KCNH2

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

Basic information

Region (hg38): 7:150944961-150978321

Previous symbols: [ "LQT2" ]

Links

ENSG00000055118NCBI:3757OMIM:152427HGNC:6251Uniprot:Q12809AlphaFoldGenCCjaxSfariGnomADPubmedClinVar

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 (2577 variants)
  • Cardiovascular_phenotype (964 variants)
  • not_provided (847 variants)
  • Cardiac_arrhythmia (775 variants)
  • Long_QT_syndrome_2 (417 variants)
  • Congenital_long_QT_syndrome (370 variants)
  • not_specified (190 variants)
  • Short_QT_syndrome_type_1 (175 variants)
  • KCNH2-related_disorder (39 variants)
  • Long_QT_syndrome_1 (7 variants)
  • SUDDEN_INFANT_DEATH_SYNDROME (7 variants)
  • Short_QT_syndrome (5 variants)
  • Hypertrophic_cardiomyopathy (4 variants)
  • Brugada_syndrome_1 (3 variants)
  • Prolonged_QT_interval (3 variants)
  • Acquired_long_QT_syndrome (3 variants)
  • Long_QT_syndrome_1/2,_digenic (3 variants)
  • Brugada_syndrome (2 variants)
  • Wolff-Parkinson-White_pattern (2 variants)
  • Ventricular_tachycardia (2 variants)
  • Sudden_unexplained_death (1 variants)
  • Long_QT_syndrome,_bradycardia-induced (1 variants)
  • Inborn_genetic_diseases (1 variants)
  • Sudden_cardiac_death (1 variants)
  • Long_QT_syndrome_2/9,_digenic (1 variants)
  • Hypertrophic_cardiomyopathy_26 (1 variants)
  • Catecholaminergic_polymorphic_ventricular_tachycardia_1 (1 variants)
  • Primary_dilated_cardiomyopathy (1 variants)
  • Primary_familial_hypertrophic_cardiomyopathy (1 variants)
  • Ventricular_fibrillation,_paroxysmal_familial,_type_1 (1 variants)
  • Reclassified_-_variant_of_unknown_significance (1 variants)
  • Arrhythmogenic_right_ventricular_cardiomyopathy (1 variants)
  • Obesity (1 variants)
  • Conduction_disorder_of_the_heart (1 variants)
  • Long_QT_syndrome_2/3,_digenic (1 variants)
  • Autoimmune_lymphoproliferative_syndrome_due_to_CTLA4_haploinsufficiency (1 variants)
  • Sudden_cardiac_arrest (1 variants)
  • Long_QT_syndrome_2/5,_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. These statistics are base on transcript: NM_000000238.4. Only rare variants are included in the table.

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.

EffectPLPVUSLBBSum
synonymous
2
clinvar
3
clinvar
18
clinvar
764
clinvar
13
clinvar
800
missense
80
clinvar
204
clinvar
1377
clinvar
42
clinvar
2
clinvar
1705
nonsense
71
clinvar
17
clinvar
1
clinvar
89
start loss
1
2
3
frameshift
289
clinvar
66
clinvar
9
clinvar
364
splice donor/acceptor (+/-2bp)
17
clinvar
41
clinvar
2
clinvar
1
clinvar
61
Total 460 331 1409 807 15

Highest pathogenic variant AF is 0.00007919128

Loading clinvar variants...

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