dilated cardiomyopathy 1D

Summary

dilated cardiomyopathy 1D (MONDO:0011095) is a disease caused by TNNT2 (GenCC Definitive), with 3 cohort genes.

At a glance

• Causal gene: TNNT2 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 777

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	dilated cardiomyopathy 1D
Mondo ID	MONDO:0011095
MeSH	C563306
OMIM	601494
DOID	DOID:0110426
UMLS	C1832243
MedGen	316943
GARD	0015332
Is cancer (heuristic)	no

Also known as: cardiomyopathy, dilated, 1D · cardiomyopathy, dilated, type 1D · CMD1D · dilated cardiomyopathy 1D · dilated cardiomyopathy type 1D · familial isolated dilated cardiomyopathy caused by mutation in TNNT2 · TNNT2 familial isolated dilated cardiomyopathy

Data availability: 777 ClinVar variants · 2 GenCC gene-disease records · 1 cell line.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › muscle tissue disorder › cardiomyopathy › intrinsic cardiomyopathy › left ventricular noncompaction › dilated cardiomyopathy 1D

Related subtypes (12): dilated cardiomyopathy 1C, left ventricular noncompaction 1, left ventricular noncompaction 2, dilated cardiomyopathy 1Y, dilated cardiomyopathy 1R, dilated cardiomyopathy 1S, left ventricular noncompaction 7, left ventricular noncompaction 8, left ventricular noncompaction 10, left ventricular noncompaction 9, left ventricular noncompaction 4, left ventricular noncompaction 5

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:

250 uncertain significance, 204 likely benign, 77 conflicting classifications of pathogenicity, 22 benign/likely benign, 18 pathogenic/likely pathogenic, 14 likely pathogenic, 8 benign, 7 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
12408	NM_001276345.2(TNNT2):c.266T>A (p.Ile89Asn)	TNNT2	Pathogenic	criteria provided, multiple submitters, no conflicts
12409	NM_001276345.2(TNNT2):c.305G>A (p.Arg102Gln)	TNNT2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12412	NM_001276345.2(TNNT2):c.358T>A (p.Phe120Ile)	TNNT2	Pathogenic	criteria provided, multiple submitters, no conflicts
12414	NM_001276345.2(TNNT2):c.451C>T (p.Arg151Trp)	TNNT2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12415	NM_001276345.2(TNNT2):c.421C>T (p.Arg141Trp)	TNNT2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12416	NM_001276345.2(TNNT2):c.644G>T (p.Arg215Leu)	TNNT2	Pathogenic	no assertion criteria provided
165533	NM_001276345.2(TNNT2):c.851+1G>T	TNNT2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
165549	NM_001276345.2(TNNT2):c.310C>T (p.Arg104Cys)	TNNT2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
177634	NM_001276345.2(TNNT2):c.566C>T (p.Ser189Phe)	TNNT2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
177644	NM_001276345.2(TNNT2):c.274G>A (p.Gly92Arg)	TNNT2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
177807	NM_001276345.2(TNNT2):c.360T>G (p.Phe120Leu)	TNNT2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
181636	NM_001276345.2(TNNT2):c.891G>A (p.Trp297Ter)	TNNT2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
181649	NM_001276345.2(TNNT2):c.851+1G>C	TNNT2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2100789	NM_001276345.2(TNNT2):c.321G>C (p.Lys107Asn)	TNNT2	Pathogenic	criteria provided, single submitter
228409	NM_001276345.2(TNNT2):c.547C>T (p.Arg183Trp)	TNNT2	Pathogenic	criteria provided, multiple submitters, no conflicts
3753583	NM_001276345.2(TNNT2):c.291T>G (p.Phe97Leu)	TNNT2	Pathogenic	criteria provided, single submitter
43626	NM_001276345.2(TNNT2):c.287A>C (p.Asp96Ala)	TNNT2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
43627	NM_001276345.2(TNNT2):c.304C>T (p.Arg102Trp)	TNNT2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
43629	NM_001276345.2(TNNT2):c.311G>T (p.Arg104Leu)	TNNT2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
43636	NM_001276345.2(TNNT2):c.418C>T (p.Arg140Cys)	TNNT2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
43637	NM_001276345.2(TNNT2):c.422G>A (p.Arg141Gln)	TNNT2	Pathogenic	criteria provided, multiple submitters, no conflicts
43639	NM_001276345.2(TNNT2):c.430C>G (p.Arg144Gly)	TNNT2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
43648	NM_001276345.2(TNNT2):c.508GAG[3] (p.Glu173del)	TNNT2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
43649	NM_001276345.2(TNNT2):c.548G>A (p.Arg183Gln)	TNNT2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
43659	NM_001276345.2(TNNT2):c.650AGA[3] (p.Lys220del)	TNNT2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3776306	NM_170707.4(LMNA):c.1175del (p.Ser392fs)	LMNA	Likely pathogenic	criteria provided, single submitter
1435754	NM_001276345.2(TNNT2):c.283G>A (p.Val95Met)	TNNT2	Likely pathogenic	criteria provided, single submitter
1699339	NM_001276345.2(TNNT2):c.299T>A (p.Ile100Asn)	TNNT2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1701922	NM_001276345.2(TNNT2):c.68-2A>G	TNNT2	Likely pathogenic	criteria provided, single submitter
177636	NM_001276345.2(TNNT2):c.890G>A (p.Trp297Ter)	TNNT2	Likely pathogenic	reviewed by expert panel

