RYR2 and catecholaminergic polymorphic ventricular tachycardia: RYR2-associated CPVT variants often cluster in four mutational hotspots reported by Priori and Chen based on aggregate data from the literature: Hotspot I (amino acids 44-466; ~18% of mutations) located in the N-terminus domain (amino acid 77-446); Hotspot II (2246-2534; ~19% of mutations) located in the central domain (2246-2534); Hotspot III (3778-4201; ~22% of mutations) and Hotspot IV (4497-4959; ~22% of mutations) located in the C-terminus domain (3778-4959) [49,97].