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KCNH2

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

Basic information

Region (hg38): 7:150944960-150978321

Previous symbols: [ "LQT2" ]

Links

ENSG00000055118 ∙ NCBI:3757 ∙ OMIM:152427 ∙ HGNC:6251 ∙ Uniprot:Q12809 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

  • Brugada syndrome (Moderate), mode of inheritance: AD
  • short QT syndrome type 1 (Moderate), mode of inheritance: AD
  • long QT syndrome 2 (Definitive), mode of inheritance: AD
  • short QT syndrome (Supportive), mode of inheritance: AD
  • short QT syndrome type 1 (Definitive), mode of inheritance: AD
  • long QT syndrome 2 (Definitive), mode of inheritance: AD
  • long QT syndrome 2 (Strong), mode of inheritance: AD
  • short QT syndrome type 1 (Strong), mode of inheritance: AD
  • Brugada syndrome (Disputed Evidence), mode of inheritance: AD
  • long QT syndrome (Definitive), mode of inheritance: AD
  • short QT syndrome (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

ConditionInheritanceIntervention CategoriesIntervention/Rationale Manifestation CategoriesReferences
Long QT syndrome 2; Short QT syndrome 1AD/DigenicCardiovascularIn 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 sequelaeCardiovascular9753711; 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
Digenic/complex inheritance has been reported

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the KCNH2 gene.

  • Long QT syndrome (1946 variants)
  • not provided (768 variants)
  • Cardiac arrhythmia (716 variants)
  • Cardiovascular phenotype (677 variants)
  • Congenital long QT syndrome (350 variants)
  • Long QT syndrome 2 (259 variants)
  • not specified (170 variants)
  • Short QT syndrome type 1;Long QT syndrome 2 (106 variants)
  • Long QT syndrome 2;Short QT syndrome type 1 (43 variants)
  • Short QT syndrome type 1 (16 variants)
  • Inborn genetic diseases (8 variants)
  • Long QT syndrome 1 (7 variants)
  • SUDDEN INFANT DEATH SYNDROME (7 variants)
  • KCNH2-related condition (7 variants)
  • Long QT syndrome 1/2, digenic (3 variants)
  • Brugada syndrome 1 (3 variants)
  • Acquired long QT syndrome (3 variants)
  • Short QT syndrome (3 variants)
  • Hypertrophic cardiomyopathy (3 variants)
  • Brugada syndrome (2 variants)
  • Prolonged QT interval (2 variants)
  • KCNH2-related disorders (2 variants)
  • Sudden unexplained death (2 variants)
  • Wolff-Parkinson-White pattern (2 variants)
  • Arrhythmogenic right ventricular cardiomyopathy (1 variants)
  • Ventricular fibrillation, paroxysmal familial, type 1 (1 variants)
  • See cases (1 variants)
  • Long QT syndrome 2/5, digenic (1 variants)
  • Torsades de pointes (1 variants)
  • Seizure (1 variants)
  • Hypertrophic cardiomyopathy;Cardiac arrhythmia (1 variants)
  • Prolonged QT interval;Sudden cardiac death (1 variants)
  • Long QT syndrome, bradycardia-induced (1 variants)
  • Obesity;Prolonged QT interval (1 variants)
  • Long QT syndrome 2, acquired, susceptibility to (1 variants)
  • Atrial fibrillation (1 variants)
  • Ventricular tachycardia (1 variants)
  • Primary dilated cardiomyopathy (1 variants)
  • Sudden cardiac death (1 variants)
  • Long QT syndrome 2/9, digenic (1 variants)
  • Conduction disorder of the heart (1 variants)
  • Primary familial hypertrophic cardiomyopathy (1 variants)
  • Long QT syndrome 2/3, digenic (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the KCNH2 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type Pathogenic Likely pathogenic VUS Likely benign Benign Sum
synonymous
13
clinvar
558
clinvar
8
clinvar
 579
missense
57
clinvar
91
clinvar
926
clinvar
22
clinvar
4
clinvar
 1100
nonsense
59
clinvar
11
clinvar
1
clinvar
 71
start loss
1
clinvar
 1
frameshift
251
clinvar
37
clinvar
8
clinvar
 296
inframe indel
2
clinvar
4
clinvar
52
clinvar
 58
splice donor/acceptor (+/-2bp)
17
clinvar
33
clinvar
2
clinvar
1
clinvar
 53
splice region
?
    Intron variants in splice region, excluding donor/acceptor (+/-2bp)
2
5
29
50
1
 87
non coding
?
    UTR, intron and other, non coding variants
1
clinvar
39
clinvar
147
clinvar
60
clinvar
 247
Total 387 177 1041 728 72

