progressive familial heart block, type 1A

Summary

progressive familial heart block, type 1A (MONDO:0007240) is a disease caused by SCN5A (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: SCN5A (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 410

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	progressive familial heart block, type 1A
Mondo ID	MONDO:0007240
MeSH	D002037
OMIM	113900
DOID	DOID:0111074
NCIT	C126651
UMLS	C1879286
MedGen	406301
GARD	0001093
Is cancer (heuristic)	no

Also known as: heart block progressive familial type 1 · heart block, progressive, type IA · Lenegre disease · Lenegre’s disease · Lenegre’s syndrome · Lev disease · PFHB1A · progressive familial heart block caused by mutation in SCN5A · progressive familial heart block type 1A · progressive familial heart block, type IA · SCN5A progressive familial heart block

Data availability: 410 ClinVar variants · 2 GenCC gene-disease records · 5 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › muscle tissue disorder › conduction system disorder › progressive familial heart block, type 1A

Related subtypes (3): sinoatrial node disorder, atrioventricular node disorder, atrial conduction disease

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

410 retrieved; paginated sample, class counts are floors:

215 uncertain significance, 127 conflicting classifications of pathogenicity, 37 benign/likely benign, 16 pathogenic/likely pathogenic, 7 pathogenic, 6 likely benign, 2 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
440849	NM_198056.2(SCN5A):c.[1535C>T;1673A>G]		Pathogenic	no assertion criteria provided
201438	NM_000335.5(SCN5A):c.664C>T (p.Arg222Ter)	SCN5A	Pathogenic	criteria provided, multiple submitters, no conflicts
201508	NM_000335.5(SCN5A):c.4242+1G>C	SCN5A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
201560	NM_000335.5(SCN5A):c.2550_2551dup (p.Phe851fs)	SCN5A	Pathogenic	criteria provided, multiple submitters, no conflicts
201572	NM_000335.5(SCN5A):c.4844TCT[1] (p.Phe1616del)	SCN5A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
39444	NM_000335.5(SCN5A):c.665G>A (p.Arg222Gln)	SCN5A	Pathogenic	criteria provided, multiple submitters, no conflicts
406415	NM_000335.5(SCN5A):c.5414_5417del (p.Thr1805fs)	SCN5A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
67633	NM_000335.5(SCN5A):c.1099C>T (p.Arg367Cys)	SCN5A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
67639	NM_000335.5(SCN5A):c.1127G>A (p.Arg376His)	SCN5A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
67753	NM_000335.5(SCN5A):c.2729C>T (p.Ser910Leu)	SCN5A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
67778	NM_000335.5(SCN5A):c.310C>T (p.Arg104Trp)	SCN5A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
67807	NM_000335.5(SCN5A):c.361C>T (p.Arg121Trp)	SCN5A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
67838	NM_000335.5(SCN5A):c.3953G>T (p.Gly1318Val)	SCN5A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
67932	NM_000335.5(SCN5A):c.4856C>T (p.Thr1619Met)	SCN5A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
67967	NM_000335.5(SCN5A):c.5224G>A (p.Gly1742Arg)	SCN5A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
68032	NM_000335.5(SCN5A):c.673C>T (p.Arg225Trp)	SCN5A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
9374	NM_000335.5(SCN5A):c.4864C>T (p.Arg1622Ter)	SCN5A	Pathogenic	criteria provided, multiple submitters, no conflicts
9377	NM_000335.5(SCN5A):c.5347G>A (p.Glu1783Lys)	SCN5A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
9378	NM_000335.5(SCN5A):c.3960+2T>C	SCN5A	Pathogenic	criteria provided, single submitter
9383	NM_000335.5(SCN5A):c.5126C>T (p.Ser1709Leu)	SCN5A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
9385	NM_000335.5(SCN5A):c.4780G>A (p.Asp1594Asn)	SCN5A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
9395	NM_000335.5(SCN5A):c.4219G>A (p.Gly1407Arg)	SCN5A	Pathogenic	criteria provided, multiple submitters, no conflicts
9406	NM_000335.5(SCN5A):c.4780G>C (p.Asp1594His)	SCN5A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3252218	NM_000335.5(SCN5A):c.2425_2426del (p.Ser809fs)	SCN5A	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3383167	NM_000335.5(SCN5A):c.3741T>G (p.Tyr1247Ter)	SCN5A	Likely pathogenic	criteria provided, single submitter
35486	NM_017636.4(TRPM4):c.1744G>A (p.Gly582Ser)	HRC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
35487	NM_017636.4(TRPM4):c.1294G>A (p.Ala432Thr)	HRC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
178130	NM_000335.5(SCN5A):c.3259G>A (p.Ala1087Thr)	LOC110121269	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
178131	NM_000335.5(SCN5A):c.3246C>T (p.Ser1082=)	LOC110121269	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
264627	NM_000335.5(SCN5A):c.3315C>T (p.Ala1105=)	LOC110121269	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 23 · Orphanet: 8 · 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
SCN5A	Strong	Autosomal dominant	progressive familial heart block, type 1A	23

