KCNH2 potassium voltage-gated channel subfamily H member 2 [Homo sapiens (human)] - Gene

Summary

Official Symbol: KCNH2provided by HGNC
Official Full Name: potassium voltage-gated channel subfamily H member 2provided by HGNC
Primary source: HGNC:HGNC:6251
See related: Ensembl:ENSG00000055118 MIM:152427; AllianceGenome:HGNC:6251
Gene type: protein coding
RefSeq status: REVIEWED
Organism: Homo sapiens
Lineage: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
Also known as: ERG1; HERG; LQT2; SQT1; ERG-1; H-ERG; HERG1; Kv11.1
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]
Expression: Broad expression in bone marrow (RPKM 13.5), testis (RPKM 10.7) and 14 other tissues See more
Orthologs: mouse all
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Genomic context

Location:: 7q36.1

Exon count:: 20

Annotation release	Status	Assembly	Chr	Location
RS_2024_08	current	GRCh38.p14 (GCF_000001405.40)	7	NC_000007.14 (150944961..150978321, complement)
RS_2024_08	current	T2T-CHM13v2.0 (GCF_009914755.1)	7	NC_060931.1 (152117824..152151201, complement)
RS_2024_09	previous assembly	GRCh37.p13 (GCF_000001405.25)	7	NC_000007.13 (150642049..150675409, complement)

Chromosome 7 - NC_000007.14 Genomic Context describing neighboring genes

Genomic regions, transcripts, and products

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Genomic Sequence:

Go to nucleotide: Graphics FASTA GenBank

Expression

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See details

Project title: HPA RNA-seq normal tissues HPA RNA-seq normal tissues
Description: RNA-seq was performed of tissue samples from 95 human individuals representing 27 different tissues in order to determine tissue-specificity of all protein-coding genes
BioProject: PRJEB4337
Publication: PMID 24309898
Analysis date: Wed Apr 4 07:08:55 2018

Bibliography

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GeneRIFs: Gene References Into Functions

What's a GeneRIF?

Rescue of expression and function of long QT syndrome-causing mutant hERG channels by enhancing channel stability in the plasma membrane.
Title: Rescue of expression and function of long QT syndrome-causing mutant hERG channels by enhancing channel stability in the plasma membrane.
An intracellular hydrophobic nexus critical for hERG1 channel slow deactivation.
Title: An intracellular hydrophobic nexus critical for hERG1 channel slow deactivation.
Clinical interpretation of KCNH2 variants using a robust PS3/BS3 functional patch-clamp assay.
Title: Clinical interpretation of KCNH2 variants using a robust PS3/BS3 functional patch-clamp assay.
An LQT2-related mutation in the voltage-sensing domain is involved in switching the gating polarity of hERG.
Title: An LQT2-related mutation in the voltage-sensing domain is involved in switching the gating polarity of hERG.
Functional and clinical characterization of a novel homozygous KCNH2 missense variant in the pore region of Kv11.1 leading to a viable but severe long-QT syndrome.
Title: Functional and clinical characterization of a novel homozygous KCNH2 missense variant in the pore region of Kv11.1 leading to a viable but severe long-QT syndrome.
Dissecting the associations of KCNH2 genetic polymorphisms with various types of cardiac arrhythmias.
Title: Dissecting the associations of KCNH2 genetic polymorphisms with various types of cardiac arrhythmias.
Identification and characterization of two novel KCNH2 mutations contributing to long QT syndrome.
Title: Identification and characterization of two novel KCNH2 mutations contributing to long QT syndrome.
Translation reinitiation in c.453delC frameshift mutation of KCNH2 producing functional hERG K+ channels with mild dominant negative effect in the heterozygote patient-derived iPSC cardiomyocytes.
Title: Translation reinitiation in c.453delC frameshift mutation of KCNH2 producing functional hERG K+ channels with mild dominant negative effect in the heterozygote patient-derived iPSC cardiomyocytes.
KCNH2A561V Heterozygous Mutation Inhibits KCNH2 Protein Expression via The Activation of UPR Mediated by ATF6.
Title: KCNH2A561V Heterozygous Mutation Inhibits KCNH2 Protein Expression via The Activation of UPR Mediated by ATF6.
Integrins regulate hERG1 dynamics by girdin-dependent Galphai3: signaling and modeling in cancer cells.
Title: Integrins regulate hERG1 dynamics by girdin-dependent Gαi3: signaling and modeling in cancer cells.

Submit: New GeneRIF Correction See all GeneRIFs (562)

Phenotypes

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Find tests for this gene in the NIH Genetic Testing Registry (GTR)

Review eQTL and phenotype association data in this region using PheGenI

Professional guidelines

Description
Professional guideline ACMG 2013 The ACMG recommends that laboratories performing clinical sequencing seek and report mutations in KCNH2 that are pathogenic or expected to be pathogenic. GuidelinePubMed

Associated conditions

Description	Tests
Long QT syndrome MedGen: C0023976 GeneReviews: Long QT Syndrome Overview	Compare labs
Long QT syndrome 2 MedGen: C3150943 OMIM: 613688 GeneReviews: Long QT Syndrome Overview	Compare labs
Short QT syndrome type 1 MedGen: C1865020 OMIM: 609620 GeneReviews: Not available	Compare labs

Copy number response

Description
Copy number response Triplosensitivity No evidence available (Last evaluated 2020-02-26) ClinGen Genome Curation Page Haploinsufficency Sufficient evidence for dosage pathogenicity (Last evaluated 2020-02-26) ClinGen Genome Curation PagePubMed

EBI GWAS Catalog

Description
Common variants at ten loci influence QT interval duration in the QTGEN Study. EBI GWAS Catalog EBI GWAS CatalogPubMed
Common variants at ten loci modulate the QT interval duration in the QTSCD Study. EBI GWAS Catalog EBI GWAS CatalogPubMed
Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization. EBI GWAS Catalog EBI GWAS CatalogPubMed
Genetic variation in SCN10A influences cardiac conduction. EBI GWAS Catalog EBI GWAS CatalogPubMed
Impact of ancestry and common genetic variants on QT interval in African Americans. EBI GWAS Catalog EBI GWAS CatalogPubMed
Several common variants modulate heart rate, PR interval and QRS duration. EBI GWAS Catalog EBI GWAS CatalogPubMed

Variation

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See variants in ClinVar

See studies and variants in dbVar

See Variation Viewer (GRCh37.p13)

See Variation Viewer (GRCh38)

HIV-1 interactions

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Protein interactions

Protein	Gene	Interaction	Pubs
Tat	tat	HIV-1 Tat protein inhibits hERG K(+) currents through the inhibition of hERG protein expression	PubMed

Go to the HIV-1, Human Interaction Database

Interactions

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Products	Interactant	Other Gene	Complex	Source	Pubs	Description

General gene information

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Markers

GDB:624527 (e-PCR)
- UniSTS:158342

RH12781 (e-PCR)
- UniSTS:19095

G20789 (e-PCR)
- UniSTS:56499

A006G22 (e-PCR)
- UniSTS:56500

LQT2 (e-PCR)
- UniSTS:50413

Gene Ontology Provided by GOA

Function	Evidence Code	Pubs
enables delayed rectifier potassium channel activity	IDA Inferred from Direct Assay more info	PubMed
enables delayed rectifier potassium channel activity	IGI Inferred from Genetic Interaction more info	PubMed
enables identical protein binding	IPI Inferred from Physical Interaction more info	PubMed
enables inward rectifier potassium channel activity	IBA Inferred from Biological aspect of Ancestor more info
NOT enables inward rectifier potassium channel activity	IDA Inferred from Direct Assay more info	PubMed
enables inward rectifier potassium channel activity	IDA Inferred from Direct Assay more info	PubMed
enables inward rectifier potassium channel activity	IMP Inferred from Mutant Phenotype more info	PubMed
enables protein binding	IPI Inferred from Physical Interaction more info	PubMed
enables protein homodimerization activity	IPI Inferred from Physical Interaction more info	PubMed
enables scaffold protein binding	IPI Inferred from Physical Interaction more info	PubMed
enables transcription cis-regulatory region binding	IDA Inferred from Direct Assay more info	PubMed
enables ubiquitin protein ligase binding	IPI Inferred from Physical Interaction more info	PubMed
enables voltage-gated potassium channel activity	IDA Inferred from Direct Assay more info	PubMed
enables voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization	IMP Inferred from Mutant Phenotype more info	PubMed

Process	Evidence Code	Pubs
involved_in cardiac muscle contraction	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in cellular response to xenobiotic stimulus	IDA Inferred from Direct Assay more info	PubMed
involved_in membrane depolarization during action potential	IDA Inferred from Direct Assay more info	PubMed
involved_in membrane repolarization	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in membrane repolarization during action potential	IDA Inferred from Direct Assay more info	PubMed
involved_in membrane repolarization during cardiac muscle cell action potential	IBA Inferred from Biological aspect of Ancestor more info
involved_in membrane repolarization during cardiac muscle cell action potential	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in membrane repolarization during ventricular cardiac muscle cell action potential	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in negative regulation of potassium ion export across plasma membrane	IDA Inferred from Direct Assay more info	PubMed
involved_in negative regulation of potassium ion transmembrane transport	IDA Inferred from Direct Assay more info	PubMed
involved_in positive regulation of DNA-templated transcription	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in positive regulation of potassium ion transmembrane transport	IDA Inferred from Direct Assay more info	PubMed
involved_in potassium ion export across plasma membrane	IDA Inferred from Direct Assay more info	PubMed
involved_in potassium ion export across plasma membrane	IGI Inferred from Genetic Interaction more info	PubMed
involved_in potassium ion homeostasis	IDA Inferred from Direct Assay more info	PubMed
involved_in potassium ion import across plasma membrane	IDA Inferred from Direct Assay more info	PubMed
involved_in potassium ion transmembrane transport	IBA Inferred from Biological aspect of Ancestor more info
involved_in potassium ion transmembrane transport	IDA Inferred from Direct Assay more info	PubMed
involved_in potassium ion transmembrane transport	IEA Inferred from Electronic Annotation more info
involved_in potassium ion transport	IDA Inferred from Direct Assay more info	PubMed
involved_in regulation of heart rate by cardiac conduction	IBA Inferred from Biological aspect of Ancestor more info
acts_upstream_of_or_within regulation of heart rate by cardiac conduction	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in regulation of heart rate by cardiac conduction	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in regulation of heart rate by hormone	TAS Traceable Author Statement more info	PubMed
involved_in regulation of membrane potential	IDA Inferred from Direct Assay more info	PubMed
involved_in regulation of membrane repolarization	IDA Inferred from Direct Assay more info	PubMed
involved_in regulation of potassium ion transmembrane transport	IDA Inferred from Direct Assay more info	PubMed
involved_in regulation of ventricular cardiac muscle cell membrane repolarization	IBA Inferred from Biological aspect of Ancestor more info
involved_in regulation of ventricular cardiac muscle cell membrane repolarization	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in ventricular cardiac muscle cell action potential	IMP Inferred from Mutant Phenotype more info	PubMed

Component	Evidence Code	Pubs
located_in cell surface	IDA Inferred from Direct Assay more info	PubMed
part_of inward rectifier potassium channel complex	IMP Inferred from Mutant Phenotype more info	PubMed
located_in perinuclear region of cytoplasm	IMP Inferred from Mutant Phenotype more info	PubMed
is_active_in plasma membrane	IBA Inferred from Biological aspect of Ancestor more info
located_in plasma membrane	IDA Inferred from Direct Assay more info	PubMed
located_in plasma membrane	IMP Inferred from Mutant Phenotype more info	PubMed
located_in plasma membrane	TAS Traceable Author Statement more info
part_of voltage-gated potassium channel complex	IDA Inferred from Direct Assay more info	PubMed
part_of voltage-gated potassium channel complex	IMP Inferred from Mutant Phenotype more info	PubMed

General protein information

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Preferred Names: voltage-gated inwardly rectifying potassium channel KCNH2; potassium voltage-gated channel subfamily H member 2

Names: eag homolog; eag-related protein 1; ether-a-go-go-related gene potassium channel 1; ether-a-go-go-related potassium channel protein; ether-a-go-go-related protein 1; human ether-a-go-go-related; long QT syndrome type 2; potassium channel, voltage gated eag related subfamily H, member 2; potassium voltage-gated channel, subfamily H (eag-related), member 2; voltage-gated potassium channel subunit Kv11.1

NCBI Reference Sequences (RefSeq)

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RefSeqs maintained independently of Annotated Genomes

These reference sequences exist independently of genome builds. Explain

These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

Genomic

NG_008916.1 RefSeqGene

Range

4613..37971

Download

GenBank, FASTA, Sequence Viewer (Graphics), LRG_288

mRNA and Protein(s)

NM_000238.4 → NP_000229.1 voltage-gated inwardly rectifying potassium channel KCNH2 isoform a

See identical proteins and their annotated locations for NP_000229.1

Status: REVIEWED

Description

Transcript Variant: This variant (1) encodes the longest isoform (a).

Source sequence(s)

AC011234, AF363636, DQ525913, U04270

Consensus CDS

CCDS5910.1

UniProtKB/Swiss-Prot

A5H1P7, C4PFH9, D3DX04, O75418, O75680, Q12809, Q708S9, Q9BT72, Q9BUT7, Q9H3P0

UniProtKB/TrEMBL

A0A090N8Q0, Q15BH2

Related

ENSP00000262186.5, ENST00000262186.10

Conserved Domains (4) summary

cd00038
Location:742 → 853

CAP_ED; effector domain of the CAP family of transcription factors; members include CAP (or cAMP receptor protein (CRP)), which binds cAMP, FNR (fumarate and nitrate reduction), which uses an iron-sulfur cluster to sense oxygen) and CooA, a heme containing CO ...

pfam00520
Location:409 → 668

Ion_trans; Ion transport protein

pfam13426
Location:29 → 130

PAS_9; PAS domain

pfam15836
Location:1012 → 1113

SSTK-IP; SSTK-interacting protein, TSSK6-activating co-chaperone protein
NM_001204798.2 → NP_001191727.1 voltage-gated inwardly rectifying potassium channel KCNH2 isoform d

See identical proteins and their annotated locations for NP_001191727.1

Status: REVIEWED

Description

Transcript Variant: This variant (4) differs in the 5' and 3' UTRs and 5' and 3' coding regions compared to variant 1, resulting in a shorter isoform (d) with different N- and C-termini compared to isoform a.

Source sequence(s)

AJ609614, BC001914, BG683210, BQ478289

UniProtKB/Swiss-Prot

Q12809

Related

ENST00000461280.2

Conserved Domains (3) summary

smart00100
Location:402 → 462

cNMP; Cyclic nucleotide-monophosphate binding domain

pfam00520
Location:109 → 328

Ion_trans; Ion transport protein

pfam07885
Location:271 → 325

Ion_trans_2; Ion channel
NM_001406753.1 → NP_001393682.1 voltage-gated inwardly rectifying potassium channel KCNH2 isoform e

Status: REVIEWED

Source sequence(s)

AC006343

Related

ENST00000684241.1
NM_001406755.1 → NP_001393684.1 voltage-gated inwardly rectifying potassium channel KCNH2 isoform f

Status: REVIEWED

Source sequence(s)

AC006343, AC011234

Related

ENST00000713700.1
NM_001406756.1 → NP_001393685.1 voltage-gated inwardly rectifying potassium channel KCNH2 isoform g

Status: REVIEWED

Source sequence(s)

AC006343
NM_001406757.1 → NP_001393686.1 voltage-gated inwardly rectifying potassium channel KCNH2 isoform h

Status: REVIEWED

Source sequence(s)

AC006343, AC011234
NM_172056.3 → NP_742053.1 voltage-gated inwardly rectifying potassium channel KCNH2 isoform b

See identical proteins and their annotated locations for NP_742053.1

Status: REVIEWED

Description

Transcript Variant: This variant (2), also known as HERG-USO, differs in the 3' UTR and 3' coding region compared to variant 1, resulting in a shorter isoform (b) with a different C-terminus compared to isoform a.

Source sequence(s)

AC006343, AC011234

UniProtKB/TrEMBL

A0A090N7W1, Q86U57

Related

ENST00000532957.5

Conserved Domains (5) summary

smart00100
Location:742 → 802

cNMP; Cyclic nucleotide-monophosphate binding domain

cd00130
Location:41 → 132

PAS; PAS domain; PAS motifs appear in archaea, eubacteria and eukarya. Probably the most surprising identification of a PAS domain was that in EAG-like K+-channels. PAS domains have been found to bind ligands, and to act as sensors for light and oxygen in ...

pfam00520
Location:449 → 668

Ion_trans; Ion transport protein

pfam07885
Location:611 → 665

Ion_trans_2; Ion channel

pfam13426
Location:29 → 130

PAS_9; PAS domain
NM_172057.3 → NP_742054.1 voltage-gated inwardly rectifying potassium channel KCNH2 isoform c

See identical proteins and their annotated locations for NP_742054.1

Status: REVIEWED

Description

Transcript Variant: This variant (3), also known as HERG1b, differs in the 5' UTR and 5' coding region compared to variant 1, resulting in a shorter isoform (c) with a different N-terminus compared to isoform a.

