ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.12298G>A (p.Val4100Ile) (rs758785338)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 1
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182814 SCV000235200 likely pathogenic not provided 2013-11-22 criteria provided, single submitter clinical testing p.Val4100Ile (GTC>ATC): c.12298 G>A in exon 90 of the RYR2 gene (NM_001035.2). The Val4100Ile variant in the RYR2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. The Val4100Ile variant is a conservative amino acid substitution as these residues share similar properties, and are least likely to impact secondary structure. However, the Val4100 residue is conserved across species. In silico analysis predicts Val4100Ile is probably damaging to the protein structure/function. Mutations in nearby residues (Ala4091Thr, Ala4091Val, Asn4097Ser, Asn4104Ile, Asn4104Lys, Leu4105Phe) have been reported in association with arrhythmia, further supporting the functional importance of this region of the protein. Val4100Ile is located in the channel region, a mutation hotspot region of the RYR2 gene (Medeiros-Domingo A et al., 2009). Furthermore, the Val4100Ile variant was not observed in approximately 6200 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, while Val4100Ile is a good candidate for a disease-causing mutation, we cannot unequivocally determine the clinical significance of this variant. The variant is found in CPVT panel(s).

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.