KCNE1

Chr 21ARAD

potassium voltage-gated channel subfamily E regulatory subunit 1

Also known as: ISK, JLNS, JLNS2, LQT2/5, LQT5, MinK

NCBI Gene: 3753 ENSG00000180509 UniProt: P15382 OMIM: 176261

The product of this gene belongs to the potassium channel KCNE family. Potassium ion channels are essential to many cellular functions and show a high degree of diversity, varying in their electrophysiologic and pharmacologic properties. This gene encodes a transmembrane protein known to associate with the product of the KVLQT1 gene to form the delayed rectifier potassium channel. Mutation in this gene are associated with both Jervell and Lange-Nielsen and Romano-Ward forms of long-QT syndrome. Alternatively spliced transcript variants encoding the same protein have been identified. [provided by RefSeq, Jul 2008]

GeneReviews OMIM Research

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismAR/ADLOEUF 1.932 OMIM phenotypes

Clinical Summary— KCNE1

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Gene-Disease Validity (ClinGen)

long QT syndrome 5 · ADLimited

Limited evidence — not for standalone diagnostic reporting

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

22 unique Pathogenic / Likely Pathogenic· 175 VUS of 1265 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — KCNE1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.93LOEUF

pLI 0.003

Z-score -0.63

OE 1.48 (0.56–1.93)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.62Z-score

OE missense 1.19 (1.01–1.41)

97 obs / 81.4 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?1.48 (0.56–1.93)

0≤0.351.4

Missense OE?1.19 (1.01–1.41)

0≤0.61.4

Synonymous OE?1.29

0≤1.21.6

LoF obs/exp: 3 / 2.0Missense obs/exp: 97 / 81.4Syn Z: -1.39

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongKCNE1-related Jervell and Lange-Nielsen syndromeOTHERAR

limitedKCNE1-related long QT syndromeOTHERAD

This gene — mechanism propensity

0.74top 25%

GOF

0.78top 25%

LOF

0.2873th %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 · 1 literature citation

DNprediction above median · 1 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

DNCoassembly of certain mutant KCNE1 monomers with wild-type KCNQ1 subunits results in RWS by a dominant negative mechanism.1

GOFGain-of-function mutations in KCNQ1 and KCNE1 shorten the action potential duration in cardiac myocytes, but their effect on beta cells and insulin secretion is unknown.CASE PRESENTATION: Two patients with atrial fibrillation due to gain-of-function mutations in KCNQ1 (R670K) and KCNE1 (G60D) were B2

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

References

ClinVar Variant Classifications

1265 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic13

Likely Pathogenic9

VUS175

Likely Benign88

Benign37

Conflicting42

Pathogenic

Likely Pathogenic

175

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	9	3	1	0	13
Likely Pathogenic	4	5	0	0	9
VUS	8	112	55	0	175
Likely Benign	0	2	29	57	88
Benign	0	1	36	0	37
Conflicting	—				42
Total	21	123	121	57	364

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

View in ClinVar →

63 pathogenic / likely-pathogenic (of 81) ClinVar copy-number / structural variants overlap KCNE1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →