Hypertrophic cardiomyopathy 15

Summary

Hypertrophic cardiomyopathy 15 (MONDO:0013200) is a disease with 2 cohort genes.

At a glance

• Cohort genes: 2
• ClinVar variants: 132

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hypertrophic cardiomyopathy 15
Mondo ID	MONDO:0013200
MeSH	C567681
OMIM	613255
DOID	DOID:0110321
UMLS	C2750459
MedGen	413312
GARD	0024908
Is cancer (heuristic)	no

Also known as: cardiomyopathy, familial hypertrophic, 15 · cardiomyopathy, familial hypertrophic, type 15 · cardiomyopathy, hypertrophic, 15 · CMH15 · hypertrophic cardiomyopathy caused by mutation in VCL · hypertrophic cardiomyopathy type 15 · VCL hypertrophic cardiomyopathy

Data availability: 132 ClinVar variants · 4 GenCC gene-disease records.

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 15

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 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

132 retrieved; paginated sample, class counts are floors:

95 uncertain significance, 16 conflicting classifications of pathogenicity, 11 benign/likely benign, 5 benign, 4 likely benign, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
217497	NM_014000.3(VCL):c.1531G>T (p.Asp511Tyr)	VCL	Likely pathogenic	criteria provided, single submitter
12198	NM_014000.3(VCL):c.829C>A (p.Leu277Met)	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
191002	NM_014000.3(VCL):c.2924G>A (p.Arg975Gln)	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
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
300787	NM_014000.3(VCL):c.1287T>A (p.Asp429Glu)	VCL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
408948	NM_014000.3(VCL):c.2823_2824delinsGT (p.Pro942Ser)	VCL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
45602	NM_014000.3(VCL):c.2862_2864del (p.Leu955del)	VCL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
468805	NM_014000.3(VCL):c.1296_1297inv (p.Arg433Cys)	VCL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
468824	NM_014000.3(VCL):c.787A>T (p.Thr263Ser)	VCL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
505024	NM_014000.3(VCL):c.1490T>C (p.Ile497Thr)	VCL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
665543	NM_014000.3(VCL):c.1620T>A (p.Asp540Glu)	VCL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
844982	NM_014000.3(VCL):c.2747C>T (p.Pro916Leu)	VCL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
879717	NM_014000.3(VCL):c.*646C>G	VCL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
560071	Single allele	AP3M1	Uncertain significance	criteria provided, single submitter
1006190	NM_014000.3(VCL):c.625A>G (p.Met209Val)	VCL	Uncertain significance	criteria provided, multiple submitters, no conflicts
1016625	NM_014000.3(VCL):c.1503G>C (p.Gln501His)	VCL	Uncertain significance	criteria provided, multiple submitters, no conflicts
1022022	NM_014000.3(VCL):c.2023-1G>C	VCL	Uncertain significance	criteria provided, multiple submitters, no conflicts
1174806	NM_014000.3(VCL):c.1558C>T (p.Arg520Trp)	VCL	Uncertain significance	criteria provided, multiple submitters, no conflicts
12197	NM_014000.3(VCL):c.2923C>T (p.Arg975Trp)	VCL	Uncertain significance	criteria provided, multiple submitters, no conflicts
1306605	NM_014000.3(VCL):c.844G>T (p.Gly282Cys)	VCL	Uncertain significance	criteria provided, multiple submitters, no conflicts
1308741	NM_014000.3(VCL):c.1465G>A (p.Ala489Thr)	VCL	Uncertain significance	criteria provided, multiple submitters, no conflicts
1309830	NM_014000.3(VCL):c.686dup (p.Asn229fs)	VCL	Uncertain significance	criteria provided, multiple submitters, no conflicts
1312612	NM_014000.3(VCL):c.482C>G (p.Thr161Arg)	VCL	Uncertain significance	criteria provided, multiple submitters, no conflicts
1372600	NM_014000.3(VCL):c.806C>G (p.Ala269Gly)	VCL	Uncertain significance	criteria provided, multiple submitters, no conflicts
1382728	NM_014000.3(VCL):c.1225C>G (p.Arg409Gly)	VCL	Uncertain significance	criteria provided, multiple submitters, no conflicts
1437756	NM_014000.3(VCL):c.2305A>G (p.Arg769Gly)	VCL	Uncertain significance	criteria provided, multiple submitters, no conflicts

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.