rs199473521 — KCNH2 K595N

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

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KCNH2 K595N — A Rare Charge Change That Can Silence the Heart's Repolarization Gate

Every normal heartbeat ends the same way: a wave of potassium ions flows out through millions of hERG channels, repolarizing ventricular muscle and resetting the electrical system for the next beat. The hERG channel11 hERG channel
encoded by KCNH2, the human ether-à-go-go related gene; it carries the rapid delayed rectifier current IKr, the dominant current driving the final phase of cardiac repolarization is so critical to this process that loss-of-function mutations anywhere in its 1,159-amino-acid sequence can prolong the QT interval and trigger life-threatening ventricular arrhythmias. rs199473521 substitutes asparagine (uncharged, polar) for the normal lysine (positively charged) at position 595 — a residue in the C-linker domain that connects the channel's last transmembrane helix to its regulatory intracellular domain.

The Mechanism

Position 595 sits in the C-linker of Kv11.1/hERG, the eight-residue segment that couples the S6 transmembrane helix to the cyclic nucleotide binding homology domain (CNBHD)22 cyclic nucleotide binding homology domain (CNBHD)
a regulatory domain that modulates channel opening and closing; mutations anywhere in the C-linker alter the allosteric coupling between the gate and this regulatory module. The lysine at position 595 contributes to the electrostatic environment of this linker. Replacing it with asparagine (K595N) removes a positive charge, disrupts the local conformation, and is predicted by multiple paralogous-annotation frameworks to destabilize channel gating and reduce IKr. The net effect is loss-of-function: fewer functional hERG channels deliver less outward potassium current during the plateau of the action potential, delaying repolarization and lengthening the QT interval on the surface ECG.

Critically, K595 is conserved across species and across the broader voltage-gated potassium channel superfamily. Ware et al.33 Ware et al.
Paralogous annotation of disease-causing variants in long QT syndrome genes. Human Mutation, 2012 developed a method that correctly classified 98.4% of known pathogenic KCNH2 variants by comparing residue conservation across paralogues — a framework that flags K595N as high-priority among likely disease-causing changes.

The Evidence

rs199473521 was submitted to ClinVar (VCV000067273, RCV000057989) by the Cardiovascular Biomedical Research Unit at Royal Brompton & Harefield NHS Foundation Trust as a literature-report entry for congenital long QT syndrome, citing the Shimizu et al. 2009 and Ware et al. 2012 publications. It carries no ClinVar star rating — the single submitter recorded it as "not provided" with no independent functional validation on record. This places it in a common clinical grey zone: an ultra-rare KCNH2 missense variant (absent from gnomAD across all populations) at a conserved charged position, in a family or patient context consistent with LQT2, but without peer-reviewed electrophysiological characterization of the K595N substitution specifically.

The clinical genetics framework for interpreting ultra-rare KCNH2 missense variants is well established. Kapa et al.44 Kapa et al.
Genetic testing for long-QT syndrome: distinguishing pathogenic mutations from benign variants. Circulation, 2009 showed that among 388 definite LQT2 patients, missense variants in the C-linker and transmembrane domains had near-100% estimated pathogenicity. Shimizu et al.55 Shimizu et al.
Genotype-phenotype aspects of type 2 long QT syndrome. JACC, 2009 documented in 858 LQT2 patients that beta-blockers reduced the risk of first cardiac events by 63% (p < 0.001), establishing the therapeutic approach that would apply to K595N carriers regardless of whether functional data are ever published.

LQT2 has a characteristic trigger profile: auditory stimuli (alarm clocks, doorbells, telephone rings) and emotional startle provoke the bulk of arrhythmic events, and events are more common during rest, sleep, or emotion than during exercise — the reverse of LQT1. Women with LQT2 experience higher event rates than men, particularly around hormonal transitions (postpartum, perimenopause).

Practical Actions

Carriers of the K595N variant should be evaluated promptly by a cardiac electrophysiologist. The primary intervention for LQT2 is beta-blocker therapy (nadolol or propranolol at weight-adjusted doses), which is protective across the LQT2 spectrum. Auditory-trigger minimization — silencing or vibrating phones and alarms at night — is a specific, genotype-appropriate lifestyle change. Maintaining potassium and magnesium in the upper-normal range is critical because both electrolytes directly support IKr function; hypokalemia can precipitate torsades de pointes even without drug provocation in LQT2 carriers. Any drug that prolongs the QT interval is contraindicated — the CredibleMeds list (crediblemeds.org) is the maintained reference.

