ClinVar Miner

Submissions for variant NM_000536.4(RAG2):c.218G>A (p.Arg73His)

gnomAD frequency: 0.00002  dbSNP: rs762407838
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Pediatric Immunology Service, The Chaim Sheba Medical Center at Tel HaShomer RCV000681577 SCV000693925 likely pathogenic Histiocytic medullary reticulosis; Atypical severe combined immunodeficiency due to complete RAG1/2 deficiency; Recombinase activating gene 2 deficiency; Inborn error of immunity 2018-03-06 criteria provided, single submitter research
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000626255 SCV000746908 uncertain significance Histiocytic medullary reticulosis 2017-12-18 criteria provided, single submitter clinical testing
GreenArray Genomic Research & Solutions of Accurate Diagnostic Private Limited RCV001815003 SCV002061918 uncertain significance Immunodeficiency 104 criteria provided, single submitter clinical testing This variant has been reported in compound heterozygous state along with a termination variant in an affected patient (Asai E et al).Functional studies revealed that the variant exhibited 59% of activity when compared to wild type. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Arg73His in RAG2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The p.Arg73His variant is novel (not in any individuals) in 1000 Genomes and is present in 0.0007% individuals in gnomAD database. For the above reasons it has been classified as Uncertain Significance.
Invitae RCV002530946 SCV003439727 pathogenic Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive 2023-12-25 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 73 of the RAG2 protein (p.Arg73His). This variant is present in population databases (rs762407838, gnomAD 0.008%). This missense change has been observed in individuals with severe combined immunodeficiency (PMID: 21131235, 26515615). ClinVar contains an entry for this variant (Variation ID: 496620). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects RAG2 function (PMID: 26515615, 29772310). This variant disrupts the p.Arg73 amino acid residue in RAG2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20603253, 24481607, 26476733; Invitae). 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 RCV003471947 SCV004200536 likely pathogenic Combined immunodeficiency with skin granulomas 2024-01-17 criteria provided, single submitter clinical testing

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