ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.1396C>G (p.Pro466Ala) (rs376612295)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000148835 SCV000050609 uncertain significance Polymorphic ventricular tachycardia 2018-04-05 criteria provided, single submitter research
GeneDx RCV000481565 SCV000565508 uncertain significance not provided 2018-12-27 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the RYR2 gene. The P466A variant has been reported previously in one individual with aborted cardiac arrest and a family history of multiple people with sudden cardiac death (Tester et al., 2005). This variant has also been reported in a patient with a normal QT interval and left ventricular hypertrophy who was referred for whole exome sequencing (Ng et al., 2013). The P466A variant was not observed with any significant frequency in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The P466A variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some 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. Finally, the P466A variant is located in one of the three hot-spot regions of the RYR2 gene, where the majority of pathogenic missense mutations occur (Medeiros-Domingo et al., 2009). However, despite the fact that several publications describe an association between the P466A variant in the RYR2 gene and arrhythmia, family history information and segregation data was not provided. Furthermore, no functional studies for the this variant have been performed.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Color RCV001175622 SCV001339291 uncertain significance Cardiomyopathy 2020-02-25 criteria provided, single submitter clinical testing
Invitae RCV001241877 SCV001414929 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2019-05-14 criteria provided, single submitter clinical testing This sequence change replaces proline with alanine at codon 466 of the RYR2 protein (p.Pro466Ala). The proline residue is highly conserved and there is a small physicochemical difference between proline and alanine. This variant is present in population databases (rs376612295, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed in individuals affected with aborted cardiac arrest or catecholaminergic polymorphic ventricular tachycardia (PMID: 16188589, 28404607, 29555771). ClinVar contains an entry for this variant (Variation ID: 161383). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
CSER _CC_NCGL, University of Washington RCV000148835 SCV000190576 uncertain significance Polymorphic ventricular tachycardia 2014-06-01 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.