ClinVar Miner

Submissions for variant NM_000536.4(RAG2):c.1309G>A (p.Glu437Lys) (rs193922573)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000030397 SCV000053066 uncertain significance not specified 2018-05-10 criteria provided, single submitter clinical testing Variant summary: RAG2 c.1309G>A (p.Glu437Lys) results in a conservative amino acid change located in the Recombination activating protein 2 PHD domain (IPR025162) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 246216 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in RAG2 causing Severe Combined Immunodeficiency Syndrome (1.6e-05 vs 7.10e-04), allowing no conclusion about variant significance. The variant, c.1309G>A, has been reported in the literature and an unpublished report in individuals affected with Severe Combined Immunodeficiency Syndrome (Nicholas_2011, Dobbs_2017) as well as in a case of common variable immunodeficiency (CVID) (Yashar_2016). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
GeneDx RCV000413563 SCV000491369 likely pathogenic not provided 2015-12-21 criteria provided, single submitter clinical testing The E437K variant in the RAG2 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The E437K variant was not observed at any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The E437K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. A missense variant in nearby residue (K440N) has been reported in the Human Gene Mutation Database in association with Omenn syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. The E437K variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
Pediatric Immunology Service,The Chaim Sheba Medical Center at Tel HaShomer RCV000681592 SCV000693940 uncertain significance Atypical severe combined immunodeficiency due to complete RAG1/2 deficiency; Recombinase activating gene 2 deficiency; Primary immunodeficiency 2018-03-06 criteria provided, single submitter research

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