This resource was built and is maintained by the Kroncke lab at the Vanderbilt University Medical Center (Kroncke lab website). Please send any questions or comments to brett.m.kroncke.1@vumc.org.

KCNH2 (also known as the human ether a-go-go related gene, hERG) encodes a 1159 amino acid protein, KV11.1, a voltage-gated potassium channel in the heart. Coding-altering variants in KCNH2 have been mostly linked to the heart arrhythmias, Long QT Syndrome Type 2 (LQT2 https://www.omim.org/entry/613688) and Short QT Syndrome (SQT1; https://www.omim.org/entry/609620). Loss-of-function variants in KCNH2 are associated LQT2 and gain-of-function variants are associated with short QT Syndrome. The risk of sudden cardiac death from these conditions can often be prevented with drug therapy or implantation of a defibrillator. KCNH2 variants are often studied in vitro in heterologous expression systems using patch clamp electrophysiology. One challenge with KCNH2-related diseases is the issue of incomplete penetrance—only a fraction of variant carriers have disease phenotypes. Therefore, we believe that curating published patient data and in vitro functional data can contribute to a better understanding of each variant’s disease risk.

The dataset described on this website is a dataset of patient data and in vitro patch clamp data. This dataset was first described in Kozek et al. (to be published soon). The data were curated from a comprehensive literature review from papers written about KCNH2 (or Kv11.1, the protein product of KCNH2). In addition, five centers that hold cardiology clinics and conduct research gathered clinical phenotypes and genotypes for individuals heterozygous for KCNH2 variants, including Unité de Rythmologie, Centre de Référence Maladies Cardiaques Héréditaires, Service de Cardiologie, Hôpital Bichat, Paris, France; the Center for Cardiac Arrhythmias of Genetic Origin Istituto Auxologico Italiano IRCCS, Milan, Italy; Shiga University of Medical Science Department of Cardiovascular and Respiratory Medicine, Shiga, Japan; National Cerebral and Cardiovascular Center, Osaka, Japan; Nagasaki University, Nagasaki, Japan. We quantified the number of carriers presenting with and without disease for 871 reported KCNH2 variants (an additional 266 KCNH2 inframe/missense variants coming from the international cohort). For ### variants, data were also available for six KV11.1 electrophysiologic parameters: steady state maximum current, peak tail current, steady state V1/2 of activation and inactivation, recovery from inactivation, and deactivation time. All six of these parameters are found in the literature collected homozygously and heterozygously. We found that heterozygously collected peak tail current significantly associated with LQT2 (p < 0.001, rho = -0.62, Spearman’s rank test). This relationship persisted across the literature and cohort datasets.

The functional parameters available in this website are Steady state (S.S.) and peak tail current are relative % to wildtype (100% being no different from wildtype). V0.5 act/inact are the voltages at which half of the maximal current is reached during an activation and inactivation protocol, each is in units of mV and relative to wildtype. Recovery from inactivation (Rec. inact.) and deactivation time (Deactivation) are the ratio of characteristic time constants with wildtype (unitless). These functional parameters are all referenced to that of wild type by either percent (peak current, recovery from inactivation, or late current) or relative change (V1/2 activation/inactivation; mV).