ClinVar Miner

Submissions for variant NM_000536.4(RAG2):c.685C>T (p.Arg229Trp)

gnomAD frequency: 0.00001  dbSNP: rs765298019
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Total submissions: 5
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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 RCV003991475 SCV004809146 pathogenic Recombinase activating gene 2 deficiency 2024-04-01 reviewed by expert panel curation The c.685C>T (NM_000536.4) variant in RAG2 is a missense variant predicted to cause the substitution of Arginine by Tryptophan at amino acid 229 (p.Arg229Trp). The filtering allele frequency (the upper threshold of the 95% CI of (11/1180024 alleles) is 0.000005000 in gnomad v4 for the European (non-Finnish) population, which is lower than the ClinGen SCID VCEP threshold (<0.0000588) for PM2_Supporting, meeting this criterion (PM2_Supporting). No homozygous has been described. 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 recombination activity assay showed activity of this variant compared to wildtype RAG2 is 10.5% (SEM 0.5), which is lower than the SCID VCEP threshold (<25%) for PS3_Moderate, meeting this criterion (PS3_Moderate, PMID 29772310). The variant has been reported to segregate in two affected family members (Proband + 1) (PP1); (Proband 30a and 30b, PMID: 11133745). At least 9 probands were reported in the literature carrying this variant. 8 of them were homozygous, reaching the maximum of 1 point for homozygous occurrence. Also, 1 proband is compound heterozygous for paternal Arg229Trp and maternal Gly95Arg, which is likely pathogenic according to SCID VCEP specifications, as phase is confirmed; 1 point—a total of 2 points, PM3_Strong. Proband 24 presents: *Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met 0.5pts + *T-B-NK+ lymphocyte subset profile 0.5pts; total 1pt, PP4 is met (PMID: 11133745). In summary, this variant meets the criteria to be classified as Pathogenic 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_Supporting, PS3_Moderate, PP1, PM3_Strong, and PP4 (VCEP specifications version 1.0).
Pediatric Immunology Service, The Chaim Sheba Medical Center at Tel HaShomer RCV000681587 SCV000693935 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
Labcorp Genetics (formerly Invitae), Labcorp RCV001042148 SCV001205814 pathogenic Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive 2023-10-12 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 229 of the RAG2 protein (p.Arg229Trp). This variant is present in population databases (rs765298019, gnomAD 0.002%). This missense change has been observed in individuals with RAG2-related disease (PMID: 11133745, 15025726, 16960852, 28747913). ClinVar contains an entry for this variant (Variation ID: 496624). 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.Arg229 amino acid residue in RAG2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11133745, 24144642, 26915675). 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.
Baylor Genetics RCV003471948 SCV004200553 pathogenic Combined immunodeficiency with skin granulomas 2023-04-18 criteria provided, single submitter clinical testing
Natera, Inc. RCV001273255 SCV001456097 pathogenic Histiocytic medullary reticulosis 2020-09-16 no assertion criteria provided clinical testing

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