ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.6506A>G (p.Glu2169Gly) (rs1064794183)

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 RCV000756609 SCV000568117 uncertain significance not provided 2017-02-20 criteria provided, single submitter clinical testing The E2169G variant of uncertain significance in the RYR2 gene has been previously reported in a 5 year-old male who experienced sudden cardiac death during exercise; postmortem findings of focal myocyte hypertrophy, disarray, and degree of perivascular fibrosis were suggestive of a diagnosis of HCM (Bagnall et al., 2016). This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Furthermore, E2169G 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 also occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Nevertheless, E2169G is not located in one of the three hot-spot regions of the RYR2 gene, where the majority of pathogenic missense variants occur (Medeiros- Domingo et al., 2009). Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000756609 SCV000884476 uncertain significance not provided 2017-10-16 criteria provided, single submitter clinical testing The p.Glu2169Gly variant (rs1064794183) has been reported in an individual who experienced sudden cardiac death and had post mortem findings that were consistent with hypertrophic cardiomyopathy; however, this patient also harbored a known pathogenic variant in MYH7 (Bagnall 2016). The p.Glu2169Gly variant is absent from general population databases such as 1000 Genomes, the NHLBI GO Exome Sequencing Project (ESP), and the Genome Aggregation Database (gnomAD) browser, but it is classified as a variant of uncertain significance in ClinVar (Variant ID: 419916). The glutamic acid at codon 2169 is highly conserved considering 10 species up to chicken (Alamut software v2.10.0), and computational analyses predict that this variant does affect the structure/function of the RYR2 protein (SIFT: damaging, PolyPhen2: probably damaging, MutationTaster: disease causing). However, based on the available information, the clinical significance of the p.Glu2169Gly variant cannot be determined with certainty.

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.