Arrhythmia & Heart Rhythm

Intergenic 4q25 variant near KCNN3 and PITX2 that confers an independent risk of atrial fibrillation by modulating atrial electrophysiology

Regulatory variant upstream of NOS1AP (CAPON) associated with QT interval prolongation via altered nNOS-mediated cardiac repolarization; the G allele extends QTc by ~3.6 ms per copy

Intronic ZFPM1 variant tagging reduced GATA cofactor regulatory activity; the C allele associates with lower mean corpuscular hemoglobin, altered plateletcrit, elevated reticulocyte count, and minor PR interval prolongation

Intronic variant in ZFPM1 (FOG1), the master transcriptional co-regulator of megakaryopoiesis; the A allele is the strongest common GWAS signal for elevated platelet count (p=1×10⁻⁵⁰) and plateletcrit, with implications for thrombotic tendency and cardiovascular risk

Common KCNH2 missense variant that alters hERG potassium channel kinetics, shortens cardiac repolarization in homozygotes, and modifies susceptibility to QT-prolonging drugs and arrhythmias

Ultra-rare KCNH2 missense variant substituting asparagine for lysine at position 595 in the C-linker domain, associated with congenital long QT syndrome type 2 through impaired hERG channel function

Intergenic variant at chromosome 4q25 near PITX2 — the strongest GWAS signal for atrial fibrillation susceptibility; the T allele reduces PITX2 expression in the left atrium, impairing suppression of a pacemaker program that normally prevents the left atrium from generating ectopic impulses

Common intronic variant in the FOG1 megakaryocyte transcription factor gene that modulates platelet count and reactivity through altered GATA-1/FOG1 transcriptional output during thrombopoiesis

Rare gain-of-function missense variant in the cardiac sodium channel Nav1.5 causing Long QT syndrome type 3 through persistent late sodium current and prolonged ventricular repolarization

Rare loss-of-function missense variant in the cardiac sodium channel Nav1.5 causing congenital sick sinus syndrome through altered channel inactivation kinetics; also reported in association with Brugada syndrome and dilated cardiomyopathy

Intronic variant in PIEZO1, the endothelial mechanosensory ion channel that senses blood flow shear stress; the G allele is associated with elevated varicose vein risk in genome-wide studies of over 800,000 individuals

Intergenic variant near KCNH2 (hERG potassium channel) at 7q36.1 that shortens QTc interval and confers ~2.4x increased risk of early-onset lone atrial fibrillation in homozygous T allele carriers

Intergenic variant at 7q36.1 near KCNH2 (hERG potassium channel) that modulates QTc interval duration; C allele shortens QTc by ~1.4–1.8 ms per allele and tags an independent repolarization-modifying signal at the KCNH2 locus

Pathogenic in-frame 3-bp deletion in the KCNQ1 potassium channel that removes phenylalanine-340 from the S6 transmembrane domain, impairing cardiac repolarization and causing Long QT syndrome type 1 with risk of torsades de pointes and sudden cardiac death

Nonsense mutation in the cardiac IKs potassium channel causing premature protein truncation; heterozygous carriers develop Romano-Ward long QT syndrome type 1 with risk of life-threatening arrhythmia, while homozygous carriers develop Jervell and Lange-Nielsen syndrome with congenital deafness

Pathogenic nonsense variant (Q359X) in KCNQ1 that truncates the IKs potassium channel, causing Long QT syndrome type 1 with markedly increased risk of life-threatening arrhythmias during exercise and emotional stress

Pathogenic 4bp frameshift deletion in KCNQ1 that eliminates the IKs potassium channel's C-terminal domain, causing autosomal dominant Long QT syndrome type 1 with characteristic exercise- and swimming-triggered cardiac events

Coding VNTR in exon 18 of the circadian clock gene PER3; 4-repeat vs 5-repeat alleles alter chronotype, cardiac autonomic balance, and circadian patterning of cardiovascular events

Intergenic variant upstream of KCNK9 (TASK3 potassium channel) associated with elevated systolic blood pressure; the T allele was identified as a suggestive hypertension signal in the Wellcome Trust GWAS and replicated in Korean and European cohorts. KCNK9 encodes a background K⁺ channel in adrenal zona glomerulosa cells that regulates aldosterone secretion.