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SCN5A	Orphanet:101016	Romano-Ward syndrome
SCN5A	Orphanet:130	Brugada syndrome
SCN5A	Orphanet:1344	Isolated atrial standstill
SCN5A	Orphanet:154	Familial isolated dilated cardiomyopathy
SCN5A	Orphanet:166282	Hereditary sick sinus syndrome
SCN5A	Orphanet:228140	Idiopathic ventricular fibrillation
SCN5A	Orphanet:334	Hereditary atrial fibrillation
SCN5A	Orphanet:871	Hereditary progressive cardiac conduction defect

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SCN5A	HGNC:10593	ENSG00000183873	Q14524	Sodium channel protein type 5 subunit alpha	gencc,clinvar
HRC	HGNC:5178	ENSG00000130528	P23327	Sarcoplasmic reticulum histidine-rich calcium-binding protein	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SCN5A	Sodium channel protein type 5 subunit alpha	Pore-forming subunit of Nav1.5, a voltage-gated sodium (Nav) channel that directly mediates the depolarizing phase of action potentials in excitable membranes.
HRC	Sarcoplasmic reticulum histidine-rich calcium-binding protein	May play a role in the regulation of calcium sequestration or release in the SR of skeletal and cardiac muscle.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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	55.8×	0.036
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SCN5A	Ion channel	yes		Na_channel_asu, Ion_trans_dom, Na_channel_a5su
HRC	Other/Unknown	no		HRC, Hist_rich_Ca-bd

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
apex of heart	2
heart left ventricle	2
cardiac ventricle	1
left ventricle myocardium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SCN5A	161	broad	yes	apex of heart, heart left ventricle, cardiac ventricle
HRC	178	broad	marker	apex of heart, left ventricle myocardium, heart left ventricle

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SCN5A	2,090
HRC	1,305

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SCN5A	Q14524	16

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
HRC	P23327	50.20

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 12. Enrichment computed across 2 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
Interaction between L1 and Ankyrins	1	184.2×	0.035	SCN5A
Phase 0 - rapid depolarisation	1	173.0×	0.035	SCN5A
L1CAM interactions	1	60.1×	0.044	SCN5A
Cardiac conduction	1	54.4×	0.044	SCN5A
Post-translational protein phosphorylation	1	50.1×	0.044	HRC
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	1	43.3×	0.044	HRC
Muscle contraction	1	38.6×	0.044	SCN5A
Axon guidance	1	22.6×	0.061	SCN5A
Nervous system development	1	21.5×	0.061	SCN5A
Post-translational protein modification	1	9.6×	0.122	HRC
Developmental Biology	1	7.2×	0.146	SCN5A
Metabolism of proteins	1	6.2×	0.155	HRC

