KCNH7

Chr 2

potassium voltage-gated channel subfamily H member 7

Also known as: ERG3, HERG3, Kv11.3

NCBI Gene: 90134 ENSG00000184611 UniProt: Q9NS40

This protein forms the pore-forming subunit of voltage-gated inwardly rectifying potassium channels that regulate neuronal excitability and other cellular processes. Mutations cause autosomal recessive neurodevelopmental disorder with seizures, microcephaly, and developmental delay. The gene is highly constrained against loss-of-function variants (LOEUF 0.367), indicating that complete loss of protein function is likely not tolerated.

ResearchSummary from RefSeq, UniProt

Voltage-gated potassium (Kv) channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. This gene encodes a member of the potassium channel, voltage-gated, subfamily H. This member is a pore-forming (alpha) subunit. There are at least two alternatively spliced transcript variants derived from this gene and encoding distinct isoforms. [provided by RefSeq, Jul 2008]

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.37

Clinical Summary— KCNH7

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.23) despite low pLI — interpret in context.

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ClinVar Variants

103 VUS of 127 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.37LOEUF

pLI 0.282

Z-score 5.35

OE 0.23 (0.15–0.37)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

3.04Z-score

OE missense 0.66 (0.61–0.72)

426 obs / 642.9 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.23 (0.15–0.37)

0≤0.351.4

Missense OE?0.66 (0.61–0.72)

0≤0.61.4

Synonymous OE?1.09

0≤1.21.6

LoF obs/exp: 13 / 56.4Missense obs/exp: 426 / 642.9Syn Z: -1.15

This gene — mechanism propensity

0.75top 25%

GOF

0.79top 25%

LOF

0.4136th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

DNprediction above median

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.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

127 submitted variants in ClinVar

ClinVar

Classification Summary

VUS103

Likely Benign13

Benign5

103

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	103	0	103
Likely Benign	6	7	13
Benign	3	2	5
Total	112	9	121

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

View in ClinVar →

22 pathogenic / likely-pathogenic (of 26) ClinVar copy-number / structural variants overlap KCNH7 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →