ClinVar Miner

Submissions for variant NM_000448.2(RAG1):c.2974A>G (p.Lys992Glu) (rs539590514)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 2
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000414066 SCV000490763 pathogenic not provided 2016-10-25 criteria provided, single submitter clinical testing The K992E variant in the RAG1 gene has been reported previously in association with Omenn syndrome (Corneo et al., 2001; Lee et al., 2014). The variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. K992E 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 within the critical C-terminal catalytic core domain that is conserved across species. Functional studies have shown that K992E significantly impairs VDJ recombination activity (Corneo et al., 2001; Lee et al., 2014). Therefore, we consider this variant to be pathogenic.
Invitae RCV000542154 SCV000638116 pathogenic Combined cellular and humoral immune defects with granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive 2017-08-09 criteria provided, single submitter clinical testing This sequence change replaces lysine with glutamic acid at codon 992 of the RAG1 protein (p.Lys992Glu). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has been reported as homozygous or in combination with a second RAG1 variant in individuals affected with Omenn syndrome (PMID: 11313270, 18442948, 24290284). ClinVar contains an entry for this variant (Variation ID: 372488). Experimental studies have shown that this missense change results in impaired VDJ recombination (PMID: 11313270, 24290284). For these reasons, this variant has been classified as Pathogenic.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.