Highest pathogenic variant AF is 0.0000525

Variants in KCNH2

This is a list of pathogenic ClinVar variants found in the KCNH2 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position Type Phenotype Significance ClinVar
7-150944968-A-G Long QT syndrome 2 Benign (Jan 12, 2018)359295
7-150944998-G-T Long QT syndrome Uncertain significance (Jun 14, 2016)359296
7-150945097-G-A Long QT syndrome 2 Uncertain significance (Jan 13, 2018)910579
7-150945137-C-T Long QT syndrome 2 Uncertain significance (Jan 12, 2018)359297
7-150945170-G-T Long QT syndrome Uncertain significance (Jun 14, 2016)359298
7-150945175-G-A Long QT syndrome 2 Benign/Likely benign (May 01, 2022)910580
7-150945218-A-T Long QT syndrome 2 Uncertain significance (Jan 13, 2018)910581
7-150945253-G-A Long QT syndrome 2 Likely benign (Jun 26, 2018)359299
7-150945273-G-A Long QT syndrome 2 Benign (Apr 20, 2018)911809
7-150945273-G-C Long QT syndrome 2 Uncertain significance (Apr 27, 2017)911810
7-150945309-G-A Long QT syndrome 2 Uncertain significance (Apr 27, 2017)911811
7-150945348-C-G not specified Likely benign (Jun 09, 2016)386840
7-150945350-C-T Long QT syndrome 2 • not specified • Cardiovascular phenotype Benign/Likely benign (Jun 30, 2022)359300
7-150945359-G-A Long QT syndrome Uncertain significance (May 16, 2023)3070534
7-150945367-A-C Long QT syndrome Uncertain significance (Dec 01, 2023)3074036
7-150945367-A-G Cardiovascular phenotype Uncertain significance (Dec 31, 2020)1731807
7-150945371-G-T Long QT syndrome Likely benign (Dec 13, 2023)3074983
7-150945372-C-G Long QT syndrome Uncertain significance (Nov 01, 2022)939464
7-150945374-C-G Long QT syndrome Likely benign (Jun 16, 2023)1640911
7-150945374-C-T Long QT syndrome • Cardiac arrhythmia Likely benign (Nov 02, 2022)665237
7-150945374-C-CG Uncertain significance (May 17, 2018)200713
7-150945375-G-A SUDDEN INFANT DEATH SYNDROME • Long QT syndrome • Cardiac arrhythmia • Cardiovascular phenotype Uncertain significance (Dec 13, 2023)67499
7-150945376-G-A Long QT syndrome • Cardiac arrhythmia • Long QT syndrome 2 • Cardiovascular phenotype Uncertain significance (Dec 23, 2023)456933
7-150945378-T-C Cardiac arrhythmia Uncertain significance (Dec 11, 2019)926485
7-150945379-C-A Long QT syndrome Uncertain significance (May 22, 2022)1957007

GnomAD

Source: gnomAD

GeneTypeBio TypeTranscript Coding Exons Length
KCNH2protein_codingprotein_codingENST00000262186 1533355
pLI Probability
LOF Intolerant 		pRec Probability
LOF Recessive 		Individuals with
no LOFs 		Individuals with
Homozygous LOFs 		Individuals with
Heterozygous LOFs 		Defined p
0.9960.004071257140331257470.000131
Z-Score Observed Expected Observed/Expected Mutation Rate Total Possible in Transcript
Missense3.374396880.6380.00004577378
Missense in Polyphen127325.140.39063263
Synonymous-1.033303071.080.00002212474
Loss of Function4.99538.30.1310.00000192435