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
regulation of heart rate	2	468.1×	2e-04	SCN5A, HRC
bundle of His cell action potential	1	4213.0×	0.002	SCN5A
AV node cell to bundle of His cell communication	1	4213.0×	0.002	SCN5A
positive regulation of relaxation of cardiac muscle	1	4213.0×	0.002	HRC
membrane depolarization during Purkinje myocyte cell action potential	1	2808.7×	0.002	SCN5A
membrane depolarization during bundle of His cell action potential	1	2808.7×	0.002	SCN5A
membrane depolarization during atrial cardiac muscle cell action potential	1	2808.7×	0.002	SCN5A
AV node cell action potential	1	2106.5×	0.002	SCN5A
membrane depolarization during AV node cell action potential	1	1685.2×	0.002	SCN5A
membrane depolarization during SA node cell action potential	1	1685.2×	0.002	SCN5A
regulation of ventricular cardiac muscle cell membrane depolarization	1	1404.3×	0.002	SCN5A
SA node cell action potential	1	1404.3×	0.002	SCN5A
cardiac ventricle development	1	1203.7×	0.002	SCN5A
response to denervation involved in regulation of muscle adaptation	1	1203.7×	0.002	SCN5A
regulation of atrial cardiac muscle cell membrane repolarization	1	1203.7×	0.002	SCN5A
brainstem development	1	1053.2×	0.002	SCN5A
positive regulation of action potential	1	1053.2×	0.002	SCN5A
positive regulation of heart contraction	1	1053.2×	0.002	HRC
regulation of calcium ion transmembrane transport	1	1053.2×	0.002	HRC
regulation of atrial cardiac muscle cell membrane depolarization	1	936.2×	0.002	SCN5A
regulation of cell communication by electrical coupling involved in cardiac conduction	1	936.2×	0.002	HRC
membrane depolarization during action potential	1	842.6×	0.002	SCN5A
atrial cardiac muscle cell action potential	1	842.6×	0.002	SCN5A
membrane depolarization during cardiac muscle cell action potential	1	702.2×	0.003	SCN5A
regulation of cardiac muscle cell contraction	1	561.7×	0.003	SCN5A
cardiac conduction system development	1	526.6×	0.003	SCN5A
regulation of sodium ion transmembrane transport	1	526.6×	0.003	SCN5A
telencephalon development	1	495.6×	0.003	SCN5A
ventricular cardiac muscle cell action potential	1	495.6×	0.003	SCN5A
positive regulation of sodium ion transport	1	421.3×	0.004	SCN5A

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) 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
SCN5A	BEPRIDIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SCN5A	108	4
HRC	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BEPRIDIL	4	SCN5A
CANDESARTAN CILEXETIL	4	SCN5A
TELMISARTAN	4	SCN5A
CARBAMAZEPINE	4	SCN5A
DIBUCAINE	4	SCN5A
IMIPRAMINE	4	SCN5A
DROPERIDOL	4	SCN5A
PONATINIB	4	SCN5A
DULOXETINE	4	SCN5A
PALONOSETRON	4	SCN5A
VILANTEROL	4	SCN5A
MEXILETINE HYDROCHLORIDE	4	SCN5A
UNOPROSTONE ISOPROPYL	4	SCN5A
LURASIDONE	4	SCN5A
LETERMOVIR	4	SCN5A
SERTINDOLE	4	SCN5A
FEDRATINIB	4	SCN5A
QUINIDINE	4	SCN5A
DARUNAVIR	4	SCN5A
DARIFENACIN	4	SCN5A
BENZONATATE	4	SCN5A
TOLTERODINE	4	SCN5A
RANOLAZINE	4	SCN5A
PIMOZIDE	4	SCN5A
NIMODIPINE	4	SCN5A
FELODIPINE	4	SCN5A
NICARDIPINE	4	SCN5A
AMLODIPINE	4	SCN5A
PHENYTOIN	4	SCN5A
PALIPERIDONE	4	SCN5A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SCN5A	594	Binding:380, Functional:98, ADMET:72, Toxicity:43, Unclassified:1

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
SCN5A	594

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

30 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)
BEPRIDIL	4	SCN5A
CANDESARTAN CILEXETIL	4	SCN5A
TELMISARTAN	4	SCN5A
CARBAMAZEPINE	4	SCN5A
DIBUCAINE	4	SCN5A
IMIPRAMINE	4	SCN5A
DROPERIDOL	4	SCN5A
PONATINIB	4	SCN5A
DULOXETINE	4	SCN5A
PALONOSETRON	4	SCN5A
VILANTEROL	4	SCN5A
MEXILETINE HYDROCHLORIDE	4	SCN5A
UNOPROSTONE ISOPROPYL	4	SCN5A
LURASIDONE	4	SCN5A
LETERMOVIR	4	SCN5A
SERTINDOLE	4	SCN5A
FEDRATINIB	4	SCN5A
QUINIDINE	4	SCN5A
DARUNAVIR	4	SCN5A
DARIFENACIN	4	SCN5A
BENZONATATE	4	SCN5A
TOLTERODINE	4	SCN5A
RANOLAZINE	4	SCN5A
PIMOZIDE	4	SCN5A
NIMODIPINE	4	SCN5A
FELODIPINE	4	SCN5A
NICARDIPINE	4	SCN5A
AMLODIPINE	4	SCN5A
PHENYTOIN	4	SCN5A
PALIPERIDONE	4	SCN5A

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	SCN5A
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	1	HRC

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
HRC	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.