KCNH2

protein-coding

potassium voltage-gated channel subfamily H member 2, the group of PAS domain containing|Potassium voltage-gated channels

Gene summary

This gene encodes a component of a voltage-activated potassium channel found in cardiac muscle, nerve cells, and microglia. Four copies of this protein interact with one copy of the KCNE2 protein to form a functional potassium channel. Mutations in this gene can cause long QT syndrome type 2 (LQT2). Transcript variants encoding distinct isoforms have been identified. [provided by RefSeq, May 2022]

Previous symbols:

LQT2

MANE transcript

NM_000238.4

Inheritance

AD, Digenic

ClinVar variants

P:850U:1515B:879

Top phenotype

Long QT syndrome 2; Short QT syndrome 1

gnomAD constraint

pLI —, LoF o/e 0.13

Max pathogenic AF

—

Genomic locus

chr7:150,944,961-150,978,321

External References & Databases

Ensembl (ENSG00000055118)

Transcript & Mutation Effects

hg38 • Region Span ~33.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

short QT syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0000453

Submitter: Orphanet

Brugada syndromeMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0015263

Submitter: Genomics England PanelApp

long QT syndrome 2DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013367

Submitter: G2P

short QT syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0000453

Submitter: ClinGen

KCNH2 encodes the alpha subunit of the rapidly activating delayed rectifier cardiac potassium channel (Ikr). Brugada et al. (PMID 14676148) were the first to identify 2 rare KCNH2 missense variants leading to the same amino-acid change (p.Asn588Lys, ClinVar Variation ID# 14436 & 14437) in 2 small families with Short QT Syndrome (SQTS) using a candidate-gene approach. This genetic evidence was subsequently supported by multiple other publications identifying rare missense KCNH2 variants in SQTS patients. Experimental evidence derived from non-patient cells, human-induced pluripotent stem cell-derived cells and a rabbit animal model (PMID 30496390) all support this gene’s relationship with SQTS. These experimental studies demonstrate that genetic variants identified in SQTS patients lead to potassium current perturbations concordant with SQTS phenotype and shortening of the QT interval. It is noteworthy that of the 18 probands with SQTS in whom KCNH2 variants were identified, 13 had one of 2 variants; 7 with p.Thr618Ile variant (ClinVar Variation ID# 67297) and 6 with p.Asn588Lys.

Brugada syndromeNO_KNOWN

Inheritance Pattern: AD

Disease ID:MONDO:0015263

Submitter: G2P

short QT syndrome type 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012312

Submitter: Labcorp Genetics (formerly Invitae)

Brugada syndromeNO_KNOWN

Inheritance Pattern: AD

Disease ID:MONDO:0015263

Submitter: ClinGen

*KCNH2* was first reported in relation to Brugada syndrome in 2005 (Verkerk, et al. PMID: 16043162). Evidence supporting this gene-disease relationship includes case-level and experimental data. Of note, this gene has previously been assessed for Long QT Syndrome. Two missense variants reported in two probands affected by Brugada syndrome from one publication were included in this curation (PMID: 39895654). Family segregation evidence supporting this gene-disease relationship was not found in the literature. Additional reported individuals with *KCNH2 *variants were not considered for this curation (PMIDs: 16043162, 18692916, 38648771) because the phenotypic specificity and associated patch clamp data were insufficient to support an association with Brugada syndrome, as determined by the ClinGen Hereditary Cardiovascular Disease GCEP. Bulk tissue gene expression data shows ubiquitous expression of *KCNH2* in human tissues, including the heart (PMID: 23715323, GTex dbGaP Accession phs000424.v10.p2). However, mice and cell culture rescue models for KCNH2 did not recapitulate the Brugada phenotype observed in human patients nor the gain of function disease mechanism indicative of Brugada syndrome (PMIDs: 12612061, 21536673). In summary, the evidence supporting the relationship between *KCNH2* and autosomal dominant Brugada syndrome has been disputed and no valid evidence remains to support the claim. More evidence is needed to either support or entirely refute the role *KCNH2* plays in this disease. This classification was approved by the ClinGen Hereditary Cardiovascular Disease GCEP on June 10th 2025 (SOP Version 11).

