Hypertrophic cardiomyopathy 3

Summary

Hypertrophic cardiomyopathy 3 (MONDO:0007267) is a disease caused by variants in TNNT2 and TPM1, with 2 cohort genes.

At a glance

• Causal genes: TNNT2 (GenCC Definitive), TPM1 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 95

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hypertrophic cardiomyopathy 3
Mondo ID	MONDO:0007267
MeSH	C566170
OMIM	115196
DOID	DOID:0110309
UMLS	C1861863
MedGen	349382
GARD	0024541
Is cancer (heuristic)	no

Also known as: cardiomyopathy, familial hypertrophic, 3 · cardiomyopathy, familial hypertrophic, type 3 · cardiomyopathy, hypertrophic, 3 · CMH3 · hypertrophic cardiomyopathy 3 · hypertrophic cardiomyopathy caused by mutation in TPM1 · hypertrophic cardiomyopathy type 3 · TPM1 hypertrophic cardiomyopathy

Data availability: 95 ClinVar variants · 3 GenCC gene-disease records · 3 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › muscle tissue disorder › cardiomyopathy › intrinsic cardiomyopathy › hypertrophic cardiomyopathy › familial hypertrophic cardiomyopathy › hypertrophic cardiomyopathy 3

Related subtypes (39): hypertrophic cardiomyopathy 2, hypertrophic cardiomyopathy 4, Beckwith-Wiedemann syndrome, myotonic dystrophy type 1, hypertrophic cardiomyopathy 1, very long chain acyl-CoA dehydrogenase deficiency, multiple acyl-CoA dehydrogenase deficiency, 46,XY complete gonadal dysgenesis, hypertrophic cardiomyopathy 6, dilated cardiomyopathy 1C, hypertrophic cardiomyopathy 25, hypertrophic cardiomyopathy 8, hypertrophic cardiomyopathy 10, long chain 3-hydroxyacyl-CoA dehydrogenase deficiency, cardiomyopathy-hypotonia-lactic acidosis syndrome, hypertrophic cardiomyopathy 11, hypertrophic cardiomyopathy 12, hypertrophic cardiomyopathy 13, hypertrophic cardiomyopathy 14, hypertrophic cardiomyopathy 15, hypertrophic cardiomyopathy 7, hypertrophic cardiomyopathy 9, hypertrophic cardiomyopathy 16, hypertrophic cardiomyopathy 17, hypertrophic cardiomyopathy 18, hypertrophic cardiomyopathy 19, hypertrophic cardiomyopathy 20, hypertrophic cardiomyopathy 21, dilated cardiomyopathy 1KK, hypertrophic cardiomyopathy 26, Noonan syndrome and Noonan-related syndrome, long chain acyl-CoA dehydrogenase deficiency, cardiomyopathy, familial hypertrophic, 28, cardiomyopathy, familial hypertrophic 27, cardiomyopathy, familial hypertrophic, 23, with or without ventricular noncompaction, cardiomyopathy, familial restrictive, 5, cardiomyopathy, familial hypertrophic, 29, with polyglucosan bodies, cardiomyopathy, familial hypertrophic, 30, atrial, cardiomyopathy, familial hypertrophic, 31

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

95 retrieved; paginated sample, class counts are floors:

46 uncertain significance, 25 conflicting classifications of pathogenicity, 6 pathogenic/likely pathogenic, 5 likely pathogenic, 4 benign, 4 benign/likely benign, 3 pathogenic, 2 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
12455	NM_001018005.2(TPM1):c.539A>G (p.Glu180Gly)	TPM1	Pathogenic	criteria provided, multiple submitters, no conflicts
12456	NM_001018005.2(TPM1):c.523G>A (p.Asp175Asn)	TPM1	Pathogenic	criteria provided, multiple submitters, no conflicts
12457	NM_001018005.2(TPM1):c.284T>C (p.Val95Ala)	TPM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1472862	NM_001018005.2(TPM1):c.292G>A (p.Glu98Lys)	TPM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
31877	NM_001018005.2(TPM1):c.188C>T (p.Ala63Val)	TPM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
31882	NM_001018005.2(TPM1):c.574G>A (p.Glu192Lys)	TPM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
31884	NM_001018005.2(TPM1):c.688G>A (p.Asp230Asn)	TPM1	Pathogenic	criteria provided, multiple submitters, no conflicts
31899	NM_001018005.2(TPM1):c.479G>A (p.Arg160His)	TPM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
43420	NM_001018005.2(TPM1):c.475G>A (p.Asp159Asn)	TPM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3381178	NM_001018005.2(TPM1):c.296T>C (p.Leu99Ser)	TPM1	Likely pathogenic	no assertion criteria provided
3775259	NM_001018005.2(TPM1):c.791A>G (p.Lys264Arg)	TPM1	Likely pathogenic	criteria provided, single submitter
3897044	NM_001018005.2(TPM1):c.476A>C (p.Asp159Ala)	TPM1	Likely pathogenic	criteria provided, single submitter
4531273	NM_001018005.2(TPM1):c.288G>T (p.Glu96Asp)	TPM1	Likely pathogenic	criteria provided, single submitter
4688011	NM_001018005.2(TPM1):c.435G>T (p.Glu145Asp)	TPM1	Likely pathogenic	criteria provided, single submitter
1111156	NM_001018005.2(TPM1):c.852-5C>T	TPM1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1193350	NM_001018005.2(TPM1):c.772+163G>C	TPM1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
137697	NM_001018005.2(TPM1):c.114+14C>T	TPM1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
165570	NM_001018005.2(TPM1):c.564-11G>A	TPM1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
178146	NM_001018005.2(TPM1):c.375-3C>T	TPM1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
181678	NM_001018005.2(TPM1):c.62G>T (p.Arg21Leu)	TPM1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2500103	NM_001018005.2(TPM1):c.772+63A>G	TPM1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
316682	NM_001018005.1(TPM1):c.-186G>A	TPM1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
316687	NM_001018005.2(TPM1):c.249C>T (p.Ala83=)	TPM1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
316688	NM_001018005.2(TPM1):c.564-5A>T	TPM1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
316689	NM_001018005.2(TPM1):c.*68A>G	TPM1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
43410	NM_001018005.2(TPM1):c.27G>A (p.Gln9=)	TPM1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
43421	NM_001018005.2(TPM1):c.493-6C>T	TPM1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
43422	NM_001018005.2(TPM1):c.522C>T (p.Ser174=)	TPM1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
43432	NM_001018005.2(TPM1):c.64G>A (p.Ala22Thr)	TPM1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
43442	NM_001018005.2(TPM1):c.829G>A (p.Ala277Thr)	TPM1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 18 · Orphanet: 5 · 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
TNNT2	Definitive	Autosomal dominant	hypertrophic cardiomyopathy 2	12
TPM1	Definitive	Autosomal dominant	hypertrophic cardiomyopathy 3	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TPM1	Orphanet:154	Familial isolated dilated cardiomyopathy
TPM1	Orphanet:54260	Left ventricular noncompaction
TNNT2	Orphanet:154	Familial isolated dilated cardiomyopathy
TNNT2	Orphanet:54260	Left ventricular noncompaction
TNNT2	Orphanet:75249	Familial isolated restrictive cardiomyopathy

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
TPM1	HGNC:12010	ENSG00000140416	P09493	Tropomyosin alpha-1 chain	gencc,clinvar
TNNT2	HGNC:11949	ENSG00000118194	P45379	Troponin T, cardiac muscle	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TPM1	Tropomyosin alpha-1 chain	Binds to actin filaments in muscle and non-muscle cells.
TNNT2	Troponin T, cardiac muscle	Troponin T is the tropomyosin-binding subunit of troponin, the thin filament regulatory complex which confers calcium-sensitivity to striated muscle actomyosin ATPase activity.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TPM1	Other/Unknown	no		Tropomyosin
TNNT2	Other/Unknown	no		Troponin, TNNT, Troponin_sf

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
heart right ventricle	1
left ventricle myocardium	1
myocardium	1
apex of heart	1
cardiac atrium	1
right atrium auricular region	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TPM1	305	ubiquitous	marker	left ventricle myocardium, heart right ventricle, myocardium
TNNT2	154	broad	marker	apex of heart, right atrium auricular region, cardiac atrium

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TPM1	3,514
TNNT2	1,944

Intra-cohort edges

A	B	Sources
TNNT2	TPM1	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TNNT2	P45379	25
TPM1	P09493	14

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. 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
Striated Muscle Contraction	2	308.6×	2e-05	TPM1, TNNT2
Smooth Muscle Contraction	1	132.8×	0.008	TPM1

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 muscle contraction	2	1685.2×	7e-06	TPM1, TNNT2
muscle filament sliding	2	1053.2×	9e-06	TPM1, TNNT2
ventricular cardiac muscle tissue morphogenesis	2	702.2×	1e-05	TPM1, TNNT2
regulation of heart contraction	2	495.6×	2e-05	TPM1, TNNT2
cardiac muscle contraction	2	401.2×	2e-05	TPM1, TNNT2
sarcomere organization	2	383.0×	2e-05	TPM1, TNNT2
positive regulation of heart rate by epinephrine	1	8426.0×	4e-04	TPM1
negative regulation of ATP-dependent activity	1	842.6×	0.003	TNNT2
negative regulation of vascular associated smooth muscle cell migration	1	842.6×	0.003	TPM1
positive regulation of ATP-dependent activity	1	702.2×	0.003	TNNT2
ruffle organization	1	648.1×	0.003	TPM1
negative regulation of vascular associated smooth muscle cell proliferation	1	337.0×	0.005	TPM1
cellular response to reactive oxygen species	1	205.5×	0.008	TPM1
response to calcium ion	1	159.0×	0.009	TNNT2
positive regulation of stress fiber assembly	1	156.0×	0.009	TPM1
positive regulation of cell adhesion	1	135.9×	0.010	TPM1
wound healing	1	113.9×	0.011	TPM1
cytoskeleton organization	1	66.3×	0.018	TPM1
regulation of cell shape	1	61.5×	0.018	TPM1
actin filament organization	1	59.3×	0.018	TPM1
negative regulation of cell migration	1	55.8×	0.018	TPM1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TPM1	0	0
TNNT2	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
TPM1	3	Binding:3
TNNT2	2	Binding:2

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

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	2	TPM1, TNNT2

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)
TPM1	3	—
TNNT2	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.