Third-degree atrioventricular block

Summary

Third-degree atrioventricular block (MONDO:0000468) is a disease with 5 cohort genes and 14 clinical trials. Top therapeutic interventions include cephalexin anhydrous, acetaminophen, and aminophylline.

At a glance

• Cohort genes: 5
• ClinVar variants: 6
• Clinical trials: 14

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	third-degree atrioventricular block
Mondo ID	MONDO:0000468
DOID	DOID:0050823
ICD-11	1147105932
NCIT	C50501
SNOMED CT	27885002
UMLS	C0151517
MedGen	56230
Is cancer (heuristic)	no

Also known as: atrioventricular block complete · atrioventricular block, third degree · AV block third degree · complete atrioventricular block · complete AV block · complete heart block · non-congenital complete atrioventricular block · third degree atrioventricular block · third degree AV block

Data availability: 6 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by body system or component › cardiovascular disorder › heart disorder › heart conduction disease › atrioventricular block › third-degree atrioventricular block

Related subtypes (3): first-degree atrioventricular block, second-degree atrioventricular block, congenital heart block

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

6 retrieved; paginated sample, class counts are floors:

2 pathogenic, 2 likely pathogenic, 1 uncertain significance, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1679818	NM_001127208.3(TET2):c.3562A>T (p.Lys1188Ter)	TET2	Pathogenic	no assertion criteria provided
202415	NM_001267550.2(TTN):c.82240C>T (p.Arg27414Ter)	TTN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1679820	NM_021830.5(TWNK):c.1485-1G>A	TWNK	Pathogenic	no assertion criteria provided
1679819	NM_182961.4(SYNE1):c.11083G>T (p.Glu3695Ter)	SYNE1	Likely pathogenic	no assertion criteria provided
634902	NM_001267550.2(TTN):c.49287C>A (p.Asn16429Lys)	TTN	Likely pathogenic	criteria provided, single submitter
1679821	NM_002234.4(KCNA5):c.1105_1112del (p.Phe369fs)	KCNA5	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 33 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TWNK	Orphanet:1186	Infantile-onset spinocerebellar ataxia
TWNK	Orphanet:254892	Autosomal dominant progressive external ophthalmoplegia
TWNK	Orphanet:363534	Mitochondrial DNA depletion syndrome, hepatocerebrorenal form
TWNK	Orphanet:642945	Perrault syndrome type 1
TWNK	Orphanet:642976	Perrault syndrome type 2
TWNK	Orphanet:70595	Sensory ataxic neuropathy-dysarthria-ophthalmoparesis syndrome
TTN	Orphanet:140922	Titin-related limb-girdle muscular dystrophy R10
TTN	Orphanet:154	Familial isolated dilated cardiomyopathy
TTN	Orphanet:169186	Autosomal recessive centronuclear myopathy
TTN	Orphanet:178464	Hereditary myopathy with early respiratory failure
TTN	Orphanet:289377	Early-onset myopathy with fatal cardiomyopathy
TTN	Orphanet:293888	Inherited isolated arrhythmogenic cardiomyopathy, dominant-left variant
TTN	Orphanet:293899	Inherited isolated arrhythmogenic ventricular dysplasia, biventricular variant
TTN	Orphanet:293910	Inherited isolated arrhythmogenic cardiomyopathy, dominant-right variant
TTN	Orphanet:324604	Classic multiminicore myopathy
TTN	Orphanet:334	Hereditary atrial fibrillation
TTN	Orphanet:466921	Childhood-onset progressive contractures-limb-girdle weakness-muscle dystrophy syndrome
TTN	Orphanet:609	Tibial muscular dystrophy
TTN	Orphanet:707983	Early-onset autosomal recessive TTN-related distal myopathy
SYNE1	Orphanet:319332	Autosomal recessive myogenic arthrogryposis multiplex congenita
SYNE1	Orphanet:88644	Autosomal recessive ataxia, Beauce type
SYNE1	Orphanet:98853	Autosomal dominant Emery-Dreifuss muscular dystrophy
TET2	Orphanet:100019	Myelodysplastic neoplasm with increased blasts type 1
TET2	Orphanet:100020	Myelodysplastic neoplasm with increased blasts type 2
TET2	Orphanet:3318	Essential thrombocythemia
TET2	Orphanet:664729	EBV-induced lymphoproliferative disease due to TET2 deficiency
TET2	Orphanet:75564	Acquired idiopathic sideroblastic anemia
TET2	Orphanet:824	Primary myelofibrosis
TET2	Orphanet:86845	Acute myeloid leukaemia with myelodysplasia-related features
TET2	Orphanet:98826	Myelodysplastic neoplasm with low blasts
TET2	Orphanet:98849	Systemic mastocytosis with associated hematologic neoplasm
TET2	Orphanet:98850	Aggressive systemic mastocytosis
KCNA5	Orphanet:334	Hereditary atrial fibrillation

