dilated cardiomyopathy 1W

Summary

dilated cardiomyopathy 1W (MONDO:0012667) is a disease caused by VCL (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: VCL (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 1,360

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	dilated cardiomyopathy 1W
Mondo ID	MONDO:0012667
MeSH	C566954
OMIM	611407
DOID	DOID:0110446
UMLS	C1969639
MedGen	370063
GARD	0015515
Is cancer (heuristic)	no

Also known as: cardiomyopathy, dilated, 1W · cardiomyopathy, dilated, type 1W · CMD1W · dilated cardiomyopathy type 1W · familial isolated dilated cardiomyopathy caused by mutation in VCL · VCL familial isolated dilated cardiomyopathy

Data availability: 1,360 ClinVar variants · 4 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 › dilated cardiomyopathy › familial dilated cardiomyopathy › familial isolated dilated cardiomyopathy › dilated cardiomyopathy 1W

Related subtypes (44): dilated cardiomyopathy 1A, dilated cardiomyopathy 3B, dilated cardiomyopathy 1B, dilated cardiomyopathy 1E, dilated cardiomyopathy 1C, dilated cardiomyopathy 1D, dilated cardiomyopathy 1G, dilated cardiomyopathy 1H, dilated cardiomyopathy 1I, dilated cardiomyopathy 1K, dilated cardiomyopathy 1L, dilated cardiomyopathy 1M, dilated cardiomyopathy 1O, dilated cardiomyopathy 1P, dilated cardiomyopathy 1Q, dilated cardiomyopathy 1X, dilated cardiomyopathy 1Y, dilated cardiomyopathy 1Z, dilated cardiomyopathy 2A, dilated cardiomyopathy 1AA, dilated cardiomyopathy 1BB, dilated cardiomyopathy 1CC, dilated cardiomyopathy 1DD, dilated cardiomyopathy 1EE, dilated cardiomyopathy 1FF, dilated cardiomyopathy 1R, dilated cardiomyopathy 1S, dilated cardiomyopathy 1GG, dilated cardiomyopathy 1U, dilated cardiomyopathy 1V, dilated cardiomyopathy 1HH, dilated cardiomyopathy 2B, dilated cardiomyopathy 1II, dilated cardiomyopathy 1JJ, dilated cardiomyopathy 1KK, left ventricular noncompaction 8, left ventricular noncompaction 10, dilated cardiomyopathy 1NN, cardiomyopathy, dilated, 2D, cardiomyopathy, dilated, 2E, cardiomyopathy, dilated, 2F, cardiomyopathy, dilated, 2G, cardiomyopathy, dilated, 2c, cardiomyopathy, dilated, 2H

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:

326 uncertain significance, 233 likely benign, 32 conflicting classifications of pathogenicity, 6 benign/likely benign, 3 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1007928	NM_014000.3(VCL):c.2762C>T (p.Ala921Val)	VCL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1017552	NM_014000.3(VCL):c.2798C>T (p.Ala933Val)	VCL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1019741	NM_014000.3(VCL):c.1757G>A (p.Arg586Gln)	VCL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
12198	NM_014000.3(VCL):c.829C>A (p.Leu277Met)	VCL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1310591	NM_014000.3(VCL):c.1006G>A (p.Ala336Thr)	VCL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
137902	NM_014000.3(VCL):c.1290C>T (p.Asp430=)	VCL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1421261	NM_014000.3(VCL):c.1756C>T (p.Arg586Trp)	VCL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
166536	NM_014000.3(VCL):c.492T>G (p.Leu164=)	VCL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
166538	NM_014000.3(VCL):c.622+4C>T	VCL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
166543	NM_014000.3(VCL):c.1294C>G (p.Leu432Val)	VCL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
166551	NM_014000.3(VCL):c.2046A>T (p.Leu682Phe)	VCL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
179157	NM_014000.3(VCL):c.1337C>G (p.Ala446Gly)	VCL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
179606	NM_014000.3(VCL):c.1973T>C (p.Val658Ala)	VCL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
179950	NM_014000.3(VCL):c.1575A>C (p.Glu525Asp)	VCL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
180088	NM_014000.3(VCL):c.808T>C (p.Leu270=)	VCL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
191002	NM_014000.3(VCL):c.2924G>A (p.Arg975Gln)	VCL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
192100	NM_014000.3(VCL):c.404T>C (p.Ile135Thr)	VCL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
192102	NM_014000.3(VCL):c.1157A>G (p.Lys386Arg)	VCL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
192103	NM_014000.3(VCL):c.1192C>T (p.Pro398Ser)	VCL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
192104	NM_014000.3(VCL):c.1225C>T (p.Arg409Ter)	VCL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
192105	NM_014000.3(VCL):c.1607C>A (p.Pro536His)	VCL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
192106	NM_014000.3(VCL):c.2521G>C (p.Asp841His)	VCL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
194864	NM_014000.3(VCL):c.2652G>A (p.Glu884=)	VCL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
202145	NM_014000.3(VCL):c.81C>T (p.His27=)	VCL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
202146	NM_014000.3(VCL):c.2000C>T (p.Thr667Met)	VCL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
202159	NM_014000.3(VCL):c.1403C>T (p.Thr468Met)	VCL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
202163	NM_014000.3(VCL):c.2828_2829del (p.Pro943fs)	VCL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2169847	NM_014000.3(VCL):c.500-10T>C	VCL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
222889	NM_014000.3(VCL):c.2468G>A (p.Arg823Gln)	VCL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
229632	NM_014000.3(VCL):c.622+4C>G	VCL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 1 · 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
VCL	Strong	Autosomal dominant	dilated cardiomyopathy 1W	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
VCL	Orphanet:154	Familial isolated dilated 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
VCL	HGNC:12665	ENSG00000035403	P18206	Vinculin	gencc,clinvar
AP3M1	HGNC:569	ENSG00000185009	Q9Y2T2	AP-3 complex subunit mu-1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
VCL	Vinculin	Actin filament (F-actin)-binding protein involved in cell-matrix adhesion and cell-cell adhesion.
AP3M1	AP-3 complex subunit mu-1	Part of the AP-3 complex, an adaptor-related complex which is not clathrin-associated.

