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

gnomAD frequency: 0.00001  dbSNP: rs193922573

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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A, has been reported in the literature and an unpublished report in individuals affected with Severe Combined Immunodeficiency Syndrome (Nicholas_2011, Dobbs_2017) as well as in a case of common variable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; Inborn error of immunity	2018-03-06	criteria provided, single submitter	research
Baylor Genetics	RCV003473151	SCV004200554	likely pathogenic	Combined immunodeficiency with skin granulomas	2023-02-21	criteria provided, single submitter	clinical testing