Hypertrophic cardiomyopathy 7

Summary

Hypertrophic cardiomyopathy 7 (MONDO:0013369) is a disease caused by TNNI3 (GenCC Definitive), with 6 cohort genes.

At a glance

• Causal gene: TNNI3 (GenCC Definitive)
• Cohort genes: 6
• ClinVar variants: 91

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hypertrophic cardiomyopathy 7
Mondo ID	MONDO:0013369
OMIM	613690
DOID	DOID:0110313
UMLS	C1860752
MedGen	348695
GARD	0024916
Is cancer (heuristic)	no

Also known as: cardiomyopathy, familial hypertrophic, 7 · cardiomyopathy, familial hypertrophic, type 7 · cardiomyopathy, hypertrophic, 7 · CMH7 · hypertrophic cardiomyopathy 7 · hypertrophic cardiomyopathy caused by mutation in TNNI3 · hypertrophic cardiomyopathy type 7 · TNNI3 hypertrophic cardiomyopathy

Data availability: 91 ClinVar variants · 2 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 7

Related subtypes (39): hypertrophic cardiomyopathy 2, hypertrophic cardiomyopathy 3, 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 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

91 retrieved; paginated sample, class counts are floors:

33 conflicting classifications of pathogenicity, 28 uncertain significance, 10 pathogenic/likely pathogenic, 8 pathogenic, 5 benign/likely benign, 4 likely pathogenic, 2 likely benign, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
12419	NM_000363.5(TNNI3):c.433C>G (p.Arg145Gly)	TNNI3	Pathogenic	criteria provided, multiple submitters, no conflicts
12420	NM_000363.5(TNNI3):c.616A>C (p.Lys206Gln)	TNNI3	Pathogenic	no assertion criteria provided
12422	NM_000363.5(TNNI3):c.586G>A (p.Asp196Asn)	TNNI3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12423	NM_000363.5(TNNI3):c.569A>G (p.Asp190Gly)	TNNI3	Pathogenic	no assertion criteria provided
12425	NM_000363.5(TNNI3):c.532A>G (p.Lys178Glu)	TNNI3	Pathogenic	criteria provided, multiple submitters, no conflicts
12426	NM_000363.5(TNNI3):c.433C>T (p.Arg145Trp)	TNNI3	Pathogenic	criteria provided, multiple submitters, no conflicts
12432	NM_000363.5(TNNI3):c.607G>A (p.Gly203Ser)	TNNI3	Pathogenic	no assertion criteria provided
12433	NM_000363.5(TNNI3):c.547_549del (p.Lys183del)	TNNI3	Pathogenic	no assertion criteria provided
12434	NM_000363.5(TNNI3):c.61C>T (p.Arg21Cys)	TNNI3	Pathogenic	criteria provided, multiple submitters, no conflicts
177630	NM_000363.5(TNNI3):c.497C>T (p.Ser166Phe)	TNNI3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
177679	NM_000363.5(TNNI3):c.611G>A (p.Arg204His)	TNNI3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
177694	NM_000363.5(TNNI3):c.592C>G (p.Leu198Val)	TNNI3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
181603	NM_000363.5(TNNI3):c.596G>A (p.Ser199Asn)	TNNI3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
43381	NM_000363.5(TNNI3):c.422G>A (p.Arg141Gln)	TNNI3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
43384	NM_000363.5(TNNI3):c.434G>A (p.Arg145Gln)	TNNI3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
43388	NM_000363.5(TNNI3):c.470C>T (p.Ala157Val)	TNNI3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
43390	NM_000363.5(TNNI3):c.485G>C (p.Arg162Pro)	TNNI3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
43395	NM_000363.5(TNNI3):c.557G>A (p.Arg186Gln)	TNNI3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
165510	NM_000363.5(TNNI3):c.574C>T (p.Arg192Cys)	TNNI3	Likely pathogenic	reviewed by expert panel
3775766	NM_000363.5(TNNI3):c.151-1G>A	TNNI3	Likely pathogenic	criteria provided, single submitter
4279105	NM_000363.5(TNNI3):c.563T>G (p.Val188Gly)	TNNI3	Likely pathogenic	criteria provided, single submitter
43389	NM_000363.5(TNNI3):c.485G>A (p.Arg162Gln)	TNNI3	Likely pathogenic	reviewed by expert panel
894093	NM_001256715.2(DNAAF3):c.990C>T (p.Thr330=)	DNAAF3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
257685	NM_001256715.2(DNAAF3):c.1248G>A (p.Val416=)	DNAAF3-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
137685	NM_000363.5(TNNI3):c.139T>C (p.Leu47=)	TNNI3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
165517	NM_000363.5(TNNI3):c.508C>G (p.Arg170Gly)	TNNI3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
165519	NM_000363.5(TNNI3):c.372+7C>T	TNNI3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
165520	NM_000363.5(TNNI3):c.370G>C (p.Glu124Gln)	TNNI3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
165522	NM_000363.5(TNNI3):c.258del (p.Leu88fs)	TNNI3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
181575	NM_000363.5(TNNI3):c.292C>T (p.Arg98Ter)	TNNI3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 12 · 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
TNNI3	Definitive	Autosomal recessive	dilated cardiomyopathy 2A	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TNNI3	Orphanet:154	Familial isolated dilated cardiomyopathy
TNNI3	Orphanet:75249	Familial isolated restrictive cardiomyopathy
TNNT2	Orphanet:154	Familial isolated dilated cardiomyopathy
TNNT2	Orphanet:54260	Left ventricular noncompaction
TNNT2	Orphanet:75249	Familial isolated restrictive cardiomyopathy
TSC2	Orphanet:210159	Adult hepatocellular carcinoma
TSC2	Orphanet:269001	Isolated focal cortical dysplasia type IIa
TSC2	Orphanet:269008	Isolated focal cortical dysplasia type IIb
TSC2	Orphanet:538	Lymphangioleiomyomatosis
TSC2	Orphanet:805	Tuberous sclerosis complex
TSC2	Orphanet:88924	Autosomal dominant polycystic kidney disease type 1 with tuberous sclerosis
DNAAF3	Orphanet:244	Primary ciliary dyskinesia