Cohort genes → proteins

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TWNK	HGNC:1160	ENSG00000107815	Q96RR1	Twinkle mtDNA helicase	clinvar
TTN	HGNC:12403	ENSG00000155657	Q8WZ42	Titin	clinvar
SYNE1	HGNC:17089	ENSG00000131018	Q8NF91	Nesprin-1	clinvar
TET2	HGNC:25941	ENSG00000168769	Q6N021	Methylcytosine dioxygenase TET2	clinvar
KCNA5	HGNC:6224	ENSG00000130037	P22460	Potassium voltage-gated channel subfamily A member 5	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TWNK	Twinkle mtDNA helicase	Mitochondrial helicase involved in mtDNA replication and repair.
TTN	Titin	Key component in the assembly and functioning of vertebrate striated muscles.
SYNE1	Nesprin-1	Multi-isomeric modular protein which forms a linking network between organelles and the actin cytoskeleton to maintain the subcellular spatial organization.
TET2	Methylcytosine dioxygenase TET2	Dioxygenase that catalyzes the conversion of the modified genomic base 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC) and plays a key role in active DNA demethylation.
KCNA5	Potassium voltage-gated channel subfamily A member 5	Voltage-gated potassium channel that mediates transmembrane potassium transport in excitable membranes.

Protein-family classification

Druggable: 3 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.6

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	22.3×	0.176
Kinase	1	5.5×	0.336
Enzyme (other)	1	2.4×	0.471
Other/Unknown	2	0.7×	0.877

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TWNK	Enzyme (other)	yes	3.6.4.12	DNA_helicase_DnaB-like_C, Twinkle-like, P-loop_NTPase
TTN	Kinase	yes	2.7.11.1	Prot_kinase_dom, Ig_sub2, Ig_sub
SYNE1	Other/Unknown	no		Actinin_actin-bd_CS, CH_dom, Spectrin_repeat
TET2	Other/Unknown	no		2OGFeDO_JBP1/TET_oxygenase_dom, TET1/2/3, TET_oxygenase
KCNA5	Ion channel	yes		BTB/POZ_dom, T1-type_BTB, K_chnl_volt-dep_Kv

Expression context

Cohort genes with no expression data: 0.

4 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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
gastrocnemius	1
male germ line stem cell (sensu Vertebrata) in testis	1
tendon of biceps brachii	1
biceps brachii	1
gluteal muscle	1
skeletal muscle tissue of biceps brachii	1
calcaneal tendon	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
amniotic fluid	1
epithelium of nasopharynx	1
palpebral conjunctiva	1
blood vessel layer	1
cardiac atrium	1
cardiac muscle of right atrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TWNK	211	ubiquitous	yes	male germ line stem cell (sensu Vertebrata) in testis, tendon of biceps brachii, gastrocnemius
TTN	223	broad	marker	biceps brachii, gluteal muscle, skeletal muscle tissue of biceps brachii
SYNE1	275	ubiquitous	marker	cerebellar hemisphere, right hemisphere of cerebellum, calcaneal tendon
TET2	249	ubiquitous	marker	palpebral conjunctiva, amniotic fluid, epithelium of nasopharynx
KCNA5	179	broad	marker	cardiac muscle of right atrium, blood vessel layer, cardiac atrium

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TTN	4,237
TET2	2,965
SYNE1	2,886
KCNA5	2,288
TWNK	1,390