LoF frequencies by population

EthnicitySum of pLOFs p
African & African-American0.0002420.000240
Ashkenazi Jewish0.00009930.0000992
East Asian0.0001090.000109
Finnish0.0005100.000508
European (Non-Finnish)0.0001070.000105
Middle Eastern0.0001090.000109
South Asian0.000.00
Other0.0001640.000163

dbNSFP

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.;
Pathway
Antiarrhythmic Pathway, Pharmacodynamics;Disopyramide Action Pathway;Procainamide (Antiarrhythmic) Action Pathway;Phenytoin (Antiarrhythmic) Action Pathway;Fosphenytoin (Antiarrhythmic) Action Pathway;Bopindolol Action Pathway;Timolol Action Pathway;Carteolol Action Pathway;Bevantolol Action Pathway;Practolol Action Pathway;Dobutamine Action Pathway;Isoprenaline Action Pathway;Arbutamine Action Pathway;Amiodarone Action Pathway;Levobunolol Action Pathway;Metipranolol Action Pathway;Mexiletine Action Pathway;Lidocaine (Antiarrhythmic) Action Pathway;Quinidine Action Pathway;Sotalol Action Pathway;Epinephrine Action Pathway;Betaxolol Action Pathway;Atenolol Action Pathway;Alprenolol Action Pathway;Acebutolol Action Pathway;Muscle/Heart Contraction;Diltiazem Action Pathway;Propranolol Action Pathway;Pindolol Action Pathway;Penbutolol Action Pathway;Oxprenolol Action Pathway;Metoprolol Action Pathway;Esmolol Action Pathway;Bisoprolol Action Pathway;Bupranolol Action Pathway;Nebivolol Action Pathway;Amlodipine Action Pathway;Verapamil Action Pathway;Nitrendipine Action Pathway;Nisoldipine Action Pathway;Nimodipine Action Pathway;Ibutilide Action Pathway;Tocainide Action Pathway;Flecainide Action Pathway;Isradipine Action Pathway;Nifedipine Action Pathway;Felodipine Action Pathway;Nadolol Action Pathway;Carvedilol Action Pathway;Labetalol Action Pathway;Hematopoietic Stem Cell Differentiation;Sudden Infant Death Syndrome (SIDS) Susceptibility Pathways;Neuronal System;Phase 3 - rapid repolarisation;Cardiac conduction;Muscle contraction;Voltage gated Potassium channels;Potassium Channels (Consensus)

Recessive Scores

pRec
0.298

Intolerance Scores

loftool
0.000827
rvis_EVS
-1.46
rvis_percentile_EVS
3.81

Haploinsufficiency Scores

pHI
0.705
hipred
Y
hipred_score
0.809
ghis
0.562

Essentials

essential_gene_CRISPR
N
essential_gene_CRISPR2
N
essential_gene_gene_trap
N
gene_indispensability_pred
E
gene_indispensability_score
0.928

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium

Mouse Genome Informatics

Gene name
Kcnh2
Phenotype
growth/size/body region phenotype; craniofacial phenotype; muscle phenotype; homeostasis/metabolism phenotype; embryo phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan);

Gene ontology

Biological process
regulation of heart rate by hormone;cellular response to drug;regulation of membrane potential;potassium ion homeostasis;cardiac muscle contraction;regulation of membrane repolarization;regulation of ventricular cardiac muscle cell membrane repolarization;potassium ion transmembrane transport;ventricular cardiac muscle cell action potential;membrane repolarization;membrane depolarization during action potential;membrane repolarization during action potential;membrane repolarization during cardiac muscle cell action potential;regulation of heart rate by cardiac conduction;potassium ion export across plasma membrane;membrane repolarization during ventricular cardiac muscle cell action potential;regulation of potassium ion transmembrane transport;negative regulation of potassium ion transmembrane transport;positive regulation of potassium ion transmembrane transport;negative regulation of potassium ion export across plasma membrane;potassium ion import across plasma membrane
Cellular component
plasma membrane;integral component of plasma membrane;voltage-gated potassium channel complex;cell surface;perinuclear region of cytoplasm;inward rectifier potassium channel complex
Molecular function
inward rectifier potassium channel activity;voltage-gated potassium channel activity;delayed rectifier potassium channel activity;protein binding;ubiquitin protein ligase binding;identical protein binding;protein homodimerization activity;C3HC4-type RING finger domain binding;voltage-gated potassium channel activity involved in cardiac muscle cell action potential repolarization;scaffold protein binding;voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization