dilated cardiomyopathy 1Y

Summary

dilated cardiomyopathy 1Y (MONDO:0012744) is a disease caused by TPM1 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: TPM1 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 103

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	dilated cardiomyopathy 1Y
Mondo ID	MONDO:0012744
MeSH	C567507
OMIM	611878
DOID	DOID:0110457
UMLS	C2678476
MedGen	437215
GARD	0015530
Is cancer (heuristic)	no

Also known as: cardiomyopathy, dilated, 1Y · cardiomyopathy, dilated, type 1Y · CMD1Y · dilated cardiomyopathy type 1Y · familial isolated dilated cardiomyopathy caused by mutation in TPM1 · TPM1 familial isolated dilated cardiomyopathy

Data availability: 103 ClinVar variants · 1 GenCC gene-disease record.

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 1Y

Related subtypes (12): dilated cardiomyopathy 1C, dilated cardiomyopathy 1D, left ventricular noncompaction 1, left ventricular noncompaction 2, 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

103 retrieved; paginated sample, class counts are floors:

45 uncertain significance, 33 conflicting classifications of pathogenicity, 8 likely pathogenic, 4 benign, 4 benign/likely benign, 4 pathogenic/likely pathogenic, 3 pathogenic, 2 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
12456	NM_001018005.2(TPM1):c.523G>A (p.Asp175Asn)	TPM1	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
31883	NM_001018005.2(TPM1):c.644C>T (p.Ser215Leu)	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
4277488	NM_001018005.2(TPM1):c.281T>A (p.Leu94Gln)	TPM1	Pathogenic	criteria provided, single submitter
43420	NM_001018005.2(TPM1):c.475G>A (p.Asp159Asn)	TPM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1012347	NM_001018005.2(TPM1):c.598G>C (p.Val200Leu)	TPM1	Likely pathogenic	no assertion criteria provided
254158	NM_001018005.2(TPM1):c.519G>C (p.Glu173Asp)	TPM1	Likely pathogenic	criteria provided, single submitter
264474	NM_001018005.2(TPM1):c.250G>A (p.Asp84Asn)	TPM1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3075681	NM_001018005.2(TPM1):c.430C>G (p.Gln144Glu)	TPM1	Likely pathogenic	criteria provided, single submitter
3780971	NM_001018005.2(TPM1):c.42C>G (p.Asp14Glu)	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
1163098	NM_001018005.2(TPM1):c.398G>A (p.Arg133Gln)	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
12458	NM_001018005.2(TPM1):c.160G>A (p.Glu54Lys)	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
177761	NM_001018005.2(TPM1):c.343G>A (p.Glu115Lys)	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
181668	NM_001018005.2(TPM1):c.602C>T (p.Thr201Met)	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

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 7 · 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
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
MED12	Orphanet:1415	Hardikar syndrome
MED12	Orphanet:293707	Blepharophimosis-intellectual disability syndrome, MKB type
MED12	Orphanet:776	Lujan-Fryns syndrome
MED12	Orphanet:777	X-linked non-syndromic intellectual disability
MED12	Orphanet:93932	FG syndrome type 1

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
MED12	HGNC:11957	ENSG00000184634	Q93074	Mediator of RNA polymerase II transcription subunit 12	clinvar

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.
MED12	Mediator of RNA polymerase II transcription subunit 12	Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes.

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
MED12	Other/Unknown	no		Mediator_Med12, Mediator_Med12_catenin-bd, Mediator_Med12_LCEWAV

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
left ovary	1
right adrenal gland	1
right adrenal gland cortex	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
MED12	281	ubiquitous	marker	right adrenal gland cortex, right adrenal gland, left ovary

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TPM1	3,514
MED12	3,322

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TPM1	P09493	14
MED12	Q93074	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 22. 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	1	154.3×	0.034	TPM1
Smooth Muscle Contraction	1	132.8×	0.034	TPM1
Epigenetic regulation of adipogenesis genes by MLL3 and MLL4 complexes	1	107.7×	0.034	MED12
Epigenetic regulation of gene expression by MLL3 and MLL4 complexes	1	98.5×	0.034	MED12
Respiratory Syncytial Virus Infection Pathway	1	98.5×	0.034	MED12
RSV-host interactions	1	78.2×	0.034	MED12
Adipogenesis	1	78.2×	0.034	MED12
Epigenetic regulation by WDR5-containing histone modifying complexes	1	77.2×	0.034	MED12
Regulation of lipid metabolism by PPARalpha	1	70.5×	0.034	MED12
Transcriptional regulation of white adipocyte differentiation	1	64.9×	0.034	MED12
PPARA activates gene expression	1	47.2×	0.042	MED12
MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis	1	41.4×	0.044	MED12
Epigenetic regulation of gene expression	1	35.7×	0.047	MED12
Metabolism of lipids	1	15.8×	0.094	MED12
Viral Infection Pathways	1	15.4×	0.094	MED12
Infectious disease	1	12.4×	0.109	MED12
RNA Polymerase II Transcription	1	11.3×	0.112	MED12
Gene expression (Transcription)	1	8.9×	0.133	MED12
Generic Transcription Pathway	1	7.5×	0.147	MED12
Developmental Biology	1	7.2×	0.147	MED12
Disease	1	6.5×	0.154	MED12
Metabolism	1	5.8×	0.165	MED12

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 by epinephrine	1	8426.0×	0.004	TPM1
axis elongation involved in somitogenesis	1	2808.7×	0.006	MED12
embryonic neurocranium morphogenesis	1	936.2×	0.008	MED12
regulation of muscle contraction	1	842.6×	0.008	TPM1
negative regulation of vascular associated smooth muscle cell migration	1	842.6×	0.008	TPM1
ruffle organization	1	648.1×	0.008	TPM1
Schwann cell development	1	526.6×	0.008	MED12
muscle filament sliding	1	526.6×	0.008	TPM1
embryonic brain development	1	401.2×	0.008	MED12
post-anal tail morphogenesis	1	366.4×	0.008	MED12
ventricular cardiac muscle tissue morphogenesis	1	351.1×	0.008	TPM1
negative regulation of vascular associated smooth muscle cell proliferation	1	337.0×	0.008	TPM1
endoderm development	1	312.1×	0.008	MED12
oligodendrocyte development	1	300.9×	0.008	MED12
spinal cord development	1	255.3×	0.009	MED12
regulation of heart contraction	1	247.8×	0.009	TPM1
Wnt signaling pathway, planar cell polarity pathway	1	227.7×	0.009	MED12
cellular response to reactive oxygen species	1	205.5×	0.009	TPM1
cardiac muscle contraction	1	200.6×	0.009	TPM1
sarcomere organization	1	191.5×	0.009	TPM1
positive regulation of stress fiber assembly	1	156.0×	0.010	TPM1
positive regulation of cell adhesion	1	135.9×	0.011	TPM1
positive regulation of transcription initiation by RNA polymerase II	1	135.9×	0.011	MED12
somatic stem cell population maintenance	1	123.9×	0.011	MED12
wound healing	1	113.9×	0.012	TPM1
neural tube closure	1	93.6×	0.014	MED12
cytoskeleton organization	1	66.3×	0.019	TPM1
regulation of cell shape	1	61.5×	0.020	TPM1
actin filament organization	1	59.3×	0.020	TPM1
negative regulation of cell migration	1	55.8×	0.020	TPM1

Therapeutics

Drug target analysis

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

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
MED12	1	2
TPM1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	MED12

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
MED12	6	Binding:6
TPM1	3	Binding:3

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

1 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)
MOLIBRESIB	2	MED12

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	1	MED12
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	TPM1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TPM1	3	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.