The variant is classified as a variant of unknown significance because its contribution to a cardiac phenotype has not been confirmed.
In a 16-year-old Japanese boy with prolonged QT interval (see 192500) discovered on a routine annual health examination, who had no history of faintness or syncope, Ohno et al. (2009) identified heterozygosity for a c.10A-G transition in the KCNE3 gene, resulting in a thr4-to-ala (T4A) substitution. The patient's resting ECG showed bradycardia for age (48 bpm) and QT prolongation (QTc = 525 ms). He was also found to carry a variant in the KCNH2 gene (G572S) known to be associated with LQT2 (see 613688). There was no family history of syncope or sudden death. His asymptomatic mother and sister, who both exhibited prolongation of QTc on ECG (520 ms and 560 ms), were also heterozygous for the same 2 variants. Ohno et al. (2009) also detected the T4A KCNE3 variant in a 68-year-old Japanese woman who experienced hypokalemia-induced torsade de pointes at age 60 years. Her asymptomatic daughter, who had borderline QTc prolongation on ECG, also carried the T4A variant. Electrophysiologic analysis showed that the T4A KCNE3 variant did not have a statistically significant effect on current density or deactivation kinetics. The KCNE3 T4A variant was not found in 200 healthy Japanese individuals from the general population.
In a 55-year-old Japanese man with syncope and a Brugada-like pattern on his electrocardiogram (see 613119), Nakajima et al. (2012) identified heterozygosity for the T4A mutation in the KCNE3 gene. Beginning in his fourth decade of life, the patient had several episodes of syncope under specific conditions, such as standing up after drinking alcohol. There was no family history of sudden cardiac death. ECG showed saddle-type ST segment elevation in the right precordial leads, with a QTc of 414 ms. After provocation with pilsicainide, a coved-type ST segment elevation appeared in the right precordial leads at the second intercostal space. Upon electrophysiologic assessment, nonsustained polymorphic ventricular tachycardia was induced, but not ventricular fibrillation. Head-up tilt test provoked hypotension and bradycardia, followed by syncope, and the patient was diagnosed as having neurally mediated (vasovagal) syncope (see 609289). Functional analysis in CHO cells showed significantly increased peak current densities with the mutant compared to wildtype channels, but there was no effect on time to peak or inactivation kinetics.