Source sequence(s)

AC006343

Consensus CDS

CCDS5911.1

UniProtKB/TrEMBL

A0A090N7X5

Related

ENSP00000328531.4, ENST00000330883.9

Conserved Domains (5) summary

COG0664
Location:396 → 516

Crp; cAMP-binding domain of CRP or a regulatory subunit of cAMP-dependent protein kinases [Signal transduction mechanisms]

cd00038
Location:402 → 513

CAP_ED; effector domain of the CAP family of transcription factors; members include CAP (or cAMP receptor protein (CRP)), which binds cAMP, FNR (fumarate and nitrate reduction), which uses an iron-sulfur cluster to sense oxygen) and CooA, a heme containing CO ...

pfam00520
Location:109 → 328

Ion_trans; Ion transport protein

pfam07885
Location:271 → 325

Ion_trans_2; Ion channel

pfam15836
Location:672 → 773

SSTK-IP; SSTK-interacting protein, TSSK6-activating co-chaperone protein

RNA

NR_176254.1 RNA Sequence

Status: REVIEWED

Source sequence(s)

AC006343, AC011234
NR_176255.1 RNA Sequence

Status: REVIEWED

Source sequence(s)

AC006343

RefSeqs of Annotated Genomes: GCF_000001405.40-RS_2024_08

The following sections contain reference sequences that belong to a specific genome build. Explain

Reference GRCh38.p14 Primary Assembly

Genomic

NC_000007.14 Reference GRCh38.p14 Primary Assembly

Range

150944961..150978321 complement

Download

GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

XM_047420348.1 → XP_047276304.1 potassium voltage-gated channel subfamily H member 2 isoform X1
XM_017012196.2 → XP_016867685.1 potassium voltage-gated channel subfamily H member 2 isoform X3

UniProtKB/TrEMBL

Q15BH2
XM_011516185.3 → XP_011514487.1 potassium voltage-gated channel subfamily H member 2 isoform X4

UniProtKB/TrEMBL

A0AAQ5BGQ9, Q15BH2

Related

ENSP00000519004.1, ENST00000713701.1

Conserved Domains (5) summary

COG0664
Location:636 → 756

Crp; cAMP-binding domain of CRP or a regulatory subunit of cAMP-dependent protein kinases [Signal transduction mechanisms]

cd00038
Location:642 → 753

CAP_ED; effector domain of the CAP family of transcription factors; members include CAP (or cAMP receptor protein (CRP)), which binds cAMP, FNR (fumarate and nitrate reduction), which uses an iron-sulfur cluster to sense oxygen) and CooA, a heme containing CO ...

pfam00520
Location:349 → 568

Ion_trans; Ion transport protein

pfam07885
Location:511 → 565

Ion_trans_2; Ion channel

pfam15836
Location:912 → 1013

SSTK-IP; SSTK-interacting protein, TSSK6-activating co-chaperone protein
XM_017012195.2 → XP_016867684.1 potassium voltage-gated channel subfamily H member 2 isoform X2

UniProtKB/TrEMBL

Q15BH2

Conserved Domains (1) summary

PLN03192
Location:360 → 797

PLN03192; Voltage-dependent potassium channel; Provisional
XM_047420349.1 → XP_047276305.1 potassium voltage-gated channel subfamily H member 2 isoform X5

Alternate T2T-CHM13v2.0

Genomic

NC_060931.1 Alternate T2T-CHM13v2.0

Range

152117824..152151201 complement

Download

GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

XM_054358168.1 → XP_054214143.1 potassium voltage-gated channel subfamily H member 2 isoform X1
XM_054358170.1 → XP_054214145.1 potassium voltage-gated channel subfamily H member 2 isoform X3
XM_054358171.1 → XP_054214146.1 potassium voltage-gated channel subfamily H member 2 isoform X4

UniProtKB/TrEMBL

A0AAQ5BGQ9
XM_054358169.1 → XP_054214144.1 potassium voltage-gated channel subfamily H member 2 isoform X2
XM_054358172.1 → XP_054214147.1 potassium voltage-gated channel subfamily H member 2 isoform X5