progressive familial heart block type IB

Summary

progressive familial heart block type IB (MONDO:0011474) is a disease caused by TRPM4 (GenCC Strong), with 3 cohort genes.

At a glance

• Causal gene: TRPM4 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 1,669

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	progressive familial heart block type IB
Mondo ID	MONDO:0011474
MeSH	C567037
OMIM	604559
DOID	DOID:0111076
SNOMED CT	698250005
UMLS	C1970298
MedGen	370220
GARD	0002610
Is cancer (heuristic)	no

Also known as: heart block progressive familial type 1B · PFHB1B · progressive familial heart block caused by mutation in TRPM4 · progressive familial heart block type 1B · progressive familial heart block, type IB · TRPM4 progressive familial heart block

Data availability: 1,669 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › cardiovascular disorder › heart disorder › heart conduction disease › progressive familial heart block › progressive familial heart block type IB

Related subtypes (2): progressive familial heart block, type 1A, progressive familial heart block type II

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

600 retrieved; paginated sample, class counts are floors:

327 uncertain significance, 230 likely benign, 32 conflicting classifications of pathogenicity, 8 benign, 2 benign/likely benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1455923	NM_017636.4(TRPM4):c.1127T>C (p.Ile376Thr)	TRPM4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1012457	NM_017636.4(TRPM4):c.1600G>C (p.Gly534Arg)	TRPM4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1024940	NM_017636.4(TRPM4):c.735C>T (p.Gly245=)	TRPM4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1038721	NM_017636.4(TRPM4):c.754C>T (p.Arg252Cys)	TRPM4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1047759	NM_017636.4(TRPM4):c.2984C>T (p.Ser995Leu)	TRPM4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1116804	NM_017636.4(TRPM4):c.1569C>T (p.Gly523=)	TRPM4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1189945	NM_017636.4(TRPM4):c.1380G>T (p.Leu460=)	TRPM4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1412816	NM_017636.4(TRPM4):c.1815C>A (p.Asp605Glu)	TRPM4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1462550	NM_017636.4(TRPM4):c.1885G>A (p.Glu629Lys)	TRPM4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1467291	NM_017636.4(TRPM4):c.2733G>A (p.Thr911=)	TRPM4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1482124	NM_017636.4(TRPM4):c.1070G>A (p.Arg357Gln)	TRPM4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1483996	NM_017636.4(TRPM4):c.3256C>G (p.Arg1086Gly)	TRPM4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1525658	NM_017636.4(TRPM4):c.10C>T (p.Pro4Ser)	TRPM4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1538223	NM_017636.4(TRPM4):c.859-4G>A	TRPM4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1559544	NM_017636.4(TRPM4):c.2976C>T (p.Asn992=)	TRPM4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1561640	NM_017636.4(TRPM4):c.2136A>G (p.Lys712=)	TRPM4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1638764	NM_017636.4(TRPM4):c.2769G>A (p.Val923=)	TRPM4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1644749	NM_017636.4(TRPM4):c.2133-5G>A	TRPM4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1664056	NM_017636.4(TRPM4):c.3443T>C (p.Leu1148Pro)	TRPM4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1700350	NM_017636.4(TRPM4):c.1424A>G (p.Asn475Ser)	TRPM4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1730017	NM_017636.4(TRPM4):c.3304T>C (p.Ser1102Pro)	TRPM4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1743158	NM_017636.4(TRPM4):c.479C>T (p.Thr160Met)	TRPM4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1764036	NM_017636.4(TRPM4):c.860G>A (p.Arg287Gln)	TRPM4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1774860	NM_017636.4(TRPM4):c.1541T>C (p.Met514Thr)	TRPM4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1775555	NM_017636.4(TRPM4):c.1574G>A (p.Trp525Ter)	TRPM4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1776988	NM_017636.4(TRPM4):c.1639C>T (p.Pro547Ser)	TRPM4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1784546	NM_017636.4(TRPM4):c.2020-5C>A	TRPM4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1786783	NM_017636.4(TRPM4):c.2153C>G (p.Thr718Arg)	TRPM4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1789209	NM_017636.4(TRPM4):c.2299C>T (p.Arg767Trp)	TRPM4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1793437	NM_017636.4(TRPM4):c.2587A>G (p.Ser863Gly)	TRPM4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 3 · 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
TRPM4	Strong	Autosomal dominant	progressive familial heart block type IB	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TRPM4	Orphanet:130	Brugada syndrome
TRPM4	Orphanet:316	Progressive symmetric erythrokeratodermia
TRPM4	Orphanet:871	Hereditary progressive cardiac conduction defect

