Atrial fibrillation, familial, 3

Summary

Atrial fibrillation, familial, 3 (MONDO:0011857) is a disease caused by KCNQ1 (GenCC Strong), with 3 cohort genes.

At a glance

• Causal gene: KCNQ1 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 206

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	atrial fibrillation, familial, 3
Mondo ID	MONDO:0011857
MeSH	C563817
OMIM	607554
UMLS	C1837014
MedGen	373232
GARD	0015414
Is cancer (heuristic)	no

Also known as: ATFB3 · atrial fibrillation, familial, 3 · atrial fibrillation, familial, type 3 · familial atrial fibrillation caused by mutation in KCNQ1 · KCNQ1 familial atrial fibrillation

Data availability: 206 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by body system or component › cardiovascular disorder › heart disorder › cardiac rhythm disease › atrial fibrillation › familial atrial fibrillation › atrial fibrillation, familial, 3

Related subtypes (17): atrial fibrillation, familial, 1, atrial fibrillation, familial, 2, atrial fibrillation, familial, 4, atrial fibrillation, familial, 5, atrial fibrillation, familial, 6, atrial fibrillation, familial, 7, atrial fibrillation, familial, 8, atrial fibrillation, familial, 9, atrial fibrillation, familial, 10, atrial fibrillation, familial, 11, atrial fibrillation, familial, 12, atrial fibrillation, familial, 13, atrial fibrillation, familial, 14, atrial fibrillation, familial, 15, atrial fibrillation, familial, 18, atrial fibrillation, familial, 17, atrial fibrillation, familial, 16

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

206 retrieved; paginated sample, class counts are floors:

63 uncertain significance, 53 conflicting classifications of pathogenicity, 26 benign/likely benign, 24 pathogenic/likely pathogenic, 16 pathogenic, 10 benign, 8 likely benign, 6 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1452627	NM_000218.3(KCNQ1):c.771_775dup (p.Arg259fs)	KCNQ1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1778018	NM_000218.3(KCNQ1):c.1686G>C (p.Arg562Ser)	KCNQ1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3118	NM_000218.3(KCNQ1):c.760G>A (p.Val254Met)	KCNQ1	Pathogenic	reviewed by expert panel
3143	NM_000218.3(KCNQ1):c.418A>G (p.Ser140Gly)	KCNQ1	Pathogenic	no assertion criteria provided
3144	NM_000218.3(KCNQ1):c.805G>A (p.Gly269Ser)	KCNQ1	Pathogenic	criteria provided, multiple submitters, no conflicts
3382790	NM_000218.3(KCNQ1):c.744G>A (p.Trp248Ter)	KCNQ1	Pathogenic	criteria provided, single submitter
449221	NM_000218.3(KCNQ1):c.200_210del (p.Pro67fs)	KCNQ1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
52930	NM_000218.3(KCNQ1):c.1014CTT[1] (p.Phe340del)	KCNQ1	Pathogenic	criteria provided, multiple submitters, no conflicts
52950	NM_000218.3(KCNQ1):c.1075C>T (p.Gln359Ter)	KCNQ1	Pathogenic	criteria provided, multiple submitters, no conflicts
52953	NM_000218.3(KCNQ1):c.1085A>G (p.Lys362Arg)	KCNQ1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
52974	NM_000218.3(KCNQ1):c.1265dup (p.Phe423fs)	KCNQ1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
52978	NM_000218.3(KCNQ1):c.1343dup (p.Glu449fs)	KCNQ1	Pathogenic	criteria provided, multiple submitters, no conflicts
52983	NM_000218.3(KCNQ1):c.1486_1487del (p.Leu496fs)	KCNQ1	Pathogenic	criteria provided, multiple submitters, no conflicts
52984	NM_000218.3(KCNQ1):c.1513C>T (p.Gln505Ter)	KCNQ1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
52996	NM_000218.3(KCNQ1):c.1588C>T (p.Gln530Ter)	KCNQ1	Pathogenic	criteria provided, multiple submitters, no conflicts
52998	NM_000218.3(KCNQ1):c.1615C>T (p.Arg539Trp)	KCNQ1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
53003	NM_000218.3(KCNQ1):c.1664G>A (p.Arg555His)	KCNQ1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
53006	NM_000218.3(KCNQ1):c.1697C>T (p.Ser566Phe)	KCNQ1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
53009	NM_000218.3(KCNQ1):c.1702G>A (p.Gly568Arg)	KCNQ1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
53018	NM_000218.3(KCNQ1):c.1781G>A (p.Arg594Gln)	KCNQ1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
53025	NM_000218.3(KCNQ1):c.1892_1911del (p.Pro631fs)	KCNQ1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
53052	NM_000218.3(KCNQ1):c.502G>A (p.Gly168Arg)	KCNQ1	Pathogenic	criteria provided, multiple submitters, no conflicts
53056	NM_000218.3(KCNQ1):c.513C>G (p.Tyr171Ter)	KCNQ1	Pathogenic	criteria provided, multiple submitters, no conflicts
53058	NM_000218.3(KCNQ1):c.520C>T (p.Arg174Cys)	KCNQ1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
53059	NM_000218.3(KCNQ1):c.521G>A (p.Arg174His)	KCNQ1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
53070	NM_000218.3(KCNQ1):c.568C>T (p.Arg190Trp)	KCNQ1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
53077	NM_000218.3(KCNQ1):c.604G>A (p.Asp202Asn)	KCNQ1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
53084	NM_000218.3(KCNQ1):c.683+5G>A	KCNQ1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
53085	NM_000218.3(KCNQ1):c.686G>A (p.Gly229Asp)	KCNQ1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
53087	NM_000218.3(KCNQ1):c.692G>A (p.Arg231His)	KCNQ1	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · Orphanet: 6 · 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
KCNQ1	Strong	Autosomal dominant	atrial fibrillation, familial, 3	12