Intra-cohort edges

A	B	Sources
SYNE1	TTN	string_interaction

Structural data

PDB: 4 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TTN	Q8WZ42	64
TET2	Q6N021	6
SYNE1	Q8NF91	3
TWNK	Q96RR1	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
KCNA5	P22460	72.64

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 19. Enrichment computed across 5 evidence-associated genes (5 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 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Reproduction	2	76.1×	0.005	SYNE1, TET2
TET1,2,3 and TDG demethylate DNA	1	571.0×	0.017	TET2
Phase 3 - rapid repolarisation	1	228.4×	0.021	KCNA5
Strand-asynchronous mitochondrial DNA replication	1	228.4×	0.021	TWNK
Specification of primordial germ cells	1	175.7×	0.022	TET2
Striated Muscle Contraction	1	61.7×	0.047	TTN
Meiosis	1	57.1×	0.047	SYNE1
Voltage gated Potassium channels	1	48.6×	0.048	KCNA5
Transcriptional activation of mitochondrial biogenesis	1	40.8×	0.051	TWNK
Meiotic synapsis	1	28.2×	0.063	SYNE1
Potassium Channels	1	26.9×	0.063	KCNA5
Mitochondrial protein degradation	1	22.8×	0.066	TWNK
Cardiac conduction	1	21.8×	0.066	KCNA5
Platelet degranulation	1	17.6×	0.076	TTN
Muscle contraction	1	15.4×	0.080	KCNA5
Epigenetic regulation of gene expression	1	14.3×	0.081	TET2
Neuronal System	1	8.8×	0.121	KCNA5
Cell Cycle	1	7.2×	0.139	SYNE1
Gene expression (Transcription)	1	3.6×	0.251	TET2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
membrane repolarization during bundle of His cell action potential	1	1685.2×	0.010	KCNA5
membrane repolarization during SA node cell action potential	1	1685.2×	0.010	KCNA5
skeletal muscle myosin thick filament assembly	1	1123.5×	0.010	TTN
sarcomerogenesis	1	1123.5×	0.010	TTN
nuclear matrix anchoring at nuclear membrane	1	1123.5×	0.010	SYNE1
leukocyte differentiation	1	674.1×	0.010	TET2
skeletal muscle thin filament assembly	1	561.7×	0.010	TTN
membrane repolarization during atrial cardiac muscle cell action potential	1	561.7×	0.010	KCNA5
mitochondrial transcription	1	481.5×	0.010	TWNK
detection of muscle stretch	1	481.5×	0.010	TTN
regulation of atrial cardiac muscle cell membrane repolarization	1	481.5×	0.010	KCNA5
membrane hyperpolarization	1	374.5×	0.010	KCNA5
cardiac muscle hypertrophy	1	337.0×	0.010	TTN
atrial cardiac muscle cell action potential	1	337.0×	0.010	KCNA5
mitochondrial DNA replication	1	306.4×	0.010	TWNK
obsolete protein kinase A signaling	1	280.9×	0.010	TTN
protein hexamerization	1	280.9×	0.010	TWNK
cardiac muscle tissue morphogenesis	1	280.9×	0.010	TTN
positive regulation of myoblast proliferation	1	280.9×	0.010	KCNA5
negative regulation of cytosolic calcium ion concentration	1	259.3×	0.010	KCNA5
cardiac myofibril assembly	1	259.3×	0.010	TTN
positive regulation of gene expression via chromosomal CpG island demethylation	1	240.7×	0.011	TET2
response to hyperoxia	1	224.7×	0.011	KCNA5
muscle filament sliding	1	210.7×	0.011	TTN
potassium ion export across plasma membrane	1	210.7×	0.011	KCNA5
mitotic chromosome condensation	1	198.3×	0.011	TTN
striated muscle contraction	1	168.5×	0.012	TTN
muscle cell differentiation	1	168.5×	0.012	SYNE1
regulation of vasoconstriction	1	160.5×	0.012	KCNA5
potassium ion homeostasis	1	153.2×	0.012	KCNA5