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · Orphanet: 30 · 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

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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
LMNA	Orphanet:154	Familial isolated dilated cardiomyopathy
LMNA	Orphanet:157973	Congenital muscular dystrophy due to LMNA mutation
LMNA	Orphanet:1662	Restrictive dermopathy
LMNA	Orphanet:168796	Heart-hand syndrome, Slovenian type
LMNA	Orphanet:2229	Dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome
LMNA	Orphanet:2348	Familial partial lipodystrophy, Dunnigan type
LMNA	Orphanet:280365	Autosomal semi-dominant severe lipodystrophic laminopathy
LMNA	Orphanet:293888	Inherited isolated arrhythmogenic cardiomyopathy, dominant-left variant
LMNA	Orphanet:293899	Inherited isolated arrhythmogenic ventricular dysplasia, biventricular variant
LMNA	Orphanet:293910	Inherited isolated arrhythmogenic cardiomyopathy, dominant-right variant
LMNA	Orphanet:300751	Familial dilated cardiomyopathy with conduction defect due to LMNA mutation
LMNA	Orphanet:363618	LMNA-related cardiocutaneous progeria syndrome
LMNA	Orphanet:54260	Left ventricular noncompaction
LMNA	Orphanet:675396	Epithelioid hemangioma
LMNA	Orphanet:740	Hutchinson-Gilford progeria syndrome
LMNA	Orphanet:79084	Familial partial lipodystrophy, Köbberling type
LMNA	Orphanet:79474	Atypical Werner syndrome
LMNA	Orphanet:90153	Mandibuloacral dysplasia with type A lipodystrophy
LMNA	Orphanet:98853	Autosomal dominant Emery-Dreifuss muscular dystrophy
LMNA	Orphanet:98855	Autosomal recessive Emery-Dreifuss muscular dystrophy
LMNA	Orphanet:98856	Charcot-Marie-Tooth disease type 2B1

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
TNNT2	HGNC:11949	ENSG00000118194	P45379	Troponin T, cardiac muscle	gencc,clinvar
TSC2	HGNC:12363	ENSG00000103197	P49815	Tuberin	clinvar
LMNA	HGNC:6636	ENSG00000160789	P02545	Prelamin-A/C	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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…
LMNA	Prelamin-A/C	Lamins are intermediate filament proteins that assemble into a filamentous meshwork, and which constitute the major components of the nuclear lamina, a fibrous layer on the nucleoplasmic side of the inner nuclear membrane.

