Table 4.

Pro-arrhythmic common variants with the potential to impact clinical decision making.

Variant	Overall MAF (ExAC)	African MAF (ExAC)	Functional Evidence	Epidemiologic evidence	SIFT/PolyPhen prediction	Current ACMG classification	Amended ACMG classification	Refs.
p.Ser1103Tyr-SCN5A	0.8%	10%	LQT3-like INa GOF	Over-represented in aLQTS, SCD in SHD, and SIDS	Possibly damaging/deleterious	Benign	Functional risk allelea	[103,104]
p.Asp85Asn-KCNE1	0.9%	0.2%	LQT1/2-like IKs and/or IKr LOF	Over-represented in aLQTS	Benign/deleterious	Likely benign	Functional risk allelea	[105–108]

Abbreviations: ACMG, American College of Medical Genetics and Genomics; aLQTS, acquired long QT syndrome; ExAC, Exome Aggregation Consortium; GOF, gain-of-function; IK r , rapid component of the delayed-rectifier potassium current; I_Na , inward depolarizing sodium current; LOF, loss-of-function; LQTS, long QT syndrome; MAF, minor allele frequency; SCD, sudden cardiac death; SHD, structural heart disease; SIDS, sudden infant death syndrome.

^aIf included on genetic testing variants, these variants should be listed under a distinct “Functional Risk Allele” or “Other Reportable” category with a disclaimer such as “This variant is NOT a self-sufficient LQTS-causative mutation in isolation. However, in the setting of either disease-causative mutations or acquired QT aggravating risk factors, the presence of this particular variant can potentially increase the patient’s risk of a potentially life threatening ventricular arrhythmia.”