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
TRPM4	HGNC:17993	ENSG00000130529	Q8TD43	Transient receptor potential cation channel subfamily M member 4	gencc,clinvar
C19orf73	HGNC:25534	ENSG00000221916	Q9NVV2	Putative uncharacterized protein C19orf73	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)
TRPM4	Transient receptor potential cation channel subfamily M member 4	Calcium-activated selective cation channel that mediates membrane depolarization.
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: 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)
TRPM4	Ion channel	yes		Ion_trans_dom, TRPM_SLOG, TRPM
C19orf73	Other/Unknown	no		DUF5538
HRC	Other/Unknown	no		HRC, Hist_rich_Ca-bd

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
apex of heart	2
mucosa of transverse colon	2
rectum	1
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1
heart left ventricle	1
left ventricle myocardium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TRPM4	201	ubiquitous	marker	mucosa of transverse colon, rectum, apex of heart
C19orf73	151	ubiquitous	yes	primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis, mucosa of transverse colon
HRC	178	broad	marker	apex of heart, left ventricle myocardium, heart left ventricle

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HRC	1,305
TRPM4	1,217
C19orf73	104

Intra-cohort edges

A	B	Sources
C19orf73	HRC	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TRPM4	Q8TD43	29

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
C19orf73	Q9NVV2	59.03
HRC	P23327	50.20

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. 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
TRP channels	1	203.9×	0.022	TRPM4
Sensory perception of sweet, bitter, and umami (glutamate) taste	1	139.3×	0.022	TRPM4
Post-translational protein phosphorylation	1	50.1×	0.034	HRC
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	1	43.3×	0.034	HRC
Post-translational protein modification	1	9.6×	0.122	HRC
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
positive regulation of heart rate	2	702.2×	7e-05	TRPM4, HRC
positive regulation of atrial cardiac muscle cell action potential	1	8426.0×	0.002	TRPM4
positive regulation of regulation of vascular associated smooth muscle cell membrane depolarization	1	8426.0×	0.002	TRPM4
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	TRPM4
membrane depolarization during bundle of His cell action potential	1	2808.7×	0.002	TRPM4
regulation of T cell cytokine production	1	2106.5×	0.003	TRPM4
membrane depolarization during AV node cell action potential	1	1685.2×	0.003	TRPM4
positive regulation of heart contraction	1	1053.2×	0.003	HRC
regulation of calcium ion transmembrane transport	1	1053.2×	0.003	HRC
metal ion transport	1	936.2×	0.003	TRPM4
regulation of cell communication by electrical coupling involved in cardiac conduction	1	936.2×	0.003	HRC
regulation of ventricular cardiac muscle cell action potential	1	702.2×	0.004	TRPM4
positive regulation of adipose tissue development	1	526.6×	0.005	TRPM4
dendritic cell chemotaxis	1	495.6×	0.005	TRPM4
negative regulation of bone mineralization	1	468.1×	0.005	TRPM4
obsolete inorganic cation transmembrane transport	1	468.1×	0.005	TRPM4
cellular response to ATP	1	443.5×	0.005	TRPM4
regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum	1	337.0×	0.005	HRC
regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion	1	337.0×	0.005	HRC
monoatomic cation transmembrane transport	1	312.1×	0.005	TRPM4
sodium ion import across plasma membrane	1	312.1×	0.005	TRPM4
positive regulation of vasoconstriction	1	300.9×	0.005	TRPM4
regulation of heart rate	1	234.1×	0.007	HRC
regulation of cytosolic calcium ion concentration	1	191.5×	0.008	HRC
positive regulation of insulin secretion involved in cellular response to glucose stimulus	1	187.2×	0.008	TRPM4
regulation of heart rate by cardiac conduction	1	187.2×	0.008	TRPM4
protein sumoylation	1	162.0×	0.008	TRPM4
positive regulation of fat cell differentiation	1	150.5×	0.009	TRPM4
negative regulation of osteoblast differentiation	1	147.8×	0.009	TRPM4

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 3

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

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TRPM4	0	0
C19orf73	0	0
HRC	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
TRPM4	14	Binding:13, Functional:1

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

0 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.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	TRPM4
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	C19orf73, HRC

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)
TRPM4	14	—
C19orf73	0	—
HRC	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.