long QT syndrome 6

Summary

long QT syndrome 6 (MONDO:0013370) is a disease with 3 cohort genes.

At a glance

• Cohort genes: 3
• ClinVar variants: 115

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	long QT syndrome 6
Mondo ID	MONDO:0013370
MeSH	C566333
OMIM	613693
DOID	DOID:0110648
UMLS	C3150953
MedGen	462303
GARD	0010434
Is cancer (heuristic)	no

Also known as: KCNE2 long QT syndrome · long QT syndrome 6 · long QT syndrome caused by mutation in KCNE2 · long QT syndrome type 6 · LQT6

Data availability: 115 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › long QT syndrome › familial long QT syndrome › long QT syndrome 6

Related subtypes (18): Jervell and Lange-Nielsen syndrome, Andersen-Tawil syndrome, cardiac arrhythmia, ankyrin-B-related, Timothy syndrome, long QT syndrome 3, long QT syndrome 9, long QT syndrome 10, long QT syndrome 11, long QT syndrome 12, long QT syndrome 13, long QT syndrome 2, long QT syndrome 5, long QT syndrome 14, long QT syndrome 15, long QT syndrome 8, long QT syndrome 16, long QT syndrome 1, long QT syndrome 4

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

115 retrieved; paginated sample, class counts are floors:

60 uncertain significance, 28 likely benign, 21 conflicting classifications of pathogenicity, 5 benign/likely benign, 1 conflicting classifications of pathogenicity; risk factor

ClinVar	Variant (HGVS)	Gene	Classification	Review
190792	NM_172201.2(KCNE2):c.354G>A (p.Gly118=)	KCNE2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
191164	NM_172201.2(KCNE2):c.209G>A (p.Ser70Asn)	KCNE2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
339714	NM_172201.2(KCNE2):c.-85G>A	KCNE2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
379226	NM_172201.2(KCNE2):c.317C>T (p.Ser106Leu)	KCNE2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
471499	NM_172201.2(KCNE2):c.190A>G (p.Ile64Val)	KCNE2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
538876	NM_172201.2(KCNE2):c.204G>A (p.Leu68=)	KCNE2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
6053	NM_172201.2(KCNE2):c.161T>C (p.Met54Thr)	KCNE2	Conflicting classifications of pathogenicity; risk factor	criteria provided, conflicting classifications
6054	NM_172201.2(KCNE2):c.170T>C (p.Ile57Thr)	KCNE2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
6055	NM_172201.2(KCNE2):c.79C>T (p.Arg27Cys)	KCNE2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
67615	NM_172201.2(KCNE2):c.22A>G (p.Thr8Ala)	KCNE2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
67616	NM_172201.2(KCNE2):c.230G>A (p.Arg77Gln)	KCNE2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
898249	NM_172201.2(KCNE2):c.*11A>C	KCNE2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1390131	NM_172201.2(KCNE2):c.346G>A (p.Ala116Thr)	LOC105372791	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1475863	NM_172201.2(KCNE2):c.144dup (p.Val49fs)	LOC105372791	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
190797	NM_172201.2(KCNE2):c.369_370del (p.Ter124IleextTer?)	LOC105372791	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
339718	NM_172201.2(KCNE2):c.153G>T (p.Leu51=)	LOC105372791	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
339719	NM_172201.2(KCNE2):c.*62G>A	LOC105372791	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
67614	NM_172201.2(KCNE2):c.229C>T (p.Arg77Trp)	LOC105372791	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
67618	NM_172201.2(KCNE2):c.281A>G (p.Glu94Gly)	LOC105372791	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
67619	NM_172201.2(KCNE2):c.29C>T (p.Thr10Met)	LOC105372791	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
67620	NM_172201.2(KCNE2):c.347C>T (p.Ala116Val)	LOC105372791	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
67623	NM_172201.2(KCNE2):c.80G>A (p.Arg27His)	LOC105372791	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1420029	NC_000021.8:g.(?35742778)(35821932_?)dup	KCNE1	Uncertain significance	criteria provided, single submitter
1003090	NM_172201.2(KCNE2):c.344G>T (p.Gly115Val)	KCNE2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1005300	NM_172201.2(KCNE2):c.221C>A (p.Ser74Tyr)	KCNE2	Uncertain significance	criteria provided, single submitter
1010050	NM_172201.2(KCNE2):c.367C>T (p.Pro123Ser)	KCNE2	Uncertain significance	criteria provided, single submitter
1017741	NC_000021.8:g.(?35742768)(35743160_?)del	KCNE2	Uncertain significance	criteria provided, single submitter
1469989	NM_172201.2(KCNE2):c.238T>C (p.Ser80Pro)	KCNE2	Uncertain significance	criteria provided, single submitter
1485015	NM_172201.2(KCNE2):c.89C>T (p.Thr30Ile)	KCNE2	Uncertain significance	criteria provided, single submitter
1730180	NM_172201.2(KCNE2):c.331C>T (p.His111Tyr)	KCNE2	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 2 · Orphanet: 5 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
KCNE2	Limited	Autosomal dominant	long QT syndrome 6	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KCNE2	Orphanet:101016	Romano-Ward syndrome
KCNE2	Orphanet:334	Hereditary atrial fibrillation
KCNE1	Orphanet:101016	Romano-Ward syndrome
KCNE1	Orphanet:334	Hereditary atrial fibrillation
KCNE1	Orphanet:90647	Jervell and Lange-Nielsen syndrome

