Hypertrophic Cardiomyopathy 11

Genetic MONDO:0012799 Pathograph 5 Show in embeddings browser Hypertrophic Cardiomyopathy Genetic Disorder

Hypertrophic cardiomyopathy 11 (CMH11) is the ACTC1-related form of familial hypertrophic cardiomyopathy. ACTC1 encodes alpha-cardiac actin, the thin-filament track along which the myosin motor generates force; it is one of the eight genes with definitive ClinGen gene-disease validity for HCM, though it accounts for a small fraction of cases. Pathogenic ACTC1 alleles are missense variants that are incorporated into the cardiomyocyte thin filament, where they perturb the actin-myosin interaction and the calcium-dependent regulation of contraction rather than acting through loss of protein. As a thin-filament HCM gene, ACTC1 disease tends toward the thin-filament clinical profile — milder and atypically distributed left ventricular hypertrophy with a greater burden of diastolic dysfunction and progression to heart failure — while sharing the sarcomeric disarray, fibrosis, and arrhythmic risk of HCM generally. Inheritance is autosomal dominant; ACTC1 is allelically pleiotropic, with other variants causing dilated cardiomyopathy, left ventricular noncompaction, and atrial septal defect.

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1
Inheritance
4
Pathophys.
4
Phenotypes
5
Pathograph
1
Genes
2
Medical Actions
1
References
🏷

Classifications

Harrison's Part
CARDIOVASCULAR GENETICS ENVIRONMENT DISEASE
👪

Inheritance

1
Autosomal dominant HP:0000006
CMH11 is inherited as an autosomal dominant trait; a single ACTC1 missense allele produces disease, with the incomplete, age-related penetrance and familial clustering characteristic of sarcomeric HCM.
Autosomal dominant inheritance Penetrance: INCOMPLETE
Show evidence (1 reference)
CGGV:assertion_2f62793b-0015-46eb-bb51-bddbae25ba0d-2021-06-23T201616.296Z SUPPORT Other
"ACTC1 | HGNC:143 | hypertrophic cardiomyopathy | MONDO:0005045 | AD | Definitive"
ClinGen's Hypertrophic Cardiomyopathy Gene Curation Expert Panel classifies the ACTC1-HCM relationship as Definitive with autosomal dominant inheritance.
⚙