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)
TNNT2	Other/Unknown	no		Troponin, TNNT, Troponin_sf
TSC2	Other/Unknown	no		Rap/Ran_GAP_dom, Tuberin, ARM-like
LMNA	Other/Unknown	no		Lamin_tail_dom, IF_conserved, Lamin_tail_dom_sf

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
cardiac atrium	1
right atrium auricular region	1
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
mucosa of stomach	1
nipple	1
skin of abdomen	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
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
LMNA	295	ubiquitous	marker	nipple, mucosa of stomach, skin of abdomen

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
LMNA	7,173
TSC2	4,135
TNNT2	1,944

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
LMNA	P02545	28
TNNT2	P45379	25
TSC2	P49815	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 23. Enrichment computed across 3 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
Breakdown of the nuclear lamina	1	1268.9×	0.015	LMNA
Inhibition of TSC complex formation by AKT (PKB)	1	761.3×	0.015	TSC2
AKT phosphorylates targets in the cytosol	1	271.9×	0.017	TSC2
Depolymerization of the Nuclear Lamina	1	253.8×	0.017	LMNA
Initiation of Nuclear Envelope (NE) Reformation	1	200.3×	0.017	LMNA
IRE1alpha activates chaperones	1	173.0×	0.017	LMNA
Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer’s disease models	1	173.0×	0.017	LMNA
Nuclear Envelope Breakdown	1	152.3×	0.017	LMNA
Constitutive Signaling by AKT1 E17K in Cancer	1	141.0×	0.017	TSC2
Energy dependent regulation of mTOR by LKB1-AMPK	1	131.3×	0.017	TSC2
Unfolded Protein Response (UPR)	1	119.0×	0.018	LMNA
Striated Muscle Contraction	1	102.9×	0.019	TNNT2
TBC/RABGAPs	1	86.5×	0.020	TSC2
Oncogenic MAPK signaling	1	82.8×	0.020	LMNA
XBP1(S) activates chaperone genes	1	71.8×	0.021	LMNA
Signaling by BRAF and RAF1 fusions	1	56.8×	0.025	LMNA
Meiotic synapsis	1	47.0×	0.029	LMNA
TP53 Regulates Metabolic Genes	1	43.3×	0.029	TSC2
Macroautophagy	1	38.5×	0.031	TSC2
Diseases of signal transduction by growth factor receptors and second messengers	1	18.9×	0.060	LMNA
Cellular responses to stress	1	12.3×	0.087	LMNA
Cellular responses to stimuli	1	10.5×	0.097	LMNA
Disease	1	4.4×	0.212	LMNA

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
DNA double-strand break attachment to nuclear envelope	1	1872.4×	0.007	LMNA
establishment or maintenance of microtubule cytoskeleton polarity	1	1404.3×	0.007	LMNA
nuclear pore localization	1	1123.5×	0.007	LMNA
negative regulation of mesenchymal cell proliferation	1	936.2×	0.007	LMNA
protein localization to nuclear envelope	1	702.2×	0.007	LMNA
regulation of protein localization to nucleus	1	702.2×	0.007	LMNA
negative regulation of cardiac muscle hypertrophy in response to stress	1	624.1×	0.007	LMNA
regulation of muscle contraction	1	561.7×	0.007	TNNT2
negative regulation of ATP-dependent activity	1	561.7×	0.007	TNNT2
regulation of insulin receptor signaling pathway	1	561.7×	0.007	TSC2
ventricular cardiac muscle cell development	1	510.7×	0.007	LMNA
negative regulation of mitophagy	1	510.7×	0.007	TSC2
protein import into nucleus	2	96.0×	0.007	TSC2, LMNA
intracellular protein localization	2	69.8×	0.007	TSC2, LMNA
negative regulation of cell population proliferation	2	28.1×	0.007	TSC2, LMNA
positive regulation of ATP-dependent activity	1	468.1×	0.007	TNNT2
anoikis	1	432.1×	0.007	TSC2
muscle filament sliding	1	351.1×	0.008	TNNT2
nuclear envelope organization	1	330.4×	0.008	LMNA
regulation of telomere maintenance	1	280.9×	0.009	LMNA
positive chemotaxis	1	267.5×	0.009	TSC2
negative regulation of release of cytochrome c from mitochondria	1	267.5×	0.009	LMNA
nuclear migration	1	244.2×	0.009	LMNA
ventricular cardiac muscle tissue morphogenesis	1	234.1×	0.009	TNNT2
negative regulation of TOR signaling	1	187.2×	0.011	TSC2
positive regulation of macroautophagy	1	175.5×	0.011	TSC2
regulation of heart contraction	1	165.2×	0.012	TNNT2
regulation of endocytosis	1	160.5×	0.012	TSC2
double-strand break repair via nonhomologous end joining	1	140.4×	0.012	LMNA
negative regulation of extrinsic apoptotic signaling pathway	1	140.4×	0.012	LMNA