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KCNQ1	Orphanet:101016	Romano-Ward syndrome
KCNQ1	Orphanet:334	Hereditary atrial fibrillation
KCNQ1	Orphanet:51083	Congenital short QT syndrome
KCNQ1	Orphanet:90647	Jervell and Lange-Nielsen syndrome
KCNQ1OT1	Orphanet:2128	Isolated hemihyperplasia
KCNQ1OT1	Orphanet:231117	Beckwith-Wiedemann syndrome due to imprinting defect of 11p15

Cohort genes → proteins

3 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
KCNQ1	HGNC:6294	ENSG00000053918	P51787	Potassium voltage-gated channel subfamily KQT member 1	gencc,clinvar
KCNQ1-AS1	HGNC:42790	ENSG00000229414		KCNQ1 antisense RNA 1	clinvar
KCNQ1OT1	HGNC:6295	ENSG00000269821		KCNQ1 opposite strand/antisense transcript 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KCNQ1	Potassium voltage-gated channel subfamily KQT member 1	Pore-forming subunit of the voltage-gated potassium (Kv) channel involved in the regulation of cardiomyocyte excitability and important in normal development and functions of myocardium, inner ear, stomach and colon.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

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	1	37.2×	0.053
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
KCNQ1	Ion channel	yes		K_chnl_volt-dep_KCNQ, Ion_trans_dom, K_chnl_volt-dep_KCQN1
KCNQ1-AS1	Other/Unknown	no
KCNQ1OT1	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

2 cohort genes 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
left adrenal gland	1
left adrenal gland cortex	1
right adrenal gland cortex	1
hindlimb stylopod muscle	1
leukocyte	1
right ovary	1
cardiac muscle of right atrium	1
kidney epithelium	1
tibia	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KCNQ1	132	broad	marker	left adrenal gland cortex, left adrenal gland, right adrenal gland cortex
KCNQ1-AS1	87		yes	right ovary, hindlimb stylopod muscle, leukocyte
KCNQ1OT1	194	ubiquitous	marker	tibia, cardiac muscle of right atrium, kidney epithelium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KCNQ1	3,235
KCNQ1-AS1	0
KCNQ1OT1	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KCNQ1	P51787	28

