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
Phenotypes
GenCC
Source:
- 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:
| Condition | Inheritance | Intervention Categories | Intervention/Rationale | Manifestation Categories | References |
|---|---|---|---|---|---|
| Long QT syndrome 2; Short QT syndrome 1 | AD/Digenic | Cardiovascular | 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 | Cardiovascular | 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 |
| Digenic/complex inheritance has been reported |
ClinVar
This is a list of variants' phenotypes submitted to
- 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.
| Effect | PathogenicP | Likely pathogenicLP | VUSVUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 18 | 764 | 13 | 800 | ||
| missense | 80 | 204 | 1377 | 42 | 1705 | |
| nonsense | 71 | 17 | 89 | |||
| start loss | 1 | 2 | 3 | |||
| frameshift | 289 | 66 | 364 | |||
| splice donor/acceptor (+/-2bp) | 17 | 41 | 61 | |||
| Total | 460 | 331 | 1409 | 807 | 15 |
Highest pathogenic variant AF is 0.00007919128
Loading clinvar variants...
GnomAD
Source:
| Gene | Type | Bio Type | Transcript | Coding Exons | Length |
|---|---|---|---|---|---|
| KCNH2 | protein_coding | protein_coding | ENST00000262186 | 15 | 33355 |
| pLI Probability LOF Intolerant | pRec Probability LOF Recessive | Individuals with no LOFs | Individuals with Homozygous LOFs | Individuals with Heterozygous LOFs | Defined | p |
|---|---|---|---|---|---|---|
| 0.996 | 0.00407 | 125714 | 0 | 33 | 125747 | 0.000131 |
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible in Transcript | |
|---|---|---|---|---|---|---|
| Missense | 3.37 | 439 | 688 | 0.638 | 0.0000457 | 7378 |
| Missense in 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 |
LoF frequencies by population
| Ethnicity | Sum of pLOFs | p |
|---|---|---|
| African & African-American | 0.000242 | 0.000240 |
| Ashkenazi Jewish | 0.0000993 | 0.0000992 |
| East Asian | 0.000109 | 0.000109 |
| Finnish | 0.000510 | 0.000508 |
| European (Non-Finnish) | 0.000107 | 0.000105 |
| Middle Eastern | 0.000109 | 0.000109 |
| South Asian | 0.00 | 0.00 |
| Other | 0.000164 | 0.000163 |
dbNSFP
Source:
- 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
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |
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