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 3 evidence-associated genes (100%) 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
LMNA	BEPRIDIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
LMNA	823	4
TNNT2	0	0
TSC2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BEPRIDIL	4	LMNA
PHENYLBUTAZONE	4	LMNA
CEFOTAXIME SODIUM	4	LMNA
DIENESTROL	4	LMNA
IFOSFAMIDE	4	LMNA
PROGESTERONE	4	LMNA
CLOTRIMAZOLE	4	LMNA
DAPSONE	4	LMNA
AMINOCAPROIC ACID	4	LMNA
FLUCONAZOLE	4	LMNA
COLCHICINE	4	LMNA
NABUMETONE	4	LMNA
OXAPROZIN	4	LMNA
BUMETANIDE	4	LMNA
GLIPIZIDE	4	LMNA
BROMFENAC	4	LMNA
ROPIVACAINE	4	LMNA
TIZANIDINE	4	LMNA
METAXALONE	4	LMNA
CARBAMAZEPINE	4	LMNA
SALMETEROL XINAFOATE	4	LMNA
AMIODARONE HYDROCHLORIDE	4	LMNA
METHYL SALICYLATE	4	LMNA
DIBUCAINE	4	LMNA
PHENELZINE	4	LMNA
HYDROCORTISONE ACETATE	4	LMNA
BRETYLIUM TOSYLATE	4	LMNA
IMIPRAMINE	4	LMNA
FURAZOLIDONE	4	LMNA
DROPERIDOL	4	LMNA

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
LMNA	12	Binding:9, Functional:3
TNNT2	2	Binding:2
TSC2	1	Binding: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

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	LMNA
PHENYLBUTAZONE	4	LMNA
CEFOTAXIME SODIUM	4	LMNA
DIENESTROL	4	LMNA
IFOSFAMIDE	4	LMNA
PROGESTERONE	4	LMNA
CLOTRIMAZOLE	4	LMNA
DAPSONE	4	LMNA
AMINOCAPROIC ACID	4	LMNA
FLUCONAZOLE	4	LMNA
COLCHICINE	4	LMNA
NABUMETONE	4	LMNA
OXAPROZIN	4	LMNA
BUMETANIDE	4	LMNA
GLIPIZIDE	4	LMNA
BROMFENAC	4	LMNA
ROPIVACAINE	4	LMNA
TIZANIDINE	4	LMNA
METAXALONE	4	LMNA
CARBAMAZEPINE	4	LMNA
SALMETEROL XINAFOATE	4	LMNA
AMIODARONE HYDROCHLORIDE	4	LMNA
METHYL SALICYLATE	4	LMNA
DIBUCAINE	4	LMNA
PHENELZINE	4	LMNA
HYDROCORTISONE ACETATE	4	LMNA
BRETYLIUM TOSYLATE	4	LMNA
IMIPRAMINE	4	LMNA
FURAZOLIDONE	4	LMNA
DROPERIDOL	4	LMNA

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	LMNA
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	TNNT2, TSC2

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)
TNNT2	2	—
TSC2	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.