ClinVar Miner

Submissions for variant NM_000536.4(RAG2):c.1332C>G (p.Ile444Met)

dbSNP: rs1564995662
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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 RCV003991476 SCV004809143 likely pathogenic Recombinase activating gene 2 deficiency 2024-04-01 reviewed by expert panel curation The c.1332C>G (NM_000536.4) variant in RAG2 is a missense variant predicted to cause the substitution of Isoleucine by Methionine at amino acid 444 (p.Ile444Met). This variant is absent from gnomAD v4 (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. The recombination activity assay showed activity of this variant compared to wildtype RAG2 is 2.7% (SEM 0.3), 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, the total is 1 point, PP4 is met (Same patient was reported in PMIDs: 19912631, 29772310, and 32691468). The proband (P32) is homozygous for this variant (0.5 pts; PM3_Supporting; PMID: 29772310). 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, PP4 and PM3_Supporting. (VCEP specifications version 1.0).
Pediatric Immunology Service, The Chaim Sheba Medical Center at Tel HaShomer RCV000681595 SCV000693943 uncertain significance Histiocytic medullary reticulosis; Recombinase activating gene 2 deficiency; Inborn error of immunity 2018-03-06 criteria provided, single submitter research
Baylor Genetics RCV001331311 SCV001523328 likely pathogenic Histiocytic medullary reticulosis 2019-12-18 criteria provided, single submitter clinical testing This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center RCV004527390 SCV005038823 likely pathogenic Severe combined immunodeficiency, B cell-negative 2024-03-14 criteria provided, single submitter clinical testing

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