ClinVar Miner

Submissions for variant NM_000536.4(RAG2):c.1421A>G (p.Asn474Ser)

gnomAD frequency: 0.00001  dbSNP: rs757913323
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen RCV003492116 SCV004242271 uncertain significance Recombinase activating gene 2 deficiency 2024-01-23 reviewed by expert panel curation The c.1421A>G (NM_000536.4) variant in RAG2 is a missense variant predicted to cause substitution of Asparagine by Serine at amino acid 474 (p.Asn474Ser). The filtering allele frequency (the upper threshold of the 95% CI of 2/30614 alleles) of the c.1421A>G variant in RAG2 is 0.00001082 for South Asian 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). No homozygotes have been observed in gnomAD. This variant is located in the PHD domain, amino acids 414-487 of RAG2, which is defined as a critical functional domain by the ClinGen SCID VCEP (PMID: 26996199); PM1_Moderate. However, two functional assays published in the literature showed that this variant did not show differences in contrast with wild-type, both in the quantitative assay: The recombination activity assay showed activity of this variant compared to wildtype RAG2 is 97.5% (SEM 5.9), which is higher than the SCID VCEP threshold for Moderate (<25%) or Supporting (25-60%) level of evidence (PMID 29772310) AND in the qualitative assay: The analyses had not yet identified any particular defect associated with the N474S mutation (PMID: 20234091); Thus, PS3 is not applied. Diagnostic criteria for SCID (Criterion 1: Very Low T cells <0.05x109/L + Criterion 3 No alternate explanation for low t-cell count AND <20% of CD4+ T cell have naive cell surface markers - based on CD45RA and CD45R0 count) 0.5pts + T-B-NK+ lymphocyte subset profile 0.5pts, the total is 1 point, PP4 is met (PMID: 11133745). This patient is homozygous, 0.5 pts, PM3 is met at supporting level. 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. Criteria applied: PM2_Supporting, PM1_Moderate, PP4, and PM3_Supporting (VCEP specifications version 1.0).
Pediatric Immunology Service, The Chaim Sheba Medical Center at Tel HaShomer RCV000681601 SCV000693949 likely benign 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
Labcorp Genetics (formerly Invitae), Labcorp RCV001247197 SCV001420605 uncertain significance Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive 2022-06-04 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 474 of the RAG2 protein (p.Asn474Ser). This variant is present in population databases (rs757913323, gnomAD 0.006%). This missense change has been observed in individual(s) with severe combined immunodeficiency (SCID) (PMID: 11133745). ClinVar contains an entry for this variant (Variation ID: 496633). 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 not expected to disrupt RAG2 protein function. Experimental studies have shown that this missense change does not substantially affect RAG2 function (PMID: 20234091, 26692406, 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.
Natera, Inc. RCV001834863 SCV002090366 uncertain significance Histiocytic medullary reticulosis 2020-02-19 no assertion criteria provided clinical testing

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