Ryanodine receptor 2 mutations in catecholaminergic polymorphic ventricular tachycardia: From molecular mechanisms to precision medicine

Table 1 Common ryanodine receptor 2 mutations and clinical characteristics

Mutation	Domain	Functional effect	Clinical severity1	Age of onset2	Penetrance3	β-blocker response	SOICR threshold4
R2474S	Central	Reduced threshold for Ca2+-induced Ca2+ release	Moderate-severe	Childhood-adolescence	80%-90%	Variable	Significantly reduced
N2386I	Central	Reduced threshold with enhanced sensitivity	Severe	Early childhood	95%	Poor	Markedly reduced
R4497C	Transmembrane	Channel structural instability	Mild-moderate	Adolescence-early adulthood	60%-70%	Good	Moderately reduced
S2246 L	Handle	Increased channel open probability	Moderate	Childhood	75%-85%	Good	Reduced
T2504M	Central	Enhanced SR Ca2+ leak with impaired termination	Severe	Early childhood	90%-95%	Variable	Severely reduced

¹Based on frequency of arrhythmic events and exercise tolerance.

²Typical age range when symptoms first appear.

³Percentage of mutation carriers who develop clinical manifestations.

⁴Relative threshold for store overload-induced calcium release activation.

SOICR: Store-overload-induced Ca²⁺ release; SR: Sarcoplasmic reticulum.