Hypertrophic cardiomyopathy 25

Summary

Hypertrophic cardiomyopathy 25 (MONDO:0011843) is a disease caused by TCAP (GenCC Strong), with 3 cohort genes.

At a glance

• Causal gene: TCAP (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 305

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hypertrophic cardiomyopathy 25
Mondo ID	MONDO:0011843
MeSH	C564388
OMIM	607487
DOID	DOID:0110328
UMLS	C4225408
MedGen	895360
GARD	0024827
Is cancer (heuristic)	no

Also known as: cardiomyopathy, familial hypertrophic, 25 · cardiomyopathy, familial hypertrophic, type 25 · cardiomyopathy, hypertrophic, 25 · CMH25 · hypertrophic cardiomyopathy caused by mutation in TCAP · hypertrophic cardiomyopathy type 25 · TCAP hypertrophic cardiomyopathy · Tcap hypertrophic cardiomyopathy

Data availability: 305 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › qualitative or quantitative protein defects in neuromuscular diseases › neuromuscular disease caused by qualitative or quantitative defects of telethonin › hypertrophic cardiomyopathy 25

Related subtypes (1): autosomal recessive limb-girdle muscular dystrophy type 2G

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

305 retrieved; paginated sample, class counts are floors:

175 uncertain significance, 75 likely benign, 27 conflicting classifications of pathogenicity, 14 pathogenic, 5 pathogenic/likely pathogenic, 4 benign/likely benign, 3 likely pathogenic, 2 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1055526	NM_003673.4(TCAP):c.110+5G>A	TCAP	Pathogenic	criteria provided, single submitter
1382475	NM_003673.4(TCAP):c.166C>T (p.Gln56Ter)	TCAP	Pathogenic	criteria provided, single submitter
1459213	NM_003673.4(TCAP):c.34del (p.Glu12fs)	TCAP	Pathogenic	criteria provided, single submitter
189787	NM_003673.4(TCAP):c.410C>T (p.Thr137Ile)	TCAP	Pathogenic	no assertion criteria provided
2023376	NM_003673.4(TCAP):c.110+2T>C	TCAP	Pathogenic	criteria provided, single submitter
2065429	NM_003673.4(TCAP):c.45_46del (p.Cys15_Glu16delinsTer)	TCAP	Pathogenic	criteria provided, single submitter
2090126	NM_003673.4(TCAP):c.151_154del (p.Tyr51fs)	TCAP	Pathogenic	criteria provided, single submitter
286261	NM_003673.4(TCAP):c.103G>T (p.Glu35Ter)	TCAP	Pathogenic	criteria provided, multiple submitters, no conflicts
290308	NM_003673.4(TCAP):c.43_49dup (p.Arg17delinsLeuTer)	TCAP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
290645	NM_003673.4(TCAP):c.66G>A (p.Trp22Ter)	TCAP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2948047	NM_003673.4(TCAP):c.50_51dup (p.Arg18fs)	TCAP	Pathogenic	criteria provided, single submitter
3757356	NM_003673.4(TCAP):c.154dup (p.His52fs)	TCAP	Pathogenic	criteria provided, single submitter
448649	NM_003673.4(TCAP):c.26_33dup (p.Glu12fs)	TCAP	Pathogenic	criteria provided, multiple submitters, no conflicts
4789023	NM_003673.4(TCAP):c.152_153insAA (p.Tyr51Ter)	TCAP	Pathogenic	criteria provided, single submitter
522598	NM_003673.4(TCAP):c.34dup (p.Glu12fs)	TCAP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
5525	NM_003673.4(TCAP):c.157C>T (p.Gln53Ter)	TCAP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
5526	NM_003673.4(TCAP):c.110_110+1del	TCAP	Pathogenic	criteria provided, multiple submitters, no conflicts
813977	NM_003673.4(TCAP):c.75G>A (p.Trp25Ter)	TCAP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
835598	NM_003673.4(TCAP):c.136_137del (p.Gln46fs)	TCAP	Pathogenic	criteria provided, single submitter
1066432	NM_003673.4(TCAP):c.171C>A (p.Cys57Ter)	TCAP	Likely pathogenic	criteria provided, single submitter
1708038	NM_003673.4(TCAP):c.360_361del (p.Glu120fs)	TCAP	Likely pathogenic	no assertion criteria provided
3752172	NM_003673.4(TCAP):c.1A>T (p.Met1Leu)	TCAP	Likely pathogenic	criteria provided, single submitter
1441277	NM_003673.4(TCAP):c.387C>G (p.Asp129Glu)	TCAP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
177939	NM_003673.4(TCAP):c.32C>T (p.Ser11Leu)	TCAP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
191776	NM_003673.4(TCAP):c.313G>C (p.Glu105Gln)	TCAP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
195198	NM_003673.4(TCAP):c.270G>A (p.Pro90=)	TCAP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
202102	NM_003673.4(TCAP):c.259C>T (p.Arg87Trp)	TCAP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
202104	NM_003673.4(TCAP):c.334C>T (p.Gln112Ter)	TCAP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
202105	NM_003673.4(TCAP):c.353C>T (p.Ala118Val)	TCAP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
202108	NM_003673.4(TCAP):c.113G>T (p.Cys38Phe)	TCAP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · 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
TCAP	Strong	Autosomal dominant	hypertrophic cardiomyopathy 25	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TCAP	Orphanet:154	Familial isolated dilated cardiomyopathy
TCAP	Orphanet:34514	Telethonin-related limb-girdle muscular dystrophy R7
TMPO	Orphanet:154	Familial isolated dilated cardiomyopathy

