VCEP threshold (<0.0000588) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). This variant resides within a region, amino acids 1-383, of RAG2 that is defined as a critical functional domain by the ClinGen SCID VCEP (PMID: 26996199) (PM1_Supporting). At least one patient with this variant displayed: Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met (0.5pt) + T-B-NK+ lymphocyte subset profile (0.5pt) total 1 pt, which is highly specific for SCID (PP4, PMID: 30307608). The variant showed disrupted V(D)J recombination activity at 8.9% of WT-RAG2 (PMID: 29772310). Additionally, an animal model homozygous for the variant recapitulates most phenotypes associated with OS (PMID: 17476358) (PS3). The variant has been reported to segregate with SCID in 02 affected siblings from one family (Proband + one) (PP1_Supporting; PMID: 30307608). Five patients (14–18) were homozygous for the variant (reaching the maximum 1 pt) PM3_Moderate (PMID: 30307608). In summary, this variant meets the criteria to be classified as pathogenic for AR SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_Supporting, PP4, PM3_Moderate, PS3, PP1, and PM1_Supporting. (VCEP specifications version 1).
Pediatric Immunology Service, The Chaim Sheba Medical Center at Tel HaShomer	RCV000681586	SCV000693934	uncertain significance	Histiocytic medullary reticulosis; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive; Recombinase activating gene 2 deficiency; Inborn error of immunity	2018-03-06	criteria provided, single submitter	research
Invitae	RCV001049147	SCV001213181	pathogenic	Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 229 of the RAG2 protein (p.Arg229Gln). This variant is present in population databases (rs121917894, gnomAD 0.002%). This missense change has been observed in individuals with RAG2-related disease (PMID: 11133745, 11313270, 30307608). ClinVar contains an entry for this variant (Variation ID: 13130). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects RAG2 function (PMID: 8810255, 11313270). This variant disrupts the p.Arg229 amino acid residue in RAG2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11133745, 15025726, 16960852, 28747913). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Kariminejad - Najmabadi Pathology & Genetics Center	RCV001813982	SCV001755546	likely pathogenic	not provided	2021-07-10	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003473086	SCV004200543	pathogenic	Combined immunodeficiency with skin granulomas	2023-09-08	criteria provided, single submitter	clinical testing
OMIM	RCV000014010	SCV000034257	pathogenic	Severe combined immunodeficiency, B cell-negative	2001-05-01	no assertion criteria provided	literature only
OMIM	RCV000014011	SCV000034258	pathogenic	Histiocytic medullary reticulosis	2001-05-01	no assertion criteria provided	literature only
Natera, Inc.	RCV000014011	SCV001456096	pathogenic	Histiocytic medullary reticulosis	2020-09-16	no assertion criteria provided	clinical testing