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

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]

Primary Disease Associations & Inheritance

Long QT syndrome 2MIM #613688

Short QT syndrome 1MIM #609620

590

ClinVar variants

Pathogenic / LP

1.00

pLI score· haploinsufficient

Active trials

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

85 Pathogenic / Likely Pathogenic· 307 VUS of 590 total submissions

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Clinical Trials

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

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

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?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.13 (0.07–0.27)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.64 (0.59–0.69)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.08

0≤1.21.6

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

ClinVar Variant Classifications

590 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic60

Likely Pathogenic25

VUS307

Likely Benign194

Benign1

Conflicting3

Pathogenic

Likely Pathogenic

307

VUS

194

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	45	1	14	0	60
Likely Pathogenic	12	7	6	0	25
VUS	7	269	28	3	307
Likely Benign	0	4	52	138	194
Benign	0	0	1	0	1
Conflicting	—				3
Total	64	281	101	141	590

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

KCNH2 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

KCNH2-related long QT syndrome

definitive

ADLoss Of FunctionAltered Gene Product Structure, Decreased Gene Product Level

Cardiac

G2P ↗

splice acceptor variantsplice donor variantframeshift variantstop gainedmissense variantinframe deletioninframe insertionstop gained NMD triggeringframeshift variant NMD triggering

KCNH2-related short QT syndrome

definitive

ADGain Of FunctionAltered Gene Product Structure

Cardiac

G2P ↗

missense variant

KCNH2-related Brugada syndrome

disputed

ADUndeterminedUncertain

Cardiac

G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org