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)
VCL	Other/Unknown	no		Vinculin_CS, Vinculin/catenin, Vinculin
AP3M1	Other/Unknown	no		Clathrin_mu, Longin-like_dom_sf, Clathrin_mu_CS

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
blood vessel layer	1
saphenous vein	1
urethra	1
epithelial cell of pancreas	1
ileal mucosa	1
pancreatic ductal cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
VCL	300	ubiquitous	marker	saphenous vein, blood vessel layer, urethra
AP3M1	250	ubiquitous	marker	pancreatic ductal cell, epithelial cell of pancreas, ileal mucosa

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
VCL	4,495
AP3M1	1,725

Intra-cohort edges

A	B	Sources
AP3M1	VCL	biogrid_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
VCL	P18206	37
AP3M1	Q9Y2T2	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 19. 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
Regulation of CDH1 Function	1	475.8×	0.012	VCL
Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells	1	178.4×	0.012	VCL
Signaling by high-kinase activity BRAF mutants	1	158.6×	0.012	VCL
Chaperonin-mediated protein folding	1	150.3×	0.012	AP3M1
Association of TriC/CCT with target proteins during biosynthesis	1	146.4×	0.012	AP3M1
MAP2K and MAPK activation	1	142.8×	0.012	VCL
Signaling by RAF1 mutants	1	139.3×	0.012	VCL
Smooth Muscle Contraction	1	132.8×	0.012	VCL
Protein folding	1	129.8×	0.012	AP3M1
Signaling by moderate kinase activity BRAF mutants	1	126.9×	0.012	VCL
Paradoxical activation of RAF signaling by kinase inactive BRAF	1	126.9×	0.012	VCL
Signaling downstream of RAS mutants	1	126.9×	0.012	VCL
Signaling by BRAF and RAF1 fusions	1	85.2×	0.016	VCL
Activation of STAT3 by cadherin engagement	1	81.6×	0.016	VCL
High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells	1	80.4×	0.016	VCL
Signaling by ALK fusions and activated point mutants	1	75.1×	0.016	VCL
Platelet degranulation	1	43.9×	0.025	VCL
Neutrophil degranulation	1	11.5×	0.090	VCL
Metabolism of proteins	1	6.2×	0.155	AP3M1

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 protein localization to adherens junction	1	8426.0×	0.003	VCL
clathrin-coated vesicle cargo loading, AP-3-mediated	1	1203.7×	0.005	AP3M1
apical junction assembly	1	1053.2×	0.005	VCL
postsynaptic neurotransmitter receptor internalization	1	1053.2×	0.005	AP3M1
regulation of establishment of endothelial barrier	1	936.2×	0.005	VCL
adherens junction assembly	1	648.1×	0.006	VCL
epithelial cell-cell adhesion	1	601.9×	0.006	VCL
anterograde synaptic vesicle transport	1	495.6×	0.006	AP3M1
melanosome assembly	1	443.5×	0.006	AP3M1
platelet dense granule organization	1	337.0×	0.006	AP3M1
protein targeting to lysosome	1	312.1×	0.006	AP3M1
regulation of focal adhesion assembly	1	300.9×	0.006	VCL
anterograde axonal transport	1	290.6×	0.006	AP3M1
protein localization to cell surface	1	247.8×	0.006	VCL
axon extension	1	247.8×	0.006	VCL
maintenance of blood-brain barrier	1	240.7×	0.006	VCL
lamellipodium assembly	1	221.7×	0.006	VCL
morphogenesis of an epithelium	1	172.0×	0.007	VCL
platelet aggregation	1	168.5×	0.007	VCL
cell-matrix adhesion	1	81.8×	0.015	VCL
negative regulation of cell migration	1	55.8×	0.020	VCL
vesicle-mediated transport	1	48.1×	0.022	AP3M1
endocytosis	1	47.6×	0.022	AP3M1
cell adhesion	1	18.7×	0.053	VCL

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
VCL	0	0
AP3M1	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
VCL	2	Binding:2
AP3M1	1	Binding:1

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	VCL, AP3M1

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)
VCL	2	—
AP3M1	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.