ClinVar Miner

Submissions for variant NM_000536.4(RAG2):c.1338C>G (p.Cys446Trp)

gnomAD frequency: 0.00001  dbSNP: rs1564995660
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Total submissions: 3
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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 RCV003492115 SCV004242269 likely pathogenic Recombinase activating gene 2 deficiency 2024-01-23 reviewed by expert panel curation The c.1338C>G (NM_000536.4) variant in RAG2 is a missense variant predicted to cause substitution of Cysteine by Tryptophan at amino acid 446 (p.Cys446Trp). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). 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. The recombination activity assay showed activity of this variant compared to wildtype RAG2 is 2.9% (SEM 0.1), which is lower than the SCID VCEP threshold (<25%) for PS3_Moderate, meeting this criterion (PS3_Moderate, PMID 29772310). Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met 0.5 pts + T-B-NK+ lymphocyte subset profile 0.5 pts, PP4 is met (PMID: 20234091). A second report describes one homozygous patient, 0.5 pts, PM3_Supporting (PMID: 31973905). In summary, this variant meets the criteria to be classified as Likely 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_Moderate, PS3_Moderate, PM3_Supporting, and PP4 (VCEP specifications version 1.0).
Pediatric Immunology Service, The Chaim Sheba Medical Center at Tel HaShomer RCV000681596 SCV000693944 likely pathogenic Recombinase activating gene 2 deficiency; Inborn error of immunity 2018-03-06 criteria provided, single submitter research
3billion RCV002283492 SCV002572554 uncertain significance Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive 2022-09-01 criteria provided, single submitter clinical testing The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.80; 3Cnet: 0.93). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with RAG2-related disorder (ClinVar ID: VCV000496629/ PMID: 20234091). However, the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline.

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