Pathophysiology

4
ACTC1 Missense Variant in Alpha-Cardiac Actin
The initiating lesion in CMH11 is a heterozygous missense variant in ACTC1, the gene encoding alpha-cardiac actin — the thin-filament protein that forms the track for myosin cross-bridge cycling and anchors the tropomyosin-troponin regulatory apparatus. The mutant actin is expressed and incorporated into the cardiomyocyte thin filament alongside wild-type actin, so disease arises from a functionally abnormal filament rather than from loss of protein.
Cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
ACTC1 hgnc:143 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves ACTC1 (hgnc:143). hgnc:143 is a gene from the HUGO Gene Nomenclature Committee.
Sarcomere Organization GO:0045214 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Sarcomere Organization (GO:0045214). GO:0045214 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Actin thin filament GO:0005884 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves Actin thin filament, annotated with actin filament (GO:0005884). GO:0005884 is a cellular component from the Gene Ontology.
Downstream
Impaired Actin-Myosin Interaction and Thin-Filament Regulation The abnormal actin filament disturbs cross-bridge cycling and the calcium-dependent regulation of contraction.
Show evidence (2 references)
PMID:22643837 SUPPORT In Vitro
"a mutant actin can be integrated into cardiomyocyte thin filaments and by its reduced mode of myosin interaction might be the basis for the initiation of HCM"
Demonstrates that mutant alpha-cardiac actin is incorporated into thin filaments and initiates HCM through a disturbed actin-myosin interaction.
PMID:36158814 SUPPORT Other
"account for as many as 30% of all cases of inherited cardiomyopathy"
Establishes ACTC1 as one of the thin-filament sarcomere genes whose variants cause inherited cardiomyopathy. Evidence source is OTHER because this is a review.
Impaired Actin-Myosin Interaction and Thin-Filament Regulation
Incorporated mutant actin perturbs the mechanochemistry of the sarcomere. Functional studies of HCM ACTC1 mutants show reduced stimulation of the cardiac beta-myosin ATPase, altered actin polymerization behaviour in the presence of tropomyosin and other partners, and, in cardiomyocytes, shortening of sarcomere length — signatures of a filament that transmits and regulates force abnormally. As a thin-filament lesion, the net effect is dysregulation of calcium-dependent contraction rather than the myosin super-relaxed-state defect seen with thick-filament genes.
Cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
Actin-Myosin Filament Sliding GO:0033275 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Actin-Myosin Filament Sliding (GO:0033275). GO:0033275 is a biological process from the Gene Ontology. ⚠ ABNORMAL Regulation of Cardiac Muscle Contraction by Calcium GO:0010882 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Regulation of Cardiac Muscle Contraction by Calcium, annotated with regulation of cardiac muscle contraction by calcium ion signaling (GO:0010882). GO:0010882 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Ventricular Hypertrophy, Myocyte Disarray and Fibrosis Chronic sarcomeric dysfunction drives the maladaptive structural remodeling of the ventricle.
Show evidence (2 references)
PMID:22643837 SUPPORT In Vitro
"Both mutants stimulated the cardiac β-myosin ATPase to only 50 % of WT cardiac F-actin."
Quantifies the impaired actin-myosin interaction: HCM ACTC1 mutants stimulate the cardiac beta-myosin ATPase to only half the wild-type level.
PMID:22643837 SUPPORT In Vitro
"the Y166C mutant led after 72 h to a shortening of the sarcomere length when compared to NRCs infected with WT actin."
Shows a cellular structural consequence of the mutant actin — sarcomere shortening in neonatal rat cardiomyocytes.
Ventricular Hypertrophy, Myocyte Disarray and Fibrosis
Sustained sarcomeric dysfunction produces the structural remodeling that defines HCM: cardiomyocyte hypertrophy, myofiber disarray, and interstitial fibrosis. In thin-filament disease, of which ACTC1 is a member, the hypertrophy tends to be milder and more atypically distributed than in thick-filament HCM, but the disarray-and-fibrosis substrate is shared.
Cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology. Cardiac Fibroblast CL:0002548 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Cardiac Fibroblast, annotated with fibroblast of cardiac tissue (CL:0002548). CL:0002548 is a cell type from the Cell Ontology.
Cardiac Muscle Hypertrophy in Response to Stress GO:0014898 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Cardiac Muscle Hypertrophy in Response to Stress (GO:0014898). GO:0014898 is a biological process from the Gene Ontology. ↑ INCREASED Extracellular Matrix Organization GO:0030198 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Extracellular Matrix Organization (GO:0030198). GO:0030198 is a biological process from the Gene Ontology. ↑ INCREASED
Interventricular septum UBERON:0002094 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in Interventricular septum (UBERON:0002094). UBERON:0002094 is an anatomical location from the Uberon multi-species anatomy ontology. Left ventricle UBERON:0002084 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in Left ventricle, annotated with heart left ventricle (UBERON:0002084). UBERON:0002084 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Diastolic Dysfunction, Heart Failure and Arrhythmic Risk
Show evidence (2 references)
PMID:28912181 SUPPORT Human Clinical
"The histological features of HCM include myocyte hypertrophy and disarray, as well as interstitial fibrosis."
Names the defining tissue-level triad — hypertrophy, disarray, and interstitial fibrosis — that this node represents.
PMID:25524337 SUPPORT Human Clinical
"milder and atypically distributed left ventricular (LV) hypertrophy (maximal wall thickness 18 ± 5 mm vs. 24 ± 6 mm; p < 0.001)"
Documents the milder, atypically distributed hypertrophy characteristic of thin-filament HCM (which includes ACTC1) relative to thick-filament disease.
Diastolic Dysfunction, Heart Failure and Arrhythmic Risk
The remodelled, fibrotic ventricle produces the clinical endpoints of CMH11. Thin-filament HCM is associated with a greater burden of diastolic dysfunction and a higher rate of progression to advanced heart failure than thick-filament disease, while the risk of malignant ventricular arrhythmia and sudden cardiac death is comparable between the two.
Cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
Heart Contraction GO:0060047 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Heart Contraction (GO:0060047). GO:0060047 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Show evidence (2 references)
PMID:25524337 SUPPORT Human Clinical
"higher rate of progression to New York Heart Association functional class III or IV (15% vs. 5%; p = 0.013)"
Quantifies the greater progression to advanced heart failure symptoms in thin-filament HCM (including ACTC1) versus thick-filament disease.
PMID:25524337 SUPPORT Human Clinical
"similar rates of malignant ventricular arrhythmias and sudden cardiac death (p = 0.593)"
Establishes that arrhythmic and sudden-death risk in thin-filament HCM is comparable to thick-filament disease, an important honesty caveat against assuming ACTC1 is lower-risk.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Hypertrophic Cardiomyopathy 11 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

4
Hypertrophic Cardiomyopathy OBLIGATE Cardiovascular HP:0001639 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypertrophic cardiomyopathy (HP:0001639). HP:0001639 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28912181 SUPPORT Human Clinical
"Hypertrophic cardiomyopathy (HCM) is a genetic disorder that is characterized by left ventricular hypertrophy unexplained by secondary causes and a nondilated left ventricle with preserved or increased ejection fraction."
States the defining clinical feature of the disease this ACTC1 form manifests.
Left Ventricular Diastolic Dysfunction Cardiovascular HP:0025168 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Left ventricular diastolic dysfunction (HP:0025168). HP:0025168 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25524337 SUPPORT Human Clinical
"higher prevalence of systolic dysfunction or restrictive LV filling at last evaluation (20% vs. 9%; p = 0.038)"
Documents the greater burden of restrictive filling and systolic dysfunction in thin-filament HCM.
Congestive Heart Failure Cardiovascular HP:0001635 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Congestive heart failure (HP:0001635). HP:0001635 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25524337 SUPPORT Human Clinical
"higher rate of progression to New York Heart Association functional class III or IV (15% vs. 5%; p = 0.013)"
Quantifies progression to advanced heart failure symptoms in thin-filament HCM.
Sudden Cardiac Death Cardiovascular HP:0001645 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sudden cardiac death (HP:0001645). HP:0001645 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25524337 SUPPORT Human Clinical
"similar rates of malignant ventricular arrhythmias and sudden cardiac death (p = 0.593)"
Establishes comparable sudden-death risk in thin-filament HCM, supporting this phenotype for the ACTC1 form.
🧬

Genetic Associations

1
ACTC1
Gene: ACTC1 hgnc:143 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is ACTC1 (hgnc:143). hgnc:143 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
CGGV:assertion_2f62793b-0015-46eb-bb51-bddbae25ba0d-2021-06-23T201616.296Z SUPPORT Other
"ACTC1 | HGNC:143 | hypertrophic cardiomyopathy | MONDO:0005045 | AD | Definitive"
ClinGen's Gene Curation Expert Panel classifies this gene-disease relationship as Definitive, which is the authority for curating the gene as CAUSATIVE rather than a candidate.
PMID:36158814 SUPPORT Other
"account for as many as 30% of all cases of inherited cardiomyopathy"
The 30% figure is measured over thin-filament genes as a class (ACTC1, TNNC1, TNNI3, TNNT2, TPM1) and over inherited cardiomyopathy generally, not over ACTC1 in hypertrophic cardiomyopathy. Curated PARTIAL for that reason, and no case_fractions record is recorded because neither the numerator nor the denominator matches this entry.
💊

Medical Actions

2
Implantable Cardioverter-Defibrillator
Action: implantable cardioverter-defibrillator placementNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is implantable cardioverter-defibrillator placement (NCIT:C80435). NCIT:C80435 is a clinical intervention from the NCI Thesaurus. Ontology label: Implantable Cardioverter-Defibrillator Placement NCIT:C80435
An implantable cardioverter-defibrillator provides primary or secondary prevention of sudden cardiac death in patients at high arrhythmic risk.
Heart Failure Pharmacotherapy and Supportive Care
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Management of diastolic dysfunction and heart failure symptoms, which are a disproportionate burden in thin-filament HCM, follows standard heart-failure and HCM medical therapy.
📊

Prevalence

1
Worldwide (ACTC1 share of HCM)
Unknown Not yet documented
ACTC1 is a definitive but numerically minor HCM gene; thin-filament genes as a class (ACTC1, TNNC1, TNNI3, TNNT2, TPM1) together account for up to about 30% of inherited cardiomyopathy, of which ACTC1 is a small share.
Show evidence (1 reference)
PMID:36158814 SUPPORT Other
"account for as many as 30% of all cases of inherited cardiomyopathy"
Gives the collective share of thin-filament sarcomere genes (including ACTC1) among inherited cardiomyopathies. Evidence source is OTHER because this is a review.
{ }

