Long QT syndrome (LQTS) is a cardiac repolarization disorder that can lead to 
arrhythmias and sudden death. Chromosome 7-linked inherited LQTS (LQT2) is 
caused by mutations in human ether-a-go-go-related gene (HERG; KCNH2), whereas 
drug-induced LQTS is caused primarily by HERG channel block. Many common 
polymorphisms are functionally silent and have been traditionally regarded as 
benign and without physiological consequence. However, the identification of 
common nonsynonymous single nucleotide polymorphisms (nSNPs; i.e., amino-acid 
coding variants) with functional phenotypes in the SCN5A Na(+) channel and MiRP1 
K(+) channel beta-subunit have challenged this viewpoint. In this report, we 
test the hypothesis that common missense HERG polymorphisms alter channel 
physiology. Comprehensive mutational analysis of HERG was performed on genomic 
DNA derived from a population-based cohort of sudden infant death syndrome and 
two reference allele cohorts derived from 100 African American and 100 Caucasian 
individuals. Amino acid-encoding variants were considered common polymorphisms 
if they were present in at least two of the three study cohorts with an allelic 
frequency >0.5%. Four nSNPs were identified: K897T, P967L, R1047L, and Q1068R. 
Wild-type (WT) and polymorphic channels were heterologously expressed in human 
embryonic kidney cells, and biochemical and voltage-clamp techniques were used 
to characterize their functional properties. All channel types were processed 
similarly, but several electrophysiological differences were identified: 1) 
K897T current density was lower than the other polymorphic channels; 2) K897T 
channels activated at more negative potentials than WT and R1047L; 3) K897T and 
Q1068R channels inactivated and recovered from inactivation faster than WT, 
P967L, and R1047L channels; and 4) K897T channels showed subtle differences 
compared with WT channels when stimulated with an action potential waveform. In 
contrast to K897T and Q1068R channels, P967L and R1047L channels were 
electrophysiologically indistinguishable from WT channels. All HERG channels had 
similar sensitivity to block by cisapride. Therefore, some HERG polymorphic 
channels are electrophysiologically different from WT channels.