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. Enrichment computed across 3 evidence-associated genes (1 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 1 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	1	1142.0×	0.005	KCNQ1
Phase 2 - plateau phase	1	761.3×	0.005	KCNQ1
Voltage gated Potassium channels	1	243.0×	0.010	KCNQ1
Potassium Channels	1	134.3×	0.013	KCNQ1
Cardiac conduction	1	108.8×	0.013	KCNQ1
Muscle contraction	1	77.2×	0.015	KCNQ1
Neuronal System	1	44.3×	0.023	KCNQ1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
gastrin-induced gastric acid secretion	1	16852.0×	0.001	KCNQ1
negative regulation of voltage-gated potassium channel activity	1	16852.0×	0.001	KCNQ1
rhythmic behavior	1	8426.0×	0.001	KCNQ1
corticosterone secretion	1	8426.0×	0.001	KCNQ1
stomach development	1	8426.0×	0.001	KCNQ1
regulation of gastric acid secretion	1	5617.3×	0.002	KCNQ1
membrane repolarization during atrial cardiac muscle cell action potential	1	2808.7×	0.002	KCNQ1
negative regulation of delayed rectifier potassium channel activity	1	2808.7×	0.002	KCNQ1
iodide transport	1	2407.4×	0.002	KCNQ1
regulation of atrial cardiac muscle cell membrane repolarization	1	2407.4×	0.002	KCNQ1
positive regulation of cardiac muscle contraction	1	2106.5×	0.002	KCNQ1
auditory receptor cell development	1	1872.4×	0.002	KCNQ1
adrenergic receptor signaling pathway	1	1872.4×	0.002	KCNQ1
intracellular chloride ion homeostasis	1	1685.2×	0.002	KCNQ1
renal absorption	1	1685.2×	0.002	KCNQ1
cardiac muscle cell contraction	1	1685.2×	0.002	KCNQ1
membrane repolarization during action potential	1	1685.2×	0.002	KCNQ1
membrane repolarization during cardiac muscle cell action potential	1	1685.2×	0.002	KCNQ1
atrial cardiac muscle cell action potential	1	1685.2×	0.002	KCNQ1
membrane repolarization during ventricular cardiac muscle cell action potential	1	1685.2×	0.002	KCNQ1
regulation of membrane repolarization	1	1296.3×	0.002	KCNQ1
cellular response to epinephrine stimulus	1	1296.3×	0.002	KCNQ1
intestinal absorption	1	1203.7×	0.002	KCNQ1
potassium ion export across plasma membrane	1	1053.2×	0.002	KCNQ1
renal sodium ion absorption	1	991.3×	0.002	KCNQ1
ventricular cardiac muscle cell action potential	1	991.3×	0.002	KCNQ1
positive regulation of potassium ion transmembrane transport	1	991.3×	0.002	KCNQ1
detection of mechanical stimulus involved in sensory perception of sound	1	936.2×	0.002	KCNQ1
regulation of ventricular cardiac muscle cell membrane repolarization	1	842.6×	0.002	KCNQ1
potassium ion homeostasis	1	766.0×	0.002	KCNQ1

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
KCNQ1	AMBRISENTAN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KCNQ1	15	4
KCNQ1-AS1	0	0
KCNQ1OT1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
AMBRISENTAN	4	KCNQ1
DULOXETINE	4	KCNQ1
PALONOSETRON	4	KCNQ1
DARUNAVIR	4	KCNQ1
DARIFENACIN	4	KCNQ1
TOLTERODINE	4	KCNQ1
SOLIFENACIN	4	KCNQ1
EVEROLIMUS	4	KCNQ1
RALTEGRAVIR	4	KCNQ1
MARAVIROC	4	KCNQ1
ALVIMOPAN	4	KCNQ1
NEBIVOLOL	4	KCNQ1
SUNITINIB	4	KCNQ1
NELFINAVIR	4	KCNQ1
VOLINANSERIN	3	KCNQ1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
KCNQ1	179	Binding:96, Functional:64, ADMET:14, Toxicity:5

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
KCNQ1	179

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

15 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	KCNQ1
DULOXETINE	4	KCNQ1
PALONOSETRON	4	KCNQ1
DARUNAVIR	4	KCNQ1
DARIFENACIN	4	KCNQ1
TOLTERODINE	4	KCNQ1
SOLIFENACIN	4	KCNQ1
EVEROLIMUS	4	KCNQ1
RALTEGRAVIR	4	KCNQ1
MARAVIROC	4	KCNQ1
ALVIMOPAN	4	KCNQ1
NEBIVOLOL	4	KCNQ1
SUNITINIB	4	KCNQ1
NELFINAVIR	4	KCNQ1
VOLINANSERIN	3	KCNQ1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	KCNQ1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	KCNQ1-AS1, KCNQ1OT1

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)
KCNQ1-AS1	0	—
KCNQ1OT1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.