Source YAML

click to show 
name: Hypertrophic Cardiomyopathy 11
creation_date: "2026-08-22T00:00:00Z"
synonyms:
- CMH11
- ACTC1 hypertrophic cardiomyopathy
- alpha-cardiac actin hypertrophic cardiomyopathy
- cardiomyopathy, familial hypertrophic, 11
- hypertrophic cardiomyopathy caused by mutation in ACTC1
description: >-
  Hypertrophic cardiomyopathy 11 (CMH11) is the ACTC1-related form of familial
  hypertrophic cardiomyopathy. ACTC1 encodes alpha-cardiac actin, the thin-filament
  track along which the myosin motor generates force; it is one of the eight genes
  with definitive ClinGen gene-disease validity for HCM, though it accounts for a
  small fraction of cases. Pathogenic ACTC1 alleles are missense variants that are
  incorporated into the cardiomyocyte thin filament, where they perturb the
  actin-myosin interaction and the calcium-dependent regulation of contraction
  rather than acting through loss of protein. As a thin-filament HCM gene, ACTC1
  disease tends toward the thin-filament clinical profile — milder and atypically
  distributed left ventricular hypertrophy with a greater burden of diastolic
  dysfunction and progression to heart failure — while sharing the sarcomeric
  disarray, fibrosis, and arrhythmic risk of HCM generally. Inheritance is autosomal
  dominant; ACTC1 is allelically pleiotropic, with other variants causing dilated
  cardiomyopathy, left ventricular noncompaction, and atrial septal defect.
category: Genetic
classifications:
  harrisons_chapter:
  - classification_value: CARDIOVASCULAR
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
disease_term:
  preferred_term: hypertrophic cardiomyopathy 11
  term:
    id: MONDO:0012799
    label: hypertrophic cardiomyopathy 11
parents:
- Hypertrophic Cardiomyopathy
- Genetic Disorder
inheritance:
- name: Autosomal dominant
  description: >-
    CMH11 is inherited as an autosomal dominant trait; a single ACTC1 missense
    allele produces disease, with the incomplete, age-related penetrance and
    familial clustering characteristic of sarcomeric HCM.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  penetrance: INCOMPLETE
  evidence:
  - reference: CGGV:assertion_2f62793b-0015-46eb-bb51-bddbae25ba0d-2021-06-23T201616.296Z
    reference_title: "ACTC1 / hypertrophic cardiomyopathy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ACTC1 | HGNC:143 | hypertrophic cardiomyopathy | MONDO:0005045 | AD | Definitive"
    explanation: >-
      ClinGen's Hypertrophic Cardiomyopathy Gene Curation Expert Panel classifies
      the ACTC1-HCM relationship as Definitive with autosomal dominant inheritance.
prevalence:
- population: Worldwide (ACTC1 share of HCM)
  measure_type: UNKNOWN
  prevalence_class: NOT_YET_DOCUMENTED
  notes: >-
    ACTC1 is a definitive but numerically minor HCM gene; thin-filament genes as a
    class (ACTC1, TNNC1, TNNI3, TNNT2, TPM1) together account for up to about 30%
    of inherited cardiomyopathy, of which ACTC1 is a small share.
  evidence:
  - reference: PMID:36158814
    reference_title: "Thin filament cardiomyopathies: A review of genetics, disease mechanisms, and emerging therapeutics."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "account for as many as 30% of all cases of inherited cardiomyopathy"
    explanation: >-
      Gives the collective share of thin-filament sarcomere genes (including
      ACTC1) among inherited cardiomyopathies. Evidence source is OTHER because
      this is a review.
pathophysiology:
- name: ACTC1 Missense Variant in Alpha-Cardiac Actin
  biological_scale: MOLECULAR
  role: trigger
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Primary Cardiomyocyte Insult"
  description: >-
    The initiating lesion in CMH11 is a heterozygous missense variant in ACTC1,
    the gene encoding alpha-cardiac actin — the thin-filament protein that forms
    the track for myosin cross-bridge cycling and anchors the tropomyosin-troponin
    regulatory apparatus. The mutant actin is expressed and incorporated into the
    cardiomyocyte thin filament alongside wild-type actin, so disease arises from a
    functionally abnormal filament rather than from loss of protein.
  genes:
  - preferred_term: ACTC1
    term:
      id: hgnc:143
      label: ACTC1
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: Sarcomere Organization
    term:
      id: GO:0045214
      label: sarcomere organization
    modifier: ABNORMAL
  cellular_components:
  - preferred_term: Actin thin filament
    term:
      id: GO:0005884
      label: actin filament
  evidence:
  - reference: PMID:22643837
    reference_title: "Functional characterization of the human α-cardiac actin mutations Y166C and M305L involved in hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      a mutant actin can be integrated into cardiomyocyte thin filaments and by
      its reduced mode of myosin interaction might be the basis for the initiation
      of HCM
    explanation: >-
      Demonstrates that mutant alpha-cardiac actin is incorporated into thin
      filaments and initiates HCM through a disturbed actin-myosin interaction.
  - reference: PMID:36158814
    reference_title: "Thin filament cardiomyopathies: A review of genetics, disease mechanisms, and emerging therapeutics."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "account for as many as 30% of all cases of inherited cardiomyopathy"
    explanation: >-
      Establishes ACTC1 as one of the thin-filament sarcomere genes whose variants
      cause inherited cardiomyopathy. Evidence source is OTHER because this is a
      review.
  downstream:
  - target: Impaired Actin-Myosin Interaction and Thin-Filament Regulation
    causal_link_type: DIRECT
    description: >-
      The abnormal actin filament disturbs cross-bridge cycling and the
      calcium-dependent regulation of contraction.
