KCNH2

Chr 7AD

potassium voltage-gated channel subfamily H member 2

Also known as: ERG-1, ERG1, H-ERG, HERG, HERG1, Kv11.1, LQT2, SQT1

NCBI Gene: 3757 ENSG00000055118 UniProt: Q12809 OMIM: 152427

The protein forms the pore-forming alpha subunit of voltage-gated inwardly rectifying potassium channels in cardiac muscle and nerve cells, characterized by rapid inactivation during depolarization and slow deactivation during repolarization. Mutations cause long QT syndrome type 2 and short QT syndrome type 1 through an autosomal dominant inheritance pattern via loss-of-function mechanisms. The gene is highly intolerant to loss-of-function variants, reflecting its critical role in cardiac repolarization.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

MultiplemechanismADLOEUF 0.272 OMIM phenotypes

Clinical Summary— KCNH2

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Gene-Disease Validity (ClinGen)

long QT syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

3 total gene-disease associations curated

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

52 unique Pathogenic / Likely Pathogenic· 158 VUS of 300 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — KCNH2

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint

0.27LOEUF

pLI 0.996

Z-score 4.99

OE 0.13 (0.07–0.27)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint

3.37Z-score

OE missense 0.64 (0.59–0.69)

439 obs / 687.9 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios

LoF OE0.13 (0.07–0.27)

0≤0.351.4

Missense OE0.64 (0.59–0.69)

0≤0.61.4

Synonymous OE1.08

0≤1.21.6

LoF obs/exp: 5 / 38.3Missense obs/exp: 439 / 687.9Syn Z: -1.03

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveKCNH2-related long QT syndromeLOFAD

definitiveKCNH2-related short QT syndromeGOFAD

limitedKCNH2-related Brugada syndromeOTHERAD

0.5870th %ile

GOF

0.74top 25%

LOF

0.65top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, gain-of-function and dominant-negative). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 1 literature citation · 88% of P/LP variants are LoF · LOEUF 0.27

GOFprediction above median · 1 literature citation

DN1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNThese results demonstrated that a trafficking-deficient mutation in the transmembrane nonpore region of KCNH2 causes a dominant negative effect and a severe clinical course in affected patients.PMID:23010577

GOFGain of function mutations in three genes encoding K(+) channels have been identified, explaining the abbreviated repolarization seen in this condition: KCNH2 for I(kr) (SQT1), KCNQ1 for I(ks) (SQT2) and KCNJ2 for I(k1) (SQT3).PMID:20126594

LOFHaploinsufficiency of PRKAG2 (aliases AAKG, AAKG2, H91620p, WPWS, and CMH6) and KCNH2 (aliases Kv11.1, HERG, and erg1) genes may be responsible of long QT syndrome observed for one patient.PMID:34582124

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.