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 5 evidence-associated genes (60%) 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
TET2	VADADUSTAT
KCNA5	DRONEDARONE HYDROCHLORIDE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KCNA5	8	4
TET2	3	4
TWNK	0	0
TTN	0	0
SYNE1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
VADADUSTAT	4	TET2
PANOBINOSTAT	4	TET2
DEFEROXAMINE	4	TET2
DRONEDARONE HYDROCHLORIDE	4	KCNA5
SERTINDOLE	4	KCNA5
QUINIDINE	4	KCNA5
NIFEDIPINE	4	KCNA5
VERNAKALANT HYDROCHLORIDE	4	KCNA5
FLECAINIDE	4	KCNA5
BMS-919373	2	KCNA5
BMS-394136	1	KCNA5

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
KCNA5	152	Binding:130, Functional:14, ADMET:5, Toxicity:3
TET2	24	Binding:24
TTN	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TWNK	3.6.4.12	DNA helicase
TTN	2.7.11.1	non-specific serine/threonine protein kinase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
KCNA5	152

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

11 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)
VADADUSTAT	4	TET2
PANOBINOSTAT	4	TET2
DEFEROXAMINE	4	TET2
DRONEDARONE HYDROCHLORIDE	4	KCNA5
SERTINDOLE	4	KCNA5
QUINIDINE	4	KCNA5
NIFEDIPINE	4	KCNA5
VERNAKALANT HYDROCHLORIDE	4	KCNA5
FLECAINIDE	4	KCNA5
BMS-919373	2	KCNA5
BMS-394136	1	KCNA5

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	TET2, KCNA5
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	2	TWNK, TTN
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	SYNE1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TWNK	0	—
TTN	1	—
SYNE1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 14.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	11
PHASE4	2
PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04931693	PHASE4	COMPLETED	PECs Block for Pacemaker Insertion in Children
NCT05666219	PHASE4	WITHDRAWN	Reversal of Complete Heart Block With Aminophylline in Inferior Wall Myocardial Infarction Patients
NCT02809131	PHASE3	COMPLETED	Perioperative Antibiotic Therapy to Prevent Cardiac Implantable Electronic Device Infections.
NCT05541679	Not specified	ACTIVE_NOT_RECRUITING	Comparison of Left Bundle Branch Area Versus Right Ventricular Septal Pacing in Patients With High-degree Conduction Disease After Transcatheter Aortic Valve Replacement (Left Bundle BRAVE)
NCT06324682	Not specified	RECRUITING	ConTempoRary Cardiac Stimulation in Clinical practicE: lEft, BivEntriculAr, Right, and conDuction System Pacing
NCT06474819	Not specified	RECRUITING	Left Septal or Deep Septal Pacing to Prevent Pacing-induced Cardiomyopathy
NCT00374608	Not specified	COMPLETED	Exercise in Chronically Paced Children
NCT01302717	Not specified	WITHDRAWN	Left Ventricular Pacing to Avoid Cardiac Enlargement Study
NCT01477658	Not specified	UNKNOWN	Effects of Chronic Right Ventricular Pacing in Children With Advanced Atrioventricular Block
NCT02881671	Not specified	UNKNOWN	Identification of Genetic Basis of Atrioventricular Conduction Defects: From Congenital Forms to Degenerative Forms
NCT03118427	Not specified	UNKNOWN	Zero-fluoroscopic Navigation Versus Conventional Fluoroscopic Navigation for Double-chamber Pacemaker Implantation
NCT03118440	Not specified	UNKNOWN	Zero-fluoroscopic Navigation Versus Conventional Fluoroscopic Navigation for Single-chamber Pacemaker Implantation
NCT04245345	Not specified	COMPLETED	Accelerometer Sensing for Micra AV Study
NCT06857201	Not specified	WITHDRAWN	RAFT-TAVR PACE: LBBAP vs. RVP Post-TAVR in Patients Requiring PPI

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
CEPHALEXIN ANHYDROUS	4	3
ACETAMINOPHEN	4	1
AMINOPHYLLINE	4	1
BACITRACIN	4	1
CHEMBL3764363	0	1
CHEMBL4096945	0	1
CHEMBL4209556	0	1
CHEMBL4303306	0	1