Cohort genes → proteins

6 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	6

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TNNI3	HGNC:11947	ENSG00000129991	P19429	Troponin I, cardiac muscle	gencc,clinvar
TNNT2	HGNC:11949	ENSG00000118194	P45379	Troponin T, cardiac muscle	clinvar
TSC2	HGNC:12363	ENSG00000103197	P49815	Tuberin	clinvar
FHOD3	HGNC:26178	ENSG00000134775	Q2V2M9	FH1/FH2 domain-containing protein 3	clinvar
DNAAF3	HGNC:30492	ENSG00000167646	Q8N9W5	Dynein axonemal assembly factor 3	clinvar
DNAAF3-AS1	HGNC:55292	ENSG00000267577		DNAAF3 antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TNNI3	Troponin I, cardiac muscle	Troponin I is the inhibitory subunit of troponin, the thin filament regulatory complex which confers calcium-sensitivity to striated muscle actomyosin ATPase activity.
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.
TSC2	Tuberin	Catalytic component of the TSC-TBC complex, a multiprotein complex that acts as a negative regulator of the canonical mTORC1 complex, an evolutionarily conserved central nutrient sensor that stimulates anabolic reactions and macromolecule…
FHOD3	FH1/FH2 domain-containing protein 3	Actin-organizing protein that may cause stress fiber formation together with cell elongation.
DNAAF3	Dynein axonemal assembly factor 3	Required for the assembly of axonemal inner and outer dynein arms.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 6 · 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	6	1.8×	0.030

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TNNI3	Other/Unknown	no		Troponin, Troponin-I_N, Troponin_sf
TNNT2	Other/Unknown	no		Troponin, TNNT, Troponin_sf
TSC2	Other/Unknown	no		Rap/Ran_GAP_dom, Tuberin, ARM-like
FHOD3	Other/Unknown	no		ARM-like, DAD_dom, GBD/FH3_dom
DNAAF3	Other/Unknown	no		DUF4470, DNAAF3_C, DNAAF3
DNAAF3-AS1	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

5 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)	6
unknown	0

Top tissues across cohort

Tissue	Cohort genes
apex of heart	5
left ventricle myocardium	2
right atrium auricular region	2
cardiac atrium	1
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
ventricular zone	1
right testis	1
right uterine tube	1
male germ line stem cell (sensu Vertebrata) in testis	1
sperm	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TNNI3	169	broad	marker	apex of heart, left ventricle myocardium, right atrium auricular region
TNNT2	154	broad	marker	apex of heart, right atrium auricular region, cardiac atrium
TSC2	282	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
FHOD3	244	ubiquitous	marker	apex of heart, left ventricle myocardium, ventricular zone
DNAAF3	158	broad	marker	apex of heart, right uterine tube, right testis
DNAAF3-AS1	110		yes	sperm, apex of heart, male germ line stem cell (sensu Vertebrata) in testis