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
TCAP	HGNC:11610	ENSG00000173991	O15273	Telethonin	gencc,clinvar
TMPO	HGNC:11875	ENSG00000120802	P42166	Lamina-associated polypeptide 2, isoform alpha	clinvar
GSDMB	HGNC:23690	ENSG00000073605	Q8TAX9	Gasdermin-B	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TCAP	Telethonin	Muscle assembly regulating factor.
TMPO	Lamina-associated polypeptide 2, isoform alpha	May be involved in the structural organization of the nucleus and in the post-mitotic nuclear assembly.
GSDMB	Gasdermin-B	Precursor of a pore-forming protein that acts as a downstream mediator of granzyme-mediated cell death.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.0

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
Other/Unknown	3	1.8×	0.174

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TCAP	Other/Unknown	no		Telethonin, Titin-like_dom_sf
TMPO	Other/Unknown	no		LEM_dom, LEM/LEM-like_dom_sf, LEM-like_dom
GSDMB	Other/Unknown	no		Gasdermin, Gasdermin_pore, Gasdermin_PUB

Expression context

Cohort genes with no expression data: 0.

3 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	1
hindlimb stylopod muscle	1
skeletal muscle tissue of rectus abdominis	1
embryo	1
ganglionic eminence	1
ventricular zone	1
mucosa of transverse colon	1
rectum	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TCAP	213	tissue_specific	marker	apex of heart, hindlimb stylopod muscle, skeletal muscle tissue of rectus abdominis
TMPO	287	ubiquitous	marker	ventricular zone, ganglionic eminence, embryo
GSDMB	206	tissue_specific	marker	rectum, right lobe of liver, mucosa of transverse colon

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TCAP	1,414
TMPO	1,127
GSDMB	703

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TMPO	P42166	14
GSDMB	Q8TAX9	11
TCAP	O15273	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 19. 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
Depolymerization of the Nuclear Lamina	1	380.7×	0.027	TMPO
Initiation of Nuclear Envelope (NE) Reformation	1	300.5×	0.027	TMPO
Nuclear Envelope Breakdown	1	228.4×	0.027	TMPO
Striated Muscle Contraction	1	154.3×	0.027	TCAP
RHOF GTPase cycle	1	129.8×	0.027	TMPO
RHOD GTPase cycle	1	102.0×	0.027	TMPO
RHOJ GTPase cycle	1	100.2×	0.027	TMPO
RHOG GTPase cycle	1	74.2×	0.029	TMPO
RHOC GTPase cycle	1	73.2×	0.029	TMPO
RAC2 GTPase cycle	1	63.4×	0.029	TMPO
RAC3 GTPase cycle	1	59.5×	0.029	TMPO
Muscle contraction	1	38.6×	0.037	TCAP
RHOA GTPase cycle	1	37.3×	0.037	TMPO
CDC42 GTPase cycle	1	36.1×	0.037	TMPO
RAC1 GTPase cycle	1	30.5×	0.039	TMPO
RHO GTPase cycle	1	30.1×	0.039	TMPO
Signaling by Rho GTPases	1	17.1×	0.062	TMPO
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1	16.7×	0.062	TMPO
Signal Transduction	1	5.1×	0.187	TMPO

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
cytotoxic T cell pyroptotic cell death	1	4213.0×	0.003	GSDMB
skeletal muscle myosin thick filament assembly	1	2808.7×	0.003	TCAP
sarcomerogenesis	1	2808.7×	0.003	TCAP
skeletal muscle thin filament assembly	1	1404.3×	0.003	TCAP
detection of muscle stretch	1	1203.7×	0.003	TCAP
otic vesicle formation	1	1053.2×	0.003	TCAP
cardiac muscle hypertrophy	1	842.6×	0.003	TCAP
obsolete killing by host of symbiont cells	1	702.2×	0.003	GSDMB
cardiac muscle tissue morphogenesis	1	702.2×	0.003	TCAP
programmed cell death	1	648.1×	0.003	GSDMB
cardiac myofibril assembly	1	648.1×	0.003	TCAP
adult heart development	1	601.9×	0.003	TCAP
detection of mechanical stimulus	1	601.9×	0.003	TCAP
cardiac muscle hypertrophy in response to stress	1	526.6×	0.003	TCAP
muscle filament sliding	1	526.6×	0.003	TCAP
response to muscle stretch	1	383.0×	0.004	TCAP
cardiac muscle cell development	1	312.1×	0.005	TCAP
skeletal muscle contraction	1	255.3×	0.005	TCAP
pyroptotic inflammatory response	1	255.3×	0.005	GSDMB
cardiac muscle contraction	1	200.6×	0.006	TCAP
sarcomere organization	1	191.5×	0.006	TCAP
somitogenesis	1	187.2×	0.006	TCAP
killing of cells of another organism	1	135.9×	0.008	GSDMB
defense response to Gram-negative bacterium	1	84.3×	0.013	GSDMB
protein-containing complex assembly	1	56.9×	0.018	TCAP
defense response to bacterium	1	54.0×	0.018	GSDMB

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
TCAP	0	0
TMPO	0	0
GSDMB	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
TMPO	7	Binding:7

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	TCAP, TMPO, GSDMB

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)
TCAP	0	—
TMPO	7	—
GSDMB	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.