short QT syndrome type 1DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0012312

Submitter: G2P

long QT syndrome 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013367

Submitter: Labcorp Genetics (formerly Invitae)

long QT syndrome 2DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013367

Submitter: Ambry Genetics

long QT syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0002442

Submitter: ClinGen

KCNH2 encodes the alpha subunit of the rapidly activating delayed rectifier cardiac potassium channel (Ikr). Curran et al. were the first to identify variants in this gene using linkage analysis in families with LQTS (PMID 7889573). An abundance of experimental and genetic evidence, including segregation and case-control data, has accumulated over the decades since this publication to support the association of KCNH2 with LQTS. Note: All LQTS genes were curated by 3 separate blinded teams. The evidence and scores reached by these 3 teams were reviewed by the LQTS Clinical Domain Expert Panel. For a detailed discussion of this group's work and the separate scores of the 3 teams please see "Adler et al. An International, Multicentered, Evidence-Based Reappraisal of Genes Reported to Cause Congenital Long QT Syndrome. Circulation 2020;141(6):418-428. doi: 10.1161/CIRCULATIONAHA.119.043132”

short QT syndrome type 1MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0012312

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Long QT syndrome 2; Short QT syndrome 1AD/Digenic

Manifestation: Cardiovascular

Intervention: Cardiovascular

Rationale: In Long QT syndrome, medical/surgical management (eg, with beta-blockers or ICD placement) may help prevent/decrease severe sequelae; Activities (eg, stress, certain types of physical activity) or agents (eg, certain medications) that contribute to further QT interval prolongation should be avoided; In Short QT syndrome, medical/surgical management (eg, with antiarrhythmics or ICD placement) may help prevent/decrease severe sequelae

Comments: Digenic/complex inheritance has been reported

Refs: 9753711; 9694858; 9927398; 9950666; 11173780; 12925462; 14676148; 15280551; 16132053; 15828882; 15890322; 15840476; 11854117; 16075043; 16922724; 19926013; 20301308; 20809527; 21070882; 21130771; 21440677; 22382559; 22821100; 22882672; 23010577; 23098067

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to KCNH2 variants in ClinVar

38 Conditions Cataloged

Long QT syndromeTotal: 2747

Cardiovascular phenotypeTotal: 1054

Cardiac arrhythmiaTotal: 948

not providedTotal: 909

Long QT syndrome 2Total: 436

Congenital long QT syndromeTotal: 370

not specifiedTotal: 210

Short QT syndrome type 1Total: 176

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000238.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous	2 clinvar	3 clinvar	17 clinvar	819 clinvar	13 clinvar	854
missense	80 clinvar	222 clinvar	1480 clinvar	44 clinvar	2 clinvar	1828
nonsense	76 clinvar	18 clinvar	2 clinvar			96
start loss	2 clinvar	1 clinvar	2 clinvar			5
frameshift	314 clinvar	69 clinvar	12 clinvar			395
splice donor/acceptor (+/-2bp)	18 clinvar	45 clinvar	2 clinvar	1 clinvar		66
Total	492	358	1515	864	15	3244

Highest pathogenic variant AF is 0.00007919128

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 27 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000238.4	RefSeq	NP_000229.1	15	MANE Select
ENST00000262186.10	Ensembl	ENSP00000262186.5	15	MANE Select
NM_001204798.2	RefSeq	NP_001191727.1	5	Standard
NM_001406753.1	RefSeq	NP_001393682.1	13	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Antiarrhythmic Pathway, Pharmacodynamics
Disopyramide Action Pathway
Procainamide (Antiarrhythmic) Action Pathway
Phenytoin (Antiarrhythmic) Action Pathway
Fosphenytoin (Antiarrhythmic) Action Pathway

Biological Process

regulation of heart rate by hormone
cellular response to drug
regulation of membrane potential
potassium ion homeostasis
cardiac muscle contraction

Molecular Function

inward rectifier potassium channel activity
voltage-gated potassium channel activity
delayed rectifier potassium channel activity
protein binding
ubiquitin protein ligase binding

Cellular Component

plasma membrane
integral component of plasma membrane
voltage-gated potassium channel complex
cell surface
perinuclear region of cytoplasm

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000262186
Coding exons: 15
Length: 33355
Individuals with no LoFs: 125714
Homozygous LoFs: 0
Heterozygous LoFs: 33
Defined: 125747
p: 0.000131

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.37	439	688	0.638	0.0000457	7378
Missense (PolyPhen)		127	325.14	0.3906		3263
Synonymous	-1.03	330	307	1.08	0.0000221	2474
Loss of Function	4.99	5	38.3	0.131	0.00000192	435

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00013	0.00012	rare
Latino/Admixed American	0.00012	0.00012	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00011	0.00011	rare
Finnish	0.00051	0.00051	rare
European (Non-Finnish)	0.00011	0.00011	rare
South Asian	0	0.0	absent
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Pore-forming (alpha) subunit of voltage-gated inwardly rectifying potassium channel. Channel properties are modulated by cAMP and subunit assembly. Mediates the rapidly activating component of the delayed rectifying potassium current in heart (IKr) (PubMed:18559421, PubMed:26363003, PubMed:27916661). {ECO:0000269|PubMed:18559421, ECO:0000269|PubMed:26363003, ECO:0000269|PubMed:27916661}.; FUNCTION: Isoform B-USO: Has no channel activity by itself, but modulates channel characteristics by forming heterotetramers with other isoforms which are retained intracellularly and undergo ubiquitin-dependent degradation. {ECO:0000269|PubMed:18559421}.;
Disease: DISEASE: Long QT syndrome 2 (LQT2) [MIM:613688]: A heart disorder characterized by a prolonged QT interval on the ECG and polymorphic ventricular arrhythmias. They cause syncope and sudden death in response to exercise or emotional stress, and can present with a sentinel event of sudden cardiac death in infancy. Deafness is often associated with long QT syndrome type 2. {ECO:0000269|PubMed:10086971, ECO:0000269|PubMed:10187793, ECO:0000269|PubMed:10220144, ECO:0000269|PubMed:10517660, ECO:0000269|PubMed:10735633, ECO:0000269|PubMed:10753933, ECO:0000269|PubMed:10862094, ECO:0000269|PubMed:10973849, ECO:0000269|PubMed:11170080, ECO:0000269|PubMed:12062363, ECO:0000269|PubMed:12354768, ECO:0000269|PubMed:12442276, ECO:0000269|PubMed:12621127, ECO:0000269|PubMed:15051636, ECO:0000269|PubMed:15840476, ECO:0000269|PubMed:16361248, ECO:0000269|PubMed:16414944, ECO:0000269|PubMed:16922724, ECO:0000269|PubMed:19716085, ECO:0000269|PubMed:22314138, ECO:0000269|PubMed:27916661, ECO:0000269|PubMed:7889573, ECO:0000269|PubMed:8635257, ECO:0000269|PubMed:8877771, ECO:0000269|PubMed:8914737, ECO:0000269|PubMed:9024139, ECO:0000269|PubMed:9452080, ECO:0000269|PubMed:9544837, ECO:0000269|PubMed:9600240, ECO:0000269|PubMed:9693036}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Short QT syndrome 1 (SQT1) [MIM:609620]: A heart disorder characterized by idiopathic persistently and uniformly short QT interval on ECG in the absence of structural heart disease in affected individuals. It causes syncope and sudden death. {ECO:0000269|PubMed:14676148, ECO:0000269|PubMed:15828882}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.298

Intolerance Scores

LoFtool: 0.000827
RVIS EVS: -1.46
RVIS percentile EVS: 3.81

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.928

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium