Classification and correlation of RYR2 missense variants in individuals with catecholaminergic polymorphic ventricular tachycardia reveals phenotypic relationships.

Journal of Human Genetics
Damilola OlubandoWilliam G Newman

Abstract

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is predominantly caused by heterozygous missense variants in the cardiac ryanodine receptor, RYR2. However, many RYR2 missense variants are classified as variants of uncertain significance (VUS). We systematically re-evaluated all RYR2 variants in healthy individuals and those with CPVT or arrhythmia using the 2015 American College of Medical Genomics guidelines. RYR2 variants were identified by the NW Genomic Laboratory Hub, from the published literature and databases of sequence variants. Each variant was assessed based on minor allele frequencies, in silico prediction tools and appraisal of functional studies and classified according to the ACMG-AMP guidelines. Phenotype data was collated where available. Of the 326 identified RYR2 missense variants, 55 (16.9%), previously disease-associated variants were reclassified as benign. Application of the gnomAD database of >140,000 controls allowed reclassification of 11 variants more than the ExAC database. CPVT-associated RYR2 variants clustered predominantly between amino acid positions 3949-4332 and 4867-4967 as well as the RyR and IP3R homology-associated and ion transport domains (p < 0.005). CPVT-associated RYR2 va...Continue Reading

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Clinvar
FATHMM
Mutation Taster
PhyloP
Mutation assessor
GraphPad prism
PolyPhen
Mutation Mapper
GERP
SiPhy

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