About the Variant Browser
The Kroncke Lab curates and shares harmonised clinical, structural, and functional data for arrhythmia-associated genes to enable transparent penetrance estimation and variant interpretation.
Questions or contributions? Email brett.m.kroncke.1@vumc.org or visit the Kroncke Lab website.
Our mission
Sequencing a genome now costs less than many routine clinical tests, yet the interpretive gap for rare variants persists. We develop statistical models that combine variant location, functional data, and in silico predictors to estimate penetrance before extensive clinical observation.
Our penetrance workflow, described in Kroncke et al. 2020, Kozek et al. 2021, O’Neill et al. 2023, and O’Neill et al. 2024, helps clinicians and researchers assess risk, prioritise follow-up, and improve variant reclassification.
How to use the browser
- Filter: Use Search Builder and Search Panes to focus on variant subsets of interest.
- Download: Export filtered results to CSV for further analysis.
- Compare: Charts summarise carrier counts and penetrance distributions for quick context.
KCNH2 background
The 1,159 amino acid voltage-gated potassium channel encoded by KCNH2 (KV11.1) is central to cardiac repolarisation. Coding variants are linked to Long QT Syndrome type 2 (LQT2) and Short QT Syndrome (SQT1). Loss-of-function variants predispose to LQT2, while gain-of-function variants are associated with SQT1.
Functional characterisation commonly leverages heterologous systems with patch clamp electrophysiology. Use the dataset navigation menu to open the full KCNH2 variant table.
Dataset highlights
- Clinical phenotypes and genotypes curated from global arrhythmia cohorts.
- Electrophysiology metrics such as steady state current, activation/inactivation V1/2, and recovery kinetics.
- First reported in Kozek et al. 2021 with 871 variants and expanded cohort contributions.
KCNQ1 background
KCNQ1 encodes a 676 amino acid transmembrane protein that partners with KCNE1 to produce the IKs current, a slow component of cardiac repolarisation. Heterozygous variants are associated with Long QT Syndrome type 1, Short QT Syndrome, and Atrial Fibrillation, while homozygous loss of function causes Jervell and Lange-Nielsen Syndrome.
Beyond cardiac phenotypes, KCNQ1 influences diverse tissues including the ear and digestive tract. The dataset aggregates literature and clinical network observations to capture 629 missense and in-frame variants among 10,389 heterozygotes.
Dataset highlights
- Integrates gnomAD carrier frequencies as unaffected controls.
- Captures structural hotspots that inform penetrance priors.
- Summarised in O’Neill et al. 2023, Genetics in Medicine.
SCN5A background
SCN5A encodes NaV1.5, the primary cardiac voltage-gated sodium channel. Missense variants are implicated in Brugada Syndrome type 1 (BrS1), Long QT Syndrome type 3 (LQT3), dilated cardiomyopathy, conduction disease, and Sick Sinus Syndrome. Loss-of-function variants tend to underlie BrS1, while gain-of-function variants drive LQT3.
Our dataset combines literature reviews and international cohorts to track 1,712 variants with carrier phenotypes, plus functional measurements of peak and late current, activation/inactivation thresholds, and recovery kinetics.
Dataset highlights
- Penetrance estimates synthesise variant priors with observed carriers.
- Functional annotations distinguish loss-, partial loss-, mild loss-, and gain-of-function signatures.
- Updated through January 2020 and described in Kroncke & Glazer et al. 2018 and Kroncke et al. 2020.