Submissions for variant NM_000536.4(RAG2):c.1352G>C (p.Gly451Ala)

gnomAD frequency: 0.00004  dbSNP: rs121918575

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	RCV003398501	SCV004102791	pathogenic	Recombinase activating gene 2 deficiency	2023-11-14	reviewed by expert panel	curation	The NM_000536.4:c.1352G>C variant in RAG2 is a missense variant predicted to cause the substitution of glycine by alanine at amino acid 451 (p.Gly451Ala). The variant has been identified in at least 8 individuals. Three individuals described by Dr. Jolan were homozygous for this variant (reaching the maximum of 1 pt for homozygous occurrence). One individual with Omenn Syndrome was heterozygous for this variant and a p.R229Q variant, which is classified as pathogenic according to the SCID VCEP specifications. The trans phase was not confirmed (0.5 points, PMID 32655540). One individual with CID was heterozygous for this variant, and p.M459L, a likely pathogenic variant classified by the SCID VCEP. The trans phase was not confirmed (0.25pt, PMID 26457731). Three other individuals were heterozygous for this variant and a VUS (p.I210T, PMID 31334206; p.G32E, PMID 26457731; p.T77N, PMID 18463379, 24331380, 26457731, 29772310). 1.75 points in total, PM3 is met. These three homozygous individuals described by Dr. Jolan are from the same family: 3 affected segregations, LOD score 1.81, PP1_Strong. The filtering allele frequency (the upper threshold of the 95% CI of 9/129174 alleles) of this variant in gnomAD v.2.1.1 is 0.00003418 for European (non-Finnish) chromosomes, 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 the PHD domain region, amino acids 414-487, of RAG2, defined as a critical functional domain by the ClinGen SCID VCEP (PM1). In one study (PMID 29772310), a recombination activity assay shows that the relevant activity of the p.G451A variant to wildtype RAG2 is 66.3%, which is higher than the SCID VCEP threshold (<60%) for PS3_supporting. However, in two other studies (PMID 18463379, 24331380), the relevant activity of the variant is shown to be 30% and 27.6%, respectively, which falls in the SCID VCEP threshold (>25% and <60%) for PS3_supporting (PS3_Supporting). Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met 0.5pts + SCID gene panel or exome/genome sequencing conducted 0.5pts; the total is 1 point, PP4 is met (PMID: 32655540). In summary, this variant meets the criteria to be classified as Pathogenic for SCID due to recombinase activating gene 2 deficiency. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: PM3, PM2_Supporting, PM1, PS3_Supporting, PP4, and PP1_Strong. (VCEP specifications version 1.0).
GeneDx	RCV000521152	SCV000616851	pathogenic	not provided	2023-10-27	criteria provided, single submitter	clinical testing	Published functional studies demonstrate that the variant has a detrimental effect on V(D)J recombination activity (Schuetz et al., 2008, Tirosh et al., 2019); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24331380, 30877075, 18463379, 26457731, 31334206, 29477728, 29772310, 31388879, 31980526, 21664875, 32655540, 27539235, 26996199, 32581362, 27825771, 20234091)
Pediatric Immunology Service, The Chaim Sheba Medical Center at Tel HaShomer	RCV000681597	SCV000693945	uncertain significance	Combined immunodeficiency with skin granulomas; Recombinase activating gene 2 deficiency; Inborn error of immunity	2018-03-06	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV000821298	SCV000962052	pathogenic	Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	2024-01-26	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 451 of the RAG2 protein (p.Gly451Ala). This variant is present in population databases (rs121918575, gnomAD 0.008%). This missense change has been observed in individual(s) with ‚ÄãRAG2-related conditions (PMID: 18463379, 26457731, 32581362, 32655540). ClinVar contains an entry for this variant (Variation ID: 13138). 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: 18463379, 24331380). For these reasons, this variant has been classified as Pathogenic.
NIHR Bioresource Rare Diseases, University of Cambridge	RCV001027616	SCV001190188	pathogenic	Common variable immunodeficiency	2019-01-01	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001731284	SCV001467800	likely pathogenic	Severe combined immunodeficiency disease	2020-12-30	criteria provided, single submitter	clinical testing	Variant summary: RAG2 c.1352G>C (p.Gly451Ala) results in a non-conservative amino acid change located in the Recombination Activating Protein 2, PHD domain (IPR025162) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 251488 control chromosomes (gnomAD). c.1352G>C has been reported in the literature in multiple compound heterozygous individuals affected with Combined Immunodeficiency Syndrome (e.g. Scheutz_2008, Walter_2015, Wu_2019). These data indicate that the variant may be associated with disease. Several publications report experimental evidence evaluating an impact on protein function, demonstrating reduced recombination activity or efficiency in cells expressing the variant protein (e.g. Scheutz_2008, Walter_2015, Tirosh_2019). Four other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, citing the variant as pathogenic (n=2) and uncertain significance (n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Revvity Omics, Revvity	RCV000521152	SCV003819090	pathogenic	not provided	2023-06-13	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000014020	SCV004200537	pathogenic	Combined immunodeficiency with skin granulomas	2024-02-29	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000521152	SCV005093230	pathogenic	not provided	2024-07-01	criteria provided, single submitter	clinical testing	RAG2: PM3:Very Strong, PM1, PM2, PP3, PS3:Supporting
OMIM	RCV000014020	SCV000034267	pathogenic	Combined immunodeficiency with skin granulomas	2008-05-08	no assertion criteria provided	literature only