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

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

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 ClinVar and linked to the KCNH2 gene.

• Long QT syndrome (253 variants)
• not provided (154 variants)
• Cardiovascular phenotype (90 variants)
• Long QT syndrome 2 (65 variants)
• Congenital long QT syndrome (42 variants)
• Cardiac arrhythmia (27 variants)
• Short QT syndrome type 1 (4 variants)
• Short QT syndrome type 1;Long QT syndrome 2 (3 variants)
• KCNH2-related disorder (3 variants)
• Long QT syndrome 2;Short QT syndrome type 1 (2 variants)
• Long QT syndrome 1/2, digenic (1 variants)
• Long QT syndrome 1 (1 variants)
• Hypertrophic cardiomyopathy 26 (1 variants)
• Short QT syndrome (1 variants)
• Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency (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			15	671	8	694
missense	58	103	1118	22	3	1304
nonsense	67	13	1			81
start loss	1		1			2
frameshift	264	50	10			324
inframe indel	6	3	52			61
splice donor/acceptor (+/-2bp)	14	36	2	1		53
splice region	2	3	32	59	1	97
non coding	4	4	50	190	59	307
Total	414	209	1249	884	70

Highest pathogenic variant AF is 0.000124

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)
7-150944998-G-T		Long QT syndrome	Uncertain significance (Jun 14, 2016)
7-150945097-G-A		Long QT syndrome 2	Uncertain significance (Jan 13, 2018)
7-150945137-C-T		Long QT syndrome 2	Uncertain significance (Jan 12, 2018)
7-150945170-G-T		Long QT syndrome	Uncertain significance (Jun 14, 2016)
7-150945175-G-A		Long QT syndrome 2	Benign/Likely benign (May 01, 2022)
7-150945218-A-T		Long QT syndrome 2	Uncertain significance (Jan 13, 2018)
7-150945253-G-A		Long QT syndrome 2	Likely benign (Jun 26, 2018)
7-150945273-G-A		Long QT syndrome 2	Benign (Apr 20, 2018)
7-150945273-G-C		Long QT syndrome 2	Uncertain significance (Apr 27, 2017)
7-150945309-G-A		Long QT syndrome 2	Uncertain significance (Apr 27, 2017)
7-150945348-C-G		not specified	Likely benign (Jun 09, 2016)
7-150945350-C-T		Long QT syndrome 2 • Cardiovascular phenotype • not specified	Benign/Likely benign (Jun 30, 2022)
7-150945359-G-A		Long QT syndrome	Uncertain significance (Jul 29, 2024)
7-150945367-A-C		Long QT syndrome	Uncertain significance (Dec 01, 2023)
7-150945367-A-G		Cardiovascular phenotype	Uncertain significance (Dec 31, 2020)
7-150945371-G-T		Long QT syndrome • Cardiovascular phenotype	Likely benign (Oct 28, 2024)
7-150945372-C-G		Long QT syndrome	Uncertain significance (Nov 01, 2022)
7-150945374-C-G		Long QT syndrome	Likely benign (Jun 16, 2023)
7-150945374-C-T		Long QT syndrome • Cardiac arrhythmia	Likely benign (Jun 22, 2024)
7-150945374-C-CG			Uncertain significance (May 17, 2018)
7-150945375-G-A		SUDDEN INFANT DEATH SYNDROME • Long QT syndrome • Cardiac arrhythmia • Cardiovascular phenotype	Uncertain significance (Jan 26, 2025)
7-150945376-G-A		Cardiac arrhythmia • Cardiovascular phenotype • Long QT syndrome • Long QT syndrome 2	Uncertain significance (Jan 07, 2025)
7-150945378-T-C		Cardiac arrhythmia	Uncertain significance (Mar 07, 2024)
7-150945379-C-A		Long QT syndrome	Uncertain significance (May 22, 2022)

GnomAD

Source: gnomAD

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: 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

	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