Hypertrophic cardiomyopathy 11

Summary

Hypertrophic cardiomyopathy 11 (MONDO:0012799) is a disease caused by ACTC1 (GenCC Definitive), with 4 cohort genes.

At a glance

• Causal gene: ACTC1 (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 605

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hypertrophic cardiomyopathy 11
Mondo ID	MONDO:0012799
MeSH	C567419
OMIM	612098
DOID	DOID:0110317
UMLS	C2677506
MedGen	436962
GARD	0024889
Is cancer (heuristic)	no

Also known as: ACTC1 hypertrophic cardiomyopathy · cardiomyopathy, familial hypertrophic, 11 · cardiomyopathy, familial hypertrophic, type 11 · cardiomyopathy, hypertrophic, 11 · CMH11 · hypertrophic cardiomyopathy 11 · hypertrophic cardiomyopathy caused by mutation in ACTC1 · hypertrophic cardiomyopathy type 11

Data availability: 605 ClinVar variants · 3 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 11

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 12, hypertrophic cardiomyopathy 13, hypertrophic cardiomyopathy 14, hypertrophic cardiomyopathy 15, 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

600 retrieved; paginated sample, class counts are floors:

290 uncertain significance, 218 likely benign, 38 conflicting classifications of pathogenicity, 33 benign/likely benign, 8 benign, 7 likely pathogenic, 3 pathogenic, 2 pathogenic/likely pathogenic, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
18325	NM_005159.5(ACTC1):c.889G>T (p.Ala297Ser)	ACTC1	Pathogenic	criteria provided, single submitter
18329	NM_005159.5(ACTC1):c.997G>C (p.Ala333Pro)	ACTC1	Pathogenic	criteria provided, single submitter
18331	NM_005159.5(ACTC1):c.301G>A (p.Glu101Lys)	ACTC1	Pathogenic	reviewed by expert panel
626827	NM_005159.5(ACTC1):c.740G>A (p.Gly247Asp)	ACTC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
177886	NM_005159.5(ACTC1):c.866T>C (p.Ile289Thr)	GJD2-DT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1469293	NM_005159.5(ACTC1):c.155A>C (p.Lys52Thr)	ACTC1	Likely pathogenic	criteria provided, single submitter
2015662	NM_005159.5(ACTC1):c.581T>A (p.Ile194Asn)	ACTC1	Likely pathogenic	criteria provided, single submitter
4783293	NM_005159.5(ACTC1):c.716A>T (p.Glu239Val)	ACTC1	Likely pathogenic	criteria provided, single submitter
177748	NM_005159.5(ACTC1):c.383C>T (p.Thr128Ile)	GJD2-DT	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2950148	NM_005159.5(ACTC1):c.951G>T (p.Lys317Asn)	GJD2-DT	Likely pathogenic	criteria provided, single submitter
3382680	NM_005159.5(ACTC1):c.766C>T (p.Arg256Cys)	GJD2-DT	Likely pathogenic	criteria provided, single submitter
45191	NM_005159.5(ACTC1):c.850A>T (p.Ile284Phe)	GJD2-DT	Likely pathogenic	reviewed by expert panel
1031511	NM_005159.5(ACTC1):c.382A>G (p.Thr128Ala)	ACTC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1272947	NM_005159.5(ACTC1):c.990+6G>A	ACTC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
136280	NM_005159.5(ACTC1):c.270C>T (p.His90=)	ACTC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
136281	NM_005159.5(ACTC1):c.809-12A>G	ACTC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1476025	NM_005159.5(ACTC1):c.725A>G (p.Tyr242Cys)	ACTC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1634056	NM_005159.5(ACTC1):c.130-11dup	ACTC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
177786	NM_005159.5(ACTC1):c.793C>G (p.Gln265Glu)	ACTC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
180771	NM_005159.5(ACTC1):c.968C>T (p.Ala323Val)	ACTC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
180773	NM_005159.5(ACTC1):c.998C>T (p.Ala333Val)	ACTC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
18323	NM_005159.5(ACTC1):c.941G>A (p.Arg314His)	ACTC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
18324	NM_005159.5(ACTC1):c.1088A>G (p.Glu363Gly)	ACTC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
217487	NM_005159.5(ACTC1):c.281A>G (p.Asn94Ser)	ACTC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
315662	NM_005159.4(ACTC1):c.*1219C>T	ACTC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
315682	NM_005159.4(ACTC1):c.*737C>T	ACTC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
315693	NM_005159.4(ACTC1):c.*393G>T	ACTC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
315708	NM_005159.5(ACTC1):c.809-58TG[21]	ACTC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
315711	NM_005159.5(ACTC1):c.537T>A (p.Arg179=)	ACTC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
315712	NM_005159.5(ACTC1):c.-23+15G>T	ACTC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · 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
ACTC1	Definitive	Autosomal dominant	hypertrophic cardiomyopathy	12

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ACTC1	Orphanet:154	Familial isolated dilated cardiomyopathy
ACTC1	Orphanet:54260	Left ventricular noncompaction
ACTC1	Orphanet:99103	Atrial septal defect, ostium secundum type
CREBBP	Orphanet:353277	Rubinstein-Taybi syndrome due to CREBBP mutations
CREBBP	Orphanet:353281	Rubinstein-Taybi syndrome due to 16p13.3 microdeletion
CREBBP	Orphanet:370026	Acute myeloid leukemia with t(8;16)(p11;p13) translocation
CREBBP	Orphanet:592574	Menke-Hennekam syndrome

Cohort genes → proteins

4 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ACTC1	HGNC:143	ENSG00000159251	P68032	Actin, alpha cardiac muscle 1	gencc,clinvar
GJD2	HGNC:19154	ENSG00000159248	Q9UKL4	Gap junction delta-2 protein	clinvar
CREBBP	HGNC:2348	ENSG00000005339	Q92793	CREB-binding protein	clinvar
GJD2-DT	HGNC:55560	ENSG00000250007		GJD2 divergent transcript	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ACTC1	Actin, alpha cardiac muscle 1	Actins are highly conserved proteins that are involved in various types of cell motility and are ubiquitously expressed in all eukaryotic cells.
GJD2	Gap junction delta-2 protein	One gap junction consists of a cluster of closely packed pairs of transmembrane channels, the connexons, through which materials of low MW diffuse from one cell to a neighboring cell.
CREBBP	CREB-binding protein	Acetylates histones, giving a specific tag for transcriptional activation.

Protein-family classification

Druggable: 0 · Difficult: 1 · 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
Transcription factor	1	2.1×	0.404
Other/Unknown	3	1.3×	0.404

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ACTC1	Other/Unknown	no		Actin, Actin_CS, Actin/actin-like_CS
GJD2	Other/Unknown	no		Connexin, Connexin36, Connexin_N
CREBBP	Transcription factor	no	2.3.1.48	Znf_TAZ, Znf_ZZ, Bromodomain
GJD2-DT	Other/Unknown	no

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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
heart right ventricle	1
left ventricle myocardium	1
myocardium	1
islet of Langerhans	1
primordial germ cell in gonad	1
tongue squamous epithelium	1
amniotic fluid	1
sural nerve	1
tibia	1
apex of heart	1
heart left ventricle	1
right atrium auricular region	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ACTC1	224	broad	marker	left ventricle myocardium, heart right ventricle, myocardium
GJD2	70	tissue_specific	marker	islet of Langerhans, primordial germ cell in gonad, tongue squamous epithelium
CREBBP	297	ubiquitous	marker	sural nerve, tibia, amniotic fluid
GJD2-DT	114		yes	right atrium auricular region, apex of heart, heart left ventricle

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CREBBP	6,959
ACTC1	996
GJD2	980
GJD2-DT	0

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CREBBP	Q92793	144
GJD2	Q9UKL4	24
ACTC1	P68032	16

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 139. Enrichment computed across 4 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
LRR FLII-interacting protein 1 (LRRFIP1) activates type I IFN production	1	761.3×	0.023	CREBBP
NFE2L2 regulating inflammation associated genes	1	761.3×	0.023	CREBBP
NFE2L2 regulating ER-stress associated genes	1	761.3×	0.023	CREBBP
Electric Transmission Across Gap Junctions	1	634.4×	0.023	GJD2
RUNX1 regulates transcription of genes involved in differentiation of myeloid cells	1	475.8×	0.023	CREBBP
NFE2L2 regulates pentose phosphate pathway genes	1	475.8×	0.023	CREBBP
NFE2L2 regulating MDR associated enzymes	1	475.8×	0.023	CREBBP
Regulation of NFE2L2 gene expression	1	475.8×	0.023	CREBBP
Regulation of FOXO transcriptional activity by acetylation	1	380.7×	0.023	CREBBP
Regulation of gene expression by Hypoxia-inducible Factor	1	317.2×	0.023	CREBBP
Activation of the TFAP2 (AP-2) family of transcription factors	1	317.2×	0.023	CREBBP
Regulation of CDH1 Function	1	317.2×	0.023	ACTC1
NFE2L2 regulating tumorigenic genes	1	317.2×	0.023	CREBBP
Cellular response to hypoxia	1	292.8×	0.023	CREBBP
Phosphorylation of CLOCK, acetylation of BMAL1 (ARNTL) at target gene promoters	1	292.8×	0.023	CREBBP
RUNX3 regulates NOTCH signaling	1	271.9×	0.023	CREBBP
TRAF3-dependent IRF activation pathway	1	253.8×	0.023	CREBBP
R-HSA-1368082	1	237.9×	0.023	CREBBP
Regulation of beta-cell development	1	237.9×	0.023	CREBBP
Regulation of gene expression in late stage (branching morphogenesis) pancreatic bud precursor cells	1	237.9×	0.023	CREBBP
FOXO-mediated transcription of cell death genes	1	237.9×	0.023	CREBBP
Maternal to zygotic transition (MZT)	1	237.9×	0.023	CREBBP
The CRY:PER:kinase complex represses transactivation by the BMAL:CLOCK (ARNTL:CLOCK) complex	1	237.9×	0.023	CREBBP
Zygotic genome activation (ZGA)	1	223.9×	0.023	CREBBP
Transcriptional regulation by the AP-2 (TFAP2) family of transcription factors	1	211.5×	0.023	CREBBP
NOTCH4 Intracellular Domain Regulates Transcription	1	190.3×	0.023	CREBBP
Transcriptional Regulation by NPAS4	1	190.3×	0.023	CREBBP
TP53 Regulates Transcription of Cell Death Genes	1	181.3×	0.023	CREBBP
TP53 Regulates Transcription of Genes Involved in Cytochrome C Release	1	181.3×	0.023	CREBBP
NFE2L2 regulating anti-oxidant/detoxification enzymes	1	181.3×	0.023	CREBBP

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
actin-myosin filament sliding	1	2808.7×	0.009	ACTC1
N-terminal peptidyl-lysine acetylation	1	1872.4×	0.009	CREBBP
cytoplasmic actin-based contraction involved in cell motility	1	1123.5×	0.009	ACTC1
mesenchyme migration	1	1123.5×	0.009	ACTC1
skeletal muscle thin filament assembly	1	936.2×	0.009	ACTC1
negative regulation of transcription by RNA polymerase I	1	802.5×	0.009	CREBBP
homeostatic process	1	561.7×	0.009	CREBBP
protein acetylation	1	468.1×	0.009	CREBBP
cardiac muscle tissue morphogenesis	1	468.1×	0.009	ACTC1
cAMP/PKA signal transduction	1	468.1×	0.009	CREBBP
cardiac myofibril assembly	1	432.1×	0.009	ACTC1
regulation of cellular response to heat	1	351.1×	0.010	CREBBP
actin filament-based movement	1	267.5×	0.012	ACTC1
heart contraction	1	255.3×	0.012	ACTC1
stimulatory C-type lectin receptor signaling pathway	1	244.2×	0.012	CREBBP
regulation of smoothened signaling pathway	1	208.1×	0.013	CREBBP
actomyosin structure organization	1	187.2×	0.013	ACTC1
positive regulation of transforming growth factor beta receptor signaling pathway	1	175.5×	0.014	CREBBP
neuronal action potential	1	160.5×	0.014	GJD2
cellular response to nutrient levels	1	156.0×	0.014	CREBBP
cardiac muscle contraction	1	133.8×	0.015	ACTC1
positive regulation of protein localization to nucleus	1	130.6×	0.015	CREBBP
positive regulation of double-strand break repair via homologous recombination	1	127.7×	0.015	CREBBP
canonical NF-kappaB signal transduction	1	122.1×	0.015	CREBBP
embryonic digit morphogenesis	1	100.3×	0.016	CREBBP
cellular response to UV	1	98.5×	0.016	CREBBP
protein destabilization	1	96.8×	0.016	CREBBP
rhythmic process	1	83.8×	0.018	CREBBP
response to ethanol	1	48.9×	0.030	ACTC1
actin filament organization	1	39.6×	0.036	ACTC1

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 4 evidence-associated genes (50%) 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
CREBBP	COLCHICINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CREBBP	13	4
ACTC1	0	0
GJD2	0	0
GJD2-DT	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
COLCHICINE	4	CREBBP
ALTRETAMINE	4	CREBBP
CURCUMIN	3	CREBBP
PAPAVERINE	3	CREBBP
EPIGALOCATECHIN GALLATE	3	CREBBP
MOLIBRESIB	2	CREBBP
FISETIN	2	CREBBP
ETAZOLATE	2	CREBBP
LUNRESERTIB	2	CREBBP
TRACAZOLATE	2	CREBBP
NOCODAZOLE	2	CREBBP
INOBRODIB	1	CREBBP
AZD-5153	1	CREBBP

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
CREBBP	687	Binding:644, Functional:43
ACTC1	6	Binding:6

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CREBBP	2.3.1.48	histone acetyltransferase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
CREBBP	687

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

13 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)
COLCHICINE	4	CREBBP
ALTRETAMINE	4	CREBBP
CURCUMIN	3	CREBBP
PAPAVERINE	3	CREBBP
EPIGALOCATECHIN GALLATE	3	CREBBP
MOLIBRESIB	2	CREBBP
FISETIN	2	CREBBP
ETAZOLATE	2	CREBBP
LUNRESERTIB	2	CREBBP
TRACAZOLATE	2	CREBBP
NOCODAZOLE	2	CREBBP
INOBRODIB	1	CREBBP
AZD-5153	1	CREBBP

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	CREBBP
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	3	ACTC1, GJD2, GJD2-DT

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ACTC1	6	—
GJD2	0	—
GJD2-DT	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.