rs1805123 — KCNH2 K897T

KCNH2 K897T — The hERG Channel Polymorphism That Rewires Cardiac Repolarization

The hERG channel (Kv11.1)¹¹ hERG channel (Kv11.1)
the voltage-gated potassium channel encoded by KCNH2 (human ether-à-go-go-related gene), responsible for the rapid delayed rectifier potassium current IKr that drives phase 3 cardiac repolarization is one of the most drug-sensitive ion channels in the human heart. Its blockade — a frequent off-target effect of drugs across dozens of pharmacological classes — is the dominant mechanism of acquired long QT syndrome. Within this gene, the K897T variant (rs1805123) is the most common nonsynonymous polymorphism, present in approximately 20% of European-ancestry alleles. It substitutes threonine for lysine at position 897 in the channel's C-terminal domain and measurably alters how the channel behaves — both at baseline and under pharmaceutical pressure.

The Mechanism

The lysine-to-threonine substitution at position 897 sits in the C-terminal intracellular domain of Kv11.1, a region involved in channel trafficking, tetramerization, and interaction with regulatory subunits. Functional studies in heterologous expression systems show that the T897 isoform (the G allele on the plus strand) produces lower current density than the K897 wild type, activates at more negative membrane potentials, and exhibits faster deactivation and inactivation kinetics compared to the common K897 channel. Paavonen et al.²² Paavonen et al.
Functional characterization of the common amino acid 897 polymorphism of the cardiac potassium channel KCNH2. Cardiovasc Res, 2003 demonstrated these biophysical differences in transfected cells and in exercise-tested patients carrying an LQT2 background mutation, where T897 carriers showed longer exercise QT intervals than K897 homozygotes on the same genetic background.

Paradoxically, despite the T897 isoform's reduced single-channel current, the net population-level effect in homozygous T/T individuals (GG on the plus strand) is a shorter QTc interval — approximately 10 milliseconds shorter than K/K homozygotes. Bezzina et al.³³ Bezzina et al.
A common polymorphism in KCNH2 (HERG) hastens cardiac repolarization. Cardiovasc Res, 2003 established this in over 1,300 Caucasians and identified the effect as recessive and more pronounced in women.

The Evidence

The K897T variant has been studied in several independent population cohorts with consistent but sometimes opposing findings depending on which phenotype is measured:

QT interval: Both the KORA study Pfeufer et al.⁴⁴ Pfeufer et al.
Common variants in myocardial ion channel genes modify the QT interval. Circ Res, 2005 (n=3,966) and the Framingham Heart Study Newton-Cheh et al.⁵⁵ Newton-Cheh et al.
Common genetic variation in KCNH2 is associated with QT interval. Circulation, 2007 (n=2,123) replicated the QT-shortening effect of the T897 allele (–1.9 ms per allele in KORA; ~3.1 ms shorter in T/T vs K/K in Framingham dominant model). A shortened QTc is generally not dangerous on its own, but at extreme values short QT syndrome confers ventricular arrhythmia risk.

Atrial fibrillation: Counterintuitively, the common K897 allele (not the T897 variant) was associated with higher atrial fibrillation risk in a two-stage case-control study. Sinner et al.⁶⁶ Sinner et al.
The non-synonymous coding IKr-channel variant KCNH2-K897T is associated with atrial fibrillation. Eur Heart J, 2008 (n=3,682) found OR=1.25 (95% CI 1.11–1.41, P=0.00033) for AF per K897 allele. This suggests the minor T897 allele may confer modest AF protection relative to the common K897.

Drug-induced QT: The T897 isoform's altered kinetics — faster deactivation, lower current density — change how much the channel can be additionally inhibited by QT-prolonging drugs. In a background of existing LQT2 mutations, T897 can compound the dysfunction. Anson et al.⁷⁷ Anson et al.
Molecular and functional characterization of common polymorphisms in HERG. Am J Physiol, 2004 found similar cisapride block sensitivity between K897 and T897, but the already-reduced baseline IKr in T897 carriers leaves less physiological reserve before repolarization is compromised.

ClinVar classifies the T897 allele (G on the plus strand) as Benign for long QT syndrome and atrial fibrillation (VCV000067427, 16/21 submissions benign, criteria provided, multiple submitters, no conflicts). Population frequency supports this: the G allele is present in ~20% of European chromosomes and cannot be a high-penetrance disease allele at that frequency.

Practical Actions

For homozygous G/G individuals carrying two T897 copies: the shortened QTc warrants awareness when prescribed Class I or III antiarrhythmics. While T897 does not dramatically increase drug sensitivity to hERG blockers, the baseline reserve is lower, and QTc should be monitored when initiating QT-prolonging medications (sotalol, dofetilide, amiodarone, certain antibiotics, antipsychotics, and antiemetics).

Heterozygous G/T carriers have an intermediate phenotype — QTc is typically in the normal range (the shortening effect is recessive), but the presence of one T897 allele can still influence the electrophysiological background on which mutations or drugs act.

The AF association (with the common K/K genotype) is modest (OR ~1.25) and represents background population risk — not a clinically actionable finding in isolation, but worth documenting in the context of an AF workup.

Interactions

K897T can act as a genetic modifier when co-inherited with pathogenic LQT2 mutations (other KCNH2 variants). In that context, T897 can substantially amplify the loss-of-function phenotype of the primary mutation. rs2968863 (7q36.1) is in high linkage disequilibrium with K897T and was independently identified as a QTc modifier in early-onset AF cohorts (Andreasen et al. 2013, PMID 24074973; OR=2.40 for homozygous rs2968863 carriers in early-onset AF). The rs3815459 SNP in the same gene shows opposite directionality (+1.7 ms/allele) and may counterbalance K897T effects in compound carriers.