ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.12272C>T (p.Ala4091Val) (rs794728783)

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 RCV000182811 SCV000235197 uncertain significance not specified 2017-03-03 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the RYR2 gene. The A4091V variant has been reported in association with CPVT, however no segregation data were available (Hayashi et al., 2009; Jabbari et al., 2013). The A4091V variant is not observed in large population cohorts (Lek et al., 2016; Exome Variant Server). This substitution occurs at a position that is conserved through mammals, and in silico analysis predicts this variant is probably damaging to the protein structure/function. A4091V is located within one of the three hot-spot regions, where the majority of pathogenic variants in RYR2 gene occur (Medeiros-Domingo et al., 2009). Furthermore, a missense variant at the same residue (A409T) and one in a nearby residue (N4097S) have been reported in the Human Genome Mutation Database in association with CPVT (Stenson et al., 2014). Nevertheless, the A4091V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Thus, this variant lacks observation in a significant number of affected individuals, segregation data, and functional evidence, which would further clarify its pathogenicity.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Medical Research Institute,Tokyo Medical and Dental University RCV000190127 SCV000221977 uncertain significance Long QT syndrome no assertion criteria provided research

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.