For high-risk carriers (prior syncope, prior cardiac arrest, QTc > 500 ms), an implantable cardioverter-defibrillator (ICD) may be indicated alongside pharmacotherapy. First-degree relatives should undergo cascade ECG screening and genetic testing.

Interactions

K595N may interact with the common KCNH2 modifier rs1805123 (K897T): homozygous K897T individuals have a baseline IKr reduction and may experience amplified QT prolongation if they co-inherit a loss-of-function variant like K595N. This interaction follows the general LQT2 modifier framework documented by Nof et al. 2010 (PMID 20181576) in which K897T GG homozygosity on a pathogenic KCNH2 background produces substantially greater IKr loss. Compound carriers of K595N and NOS1AP rs10918594 G alleles (PMID 19822806) may face additional QT prolongation through independent electrophysiological mechanisms.

Drug Interactions

sotalol contraindicated literature
dofetilide contraindicated literature
amiodarone increased_toxicity literature
erythromycin increased_toxicity FDA
clarithromycin increased_toxicity FDA
azithromycin increased_toxicity FDA
haloperidol increased_toxicity FDA
ondansetron increased_toxicity FDA
cisapride contraindicated FDA
methadone increased_toxicity FDA
domperidone increased_toxicity literature

Genotype Interpretations

What each possible genotype means for this variant.

TT No Variant Detected Normal

Standard KCNH2 K595 genotype — no K595N variant detected

The absence of K595N does not guarantee absence of other KCNH2 variants — there are hundreds of pathogenic LQT2 mutations described in the literature, and the GeneOps catalog includes those present on consumer and WGS platforms. If you have a personal or family history of unexplained syncope, seizures, or sudden cardiac death, a comprehensive KCNH2 sequencing panel through a clinical genetics service is the appropriate workup — not reassurance from a negative result on one variant.

AT K595N Carrier High Risk

One copy of K595N — ultra-rare KCNH2 loss-of-function variant associated with Long QT syndrome type 2

LQT2 caused by KCNH2 haploinsufficiency is distinguished from LQT1 and LQT3 by its characteristic trigger profile. Auditory stimuli — alarm clocks, doorbells, telephone ringtones, sudden loud sounds — trigger the majority of arrhythmic events in LQT2, presumably because the startle response causes rapid adrenergic activation that transiently worsens the repolarization imbalance. Events tend to occur at rest or during emotional arousal rather than during sustained exercise (where LQT1 events cluster). Women with LQT2 have higher cumulative event rates than men, and the postpartum period is a recognized high-risk window.

The K595N substitution replaces a positively charged lysine with neutral asparagine in the C-linker domain, which couples the channel gate to its regulatory intracellular domain. Computational and paralogous-annotation analyses (Ware et al., Human Mutation 2012) predict this charge neutralization impairs channel gating. No published electrophysiological study of K595N specifically has been identified, so the pathogenicity assignment rests on the combination of extreme rarity (gnomAD frequency zero across all ancestry groups), conservation of the K595 residue across species, domain location (C-linker), and clinical context (LQT family).

Because LQT2 follows autosomal dominant inheritance, a single heterozygous copy is sufficient to cause disease in most carriers. Penetrance is incomplete — some carriers have QTc values in the normal range at rest — but symptomatic events and sudden death have occurred in LQT2 mutation carriers with normal-appearing ECGs. Clinical evaluation including a 12-lead ECG, Holter monitoring, and exercise testing is required to establish your individual phenotype.

AA Homozygous K595N High Risk

Two copies of K595N — extremely rare homozygous state; expected severe LQT2 phenotype

Because K595N is ultra-rare (absent from population databases), homozygosity would be extraordinary and would most likely reflect consanguinity or an extremely rare coincidence. Functional consequence is expected to be complete or near-complete loss of IKr, as seen in other homozygous KCNH2 loss-of-function variants (Johnson et al., Pediatric Research, 2003 — R752Q homozygosity abolished IKr and caused severe neonatal LQTS requiring in-utero detection). A QTc exceeding 600 ms at rest would be expected and life-threatening arrhythmias without an ICD are highly probable. If this result appears on a report, verify sample integrity and repeat genotyping before acting — laboratory or interpretation errors must be excluded given the extreme rarity of this state.