Submissions for variant NM_000536.4(RAG2):c.328A>C (p.Met110Leu)

gnomAD frequency: 0.00001  dbSNP: rs193922575

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	RCV004765310	SCV005375454	uncertain significance	Recombinase activating gene 2 deficiency	2024-05-13	reviewed by expert panel	curation	The c.328A>C (NM_000536.4) variant in RAG2 is a missense variant predicted to cause the substitution of Methionine by Leucine at amino acid 110 (p.Met110Leu). The filtering allele frequency (the upper threshold of the 95% CI of 7/1180032 alleles) of the c.328A>C variant in RAG2 is 0.000001940 for European (non-Finnish) chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP 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. The variant has a mean recombination activity of 74.6% (SEM 1.8) compared to WT hRAG2, which is higher than 60% of wild-type activity (to be considered at least a supporting level). So, PS3 is not applied at any strength level. (PMID: 29772310). At least one patient in the literature seems to be a carrier of this variant (PMID: 29772310); however, the complete genetic and clinical information for the patient is not available. PP4 is not met. 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).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000030399	SCV000053068	likely pathogenic	Severe combined immunodeficiency disease	2011-08-18	criteria provided, single submitter	curation	Converted during submission to Likely pathogenic.
Pediatric Immunology Service, The Chaim Sheba Medical Center at Tel HaShomer	RCV000681580	SCV000693928	uncertain significance	Recombinase activating gene 2 deficiency; Inborn error of immunity	2018-03-06	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV001205369	SCV001376621	uncertain significance	Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	2021-08-27	criteria provided, single submitter	clinical testing	This sequence change replaces methionine with leucine at codon 110 of the RAG2 protein (p.Met110Leu). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and leucine. This variant is not present in population databases (ExAC 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: 36720). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects RAG2 function (PMID: 29772310). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.