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
KCNE2	HGNC:6242	ENSG00000159197	Q9Y6J6	Potassium voltage-gated channel subfamily E member 2	gencc,clinvar
SMIM11	HGNC:1293	ENSG00000205670	P58511	Small integral membrane protein 11	clinvar
KCNE1	HGNC:6240	ENSG00000180509	P15382	Potassium voltage-gated channel subfamily E member 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KCNE2	Potassium voltage-gated channel subfamily E member 2	Ancillary protein that functions as a regulatory subunit of the voltage-gated potassium (Kv) channel complex composed of pore-forming and potassium-conducting alpha subunits and of regulatory beta subunits.
KCNE1	Potassium voltage-gated channel subfamily E member 1	Ancillary protein that functions as a regulatory subunit of the voltage-gated potassium (Kv) channel complex composed of pore-forming and potassium-conducting alpha subunits and of regulatory beta subunits.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.67

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Ion channel	2	74.3×	5e-04
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
KCNE2	Ion channel	yes		K_chnl_KCNE, K_chnl_volt-dep_bsu_KCNE2
SMIM11	Other/Unknown	no		SMIM11
KCNE1	Ion channel	yes		K_chnl_KCNE, KCNE1

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
body of stomach	2
cardia of stomach	1
pylorus	1
fundus of stomach	1
hindlimb stylopod muscle	1
blood	1
leukocyte	1
monocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KCNE2	161	tissue_specific	yes	body of stomach, pylorus, cardia of stomach
SMIM11	134		yes	body of stomach, hindlimb stylopod muscle, fundus of stomach
KCNE1	121	broad	marker	blood, monocyte, leukocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KCNE1	1,005
KCNE2	749
SMIM11	287

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KCNE1	P15382	5
KCNE2	Q9Y6J6	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SMIM11	P58511	82.10

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. Enrichment computed across 3 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Phase 3 - rapid repolarisation	2	1142.0×	3e-06	KCNE2, KCNE1
Phase 2 - plateau phase	2	761.3×	3e-06	KCNE2, KCNE1
Cardiac conduction	2	108.8×	1e-04	KCNE2, KCNE1
Muscle contraction	2	77.2×	2e-04	KCNE2, KCNE1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
negative regulation of delayed rectifier potassium channel activity	2	2808.7×	3e-06	KCNE2, KCNE1
membrane repolarization during action potential	2	1685.2×	3e-06	KCNE2, KCNE1
membrane repolarization during ventricular cardiac muscle cell action potential	2	1685.2×	3e-06	KCNE2, KCNE1
membrane repolarization	2	1296.3×	4e-06	KCNE2, KCNE1
potassium ion export across plasma membrane	2	1053.2×	4e-06	KCNE2, KCNE1
ventricular cardiac muscle cell action potential	2	991.3×	4e-06	KCNE2, KCNE1
regulation of ventricular cardiac muscle cell membrane repolarization	2	842.6×	5e-06	KCNE2, KCNE1
cardiac muscle cell action potential involved in contraction	2	702.2×	6e-06	KCNE2, KCNE1
regulation of potassium ion transmembrane transport	2	624.1×	7e-06	KCNE2, KCNE1
regulation of heart rate by cardiac conduction	2	374.5×	2e-05	KCNE2, KCNE1
potassium ion transmembrane transport	2	135.9×	1e-04	KCNE2, KCNE1
vestibular nucleus development	1	4213.0×	5e-04	KCNE1
secretory granule organization	1	1685.2×	0.001	KCNE1
negative regulation of protein targeting to membrane	1	1404.3×	0.001	KCNE1
regulation of potassium ion transport	1	936.2×	0.002	KCNE1
cardiac muscle cell contraction	1	842.6×	0.002	KCNE1
membrane repolarization during cardiac muscle cell action potential	1	842.6×	0.002	KCNE1
epithelial cell maturation	1	766.0×	0.002	KCNE1
regulation of membrane repolarization	1	648.1×	0.002	KCNE2
positive regulation of potassium ion transmembrane transport	1	495.6×	0.002	KCNE1
positive regulation of proteasomal protein catabolic process	1	495.6×	0.002	KCNE2
potassium ion import across plasma membrane	1	183.2×	0.006	KCNE2
cellular response to cAMP	1	145.3×	0.008	KCNE1
cellular response to xenobiotic stimulus	1	120.4×	0.009	KCNE2
regulation of membrane potential	1	115.4×	0.009	KCNE1
sensory perception of sound	1	50.5×	0.020	KCNE1

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 2

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
KCNE1	AMBRISENTAN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KCNE1	14	4
KCNE2	0	0
SMIM11	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
AMBRISENTAN	4	KCNE1
DULOXETINE	4	KCNE1
PALONOSETRON	4	KCNE1
DARUNAVIR	4	KCNE1
DARIFENACIN	4	KCNE1
TOLTERODINE	4	KCNE1
SOLIFENACIN	4	KCNE1
EVEROLIMUS	4	KCNE1
RALTEGRAVIR	4	KCNE1
MARAVIROC	4	KCNE1
ALVIMOPAN	4	KCNE1
NEBIVOLOL	4	KCNE1
SUNITINIB	4	KCNE1
NELFINAVIR	4	KCNE1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
KCNE1	117	Functional:63, Binding:47, ADMET:6, Toxicity:1

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
KCNE1	117

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

14 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
AMBRISENTAN	4	KCNE1
DULOXETINE	4	KCNE1
PALONOSETRON	4	KCNE1
DARUNAVIR	4	KCNE1
DARIFENACIN	4	KCNE1
TOLTERODINE	4	KCNE1
SOLIFENACIN	4	KCNE1
EVEROLIMUS	4	KCNE1
RALTEGRAVIR	4	KCNE1
MARAVIROC	4	KCNE1
ALVIMOPAN	4	KCNE1
NEBIVOLOL	4	KCNE1
SUNITINIB	4	KCNE1
NELFINAVIR	4	KCNE1

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	KCNE1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	KCNE2
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	SMIM11

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
KCNE2	0	—
SMIM11	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.