Long QT syndrome (LQTS) 1 is the most common type of inherited LQTS and is 
linked to mutations in the KCNQ1 gene. We identified a KCNQ1 missense mutation, 
KCNQ1 G325R, in an asymptomatic patient presenting with significant QT 
prolongation (QTc, 448-600ms). Prior clinical reports revealed phenotypic 
variability ranging from the absence of symptoms to syncope among KCNQ1 G325R 
mutation carriers. The present study was designed to determine the G325R ion 
channel phenotype and its association with the clinical LQTS presentation. 
Electrophysiological testing was performed using the Xenopus oocyte expression 
system. KCNQ1 G325R channels were non-functional and suppressed wild type (WT) 
currents by 71.1%. In the presence of the native cardiac regulatory ß-subunit, 
KCNE1, currents conducted by G325R and WT KCNQ1 were reduced by 52.9%. 
Co-expression of G325R and WT KCNQ1 with KCNE1 shifted the voltage-dependence of 
I(Ks) activation by 12.0mV, indicating co-assembly of mutant and WT subunits. 
The dysfunctional biophysical phenotype validates the pathogenicity of the KCNQ1 
G325R mutation and corresponds well with the severe clinical presentation 
revealed in some reports. However, the index patient and other mutation carriers 
were asymptomatic, highlighting potential limitations of risk assessment schemes 
based on ion channel data.