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TSC2	4,135
TNNT2	1,944
TNNI3	1,836
DNAAF3	794
FHOD3	407
DNAAF3-AS1	0

Intra-cohort edges

A	B	Sources
TNNI3	TNNT2	biogrid_interaction, string_interaction

Structural data

PDB: 3 · AlphaFold-only: 2 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TNNI3	P19429	39
TNNT2	P45379	25
TSC2	P49815	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DNAAF3	Q8N9W5	81.06
FHOD3	Q2V2M9	64.62

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. Enrichment computed across 6 evidence-associated genes (3 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 3 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	205.8×	3e-04	TNNI3, TNNT2
Inhibition of TSC complex formation by AKT (PKB)	1	761.3×	0.006	TSC2
AKT phosphorylates targets in the cytosol	1	271.9×	0.011	TSC2
Constitutive Signaling by AKT1 E17K in Cancer	1	141.0×	0.014	TSC2
Energy dependent regulation of mTOR by LKB1-AMPK	1	131.3×	0.014	TSC2
TBC/RABGAPs	1	86.5×	0.017	TSC2
Ion homeostasis	1	68.0×	0.019	TNNI3
TP53 Regulates Metabolic Genes	1	43.3×	0.026	TSC2
Macroautophagy	1	38.5×	0.026	TSC2

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
negative regulation of ATP-dependent activity	2	674.1×	2e-04	TNNI3, TNNT2
muscle filament sliding	2	421.3×	2e-04	TNNI3, TNNT2
ventricular cardiac muscle tissue morphogenesis	2	280.9×	3e-04	TNNI3, TNNT2
heart development	3	47.2×	3e-04	TNNI3, TSC2, DNAAF3
cardiac muscle contraction	2	160.5×	6e-04	TNNI3, TNNT2
sarcomere organization	2	153.2×	6e-04	TNNT2, FHOD3
regulation of systemic arterial blood pressure by ischemic conditions	1	1685.2×	0.004	TNNI3
regulation of muscle contraction	1	337.0×	0.014	TNNT2
regulation of insulin receptor signaling pathway	1	337.0×	0.014	TSC2
negative regulation of mitophagy	1	306.4×	0.014	TSC2
positive regulation of ATP-dependent activity	1	280.9×	0.014	TNNT2
regulation of cardiac muscle contraction by calcium ion signaling	1	259.3×	0.014	TNNI3
anoikis	1	259.3×	0.014	TSC2
cardiac myofibril assembly	1	259.3×	0.014	FHOD3
regulation of smooth muscle contraction	1	240.7×	0.014	TNNI3
axonemal dynein complex assembly	1	210.7×	0.015	DNAAF3
cerebrospinal fluid circulation	1	177.4×	0.017	DNAAF3
positive chemotaxis	1	160.5×	0.017	TSC2
heart contraction	1	153.2×	0.017	TNNI3
seminiferous tubule development	1	153.2×	0.017	DNAAF3
motile cilium assembly	1	116.2×	0.020	DNAAF3
negative regulation of TOR signaling	1	112.3×	0.020	TSC2
positive regulation of macroautophagy	1	105.3×	0.020	TSC2
skeletal muscle contraction	1	102.1×	0.020	TNNI3
regulation of heart contraction	1	99.1×	0.020	TNNT2
regulation of endocytosis	1	96.3×	0.020	TSC2
determination of adult lifespan	1	86.4×	0.022	DNAAF3
negative regulation of insulin receptor signaling pathway	1	74.9×	0.024	TSC2
negative regulation of Wnt signaling pathway	1	68.8×	0.025	TSC2
negative regulation of TORC1 signaling	1	64.8×	0.025	TSC2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 6

Druggability breadth: 3 of 6 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TNNI3	0	0
TNNT2	0	0
TSC2	0	0
FHOD3	0	0
DNAAF3	0	0
DNAAF3-AS1	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
TNNI3	2	Binding:2
TNNT2	2	Binding:2
TSC2	1	Binding:1

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

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	6	TNNI3, TNNT2, TSC2, FHOD3, DNAAF3, DNAAF3-AS1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TNNI3	2	—
TNNT2	2	—
TSC2	1	—
FHOD3	0	—
DNAAF3	0	—
DNAAF3-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.