- name: Impaired Actin-Myosin Interaction and Thin-Filament Regulation
  biological_scale: MOLECULAR
  role: effector
  description: >-
    Incorporated mutant actin perturbs the mechanochemistry of the sarcomere.
    Functional studies of HCM ACTC1 mutants show reduced stimulation of the
    cardiac beta-myosin ATPase, altered actin polymerization behaviour in the
    presence of tropomyosin and other partners, and, in cardiomyocytes, shortening
    of sarcomere length — signatures of a filament that transmits and regulates
    force abnormally. As a thin-filament lesion, the net effect is dysregulation
    of calcium-dependent contraction rather than the myosin super-relaxed-state
    defect seen with thick-filament genes.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: Actin-Myosin Filament Sliding
    term:
      id: GO:0033275
      label: actin-myosin filament sliding
    modifier: ABNORMAL
  - preferred_term: Regulation of Cardiac Muscle Contraction by Calcium
    term:
      id: GO:0010882
      label: regulation of cardiac muscle contraction by calcium ion signaling
    modifier: ABNORMAL
  evidence:
  - reference: PMID:22643837
    reference_title: "Functional characterization of the human α-cardiac actin mutations Y166C and M305L involved in hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Both mutants stimulated the cardiac β-myosin ATPase to only 50 % of WT cardiac F-actin."
    explanation: >-
      Quantifies the impaired actin-myosin interaction: HCM ACTC1 mutants stimulate
      the cardiac beta-myosin ATPase to only half the wild-type level.
  - reference: PMID:22643837
    reference_title: "Functional characterization of the human α-cardiac actin mutations Y166C and M305L involved in hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "the Y166C mutant led after 72 h to a shortening of the sarcomere length when compared to NRCs infected with WT actin."
    explanation: >-
      Shows a cellular structural consequence of the mutant actin — sarcomere
      shortening in neonatal rat cardiomyocytes.
  downstream:
  - target: Ventricular Hypertrophy, Myocyte Disarray and Fibrosis
    causal_link_type: DIRECT
    description: >-
      Chronic sarcomeric dysfunction drives the maladaptive structural remodeling
      of the ventricle.
- name: Ventricular Hypertrophy, Myocyte Disarray and Fibrosis
  biological_scale: TISSUE
  role: central_effector
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Ventricular Remodeling"
  description: >-
    Sustained sarcomeric dysfunction produces the structural remodeling that
    defines HCM: cardiomyocyte hypertrophy, myofiber disarray, and interstitial
    fibrosis. In thin-filament disease, of which ACTC1 is a member, the hypertrophy
    tends to be milder and more atypically distributed than in thick-filament HCM,
    but the disarray-and-fibrosis substrate is shared.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  - preferred_term: Cardiac Fibroblast
    term:
      id: CL:0002548
      label: fibroblast of cardiac tissue
  biological_processes:
  - preferred_term: Cardiac Muscle Hypertrophy in Response to Stress
    term:
      id: GO:0014898
      label: cardiac muscle hypertrophy in response to stress
    modifier: INCREASED
  - preferred_term: Extracellular Matrix Organization
    term:
      id: GO:0030198
      label: extracellular matrix organization
    modifier: INCREASED
  locations:
  - preferred_term: Interventricular septum
    term:
      id: UBERON:0002094
      label: interventricular septum
  - preferred_term: Left ventricle
    term:
      id: UBERON:0002084
      label: heart left ventricle
  evidence:
  - reference: PMID:28912181
    reference_title: "Hypertrophic Cardiomyopathy: Genetics, Pathogenesis, Clinical Manifestations, Diagnosis, and Therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The histological features of HCM include myocyte hypertrophy and disarray, as well as interstitial fibrosis."
    explanation: >-
      Names the defining tissue-level triad — hypertrophy, disarray, and
      interstitial fibrosis — that this node represents.
  - reference: PMID:25524337
    reference_title: "Clinical phenotype and outcome of hypertrophic cardiomyopathy associated with thin-filament gene mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      milder and atypically distributed left ventricular (LV) hypertrophy (maximal
      wall thickness 18 ± 5 mm vs. 24 ± 6 mm; p < 0.001)
    explanation: >-
      Documents the milder, atypically distributed hypertrophy characteristic of
      thin-filament HCM (which includes ACTC1) relative to thick-filament disease.
  downstream:
  - target: Diastolic Dysfunction, Heart Failure and Arrhythmic Risk
    causal_link_type: DIRECT
- name: Diastolic Dysfunction, Heart Failure and Arrhythmic Risk
  biological_scale: ORGANISM
  role: consequence
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Structural Cardiac Impairment and Heart Failure"
  description: >-
    The remodelled, fibrotic ventricle produces the clinical endpoints of CMH11.
    Thin-filament HCM is associated with a greater burden of diastolic dysfunction
    and a higher rate of progression to advanced heart failure than thick-filament
    disease, while the risk of malignant ventricular arrhythmia and sudden cardiac
    death is comparable between the two.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: Heart Contraction
    term:
      id: GO:0060047
      label: heart contraction
    modifier: ABNORMAL
  evidence:
  - reference: PMID:25524337
    reference_title: "Clinical phenotype and outcome of hypertrophic cardiomyopathy associated with thin-filament gene mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      higher rate of progression to New York Heart Association functional class III
      or IV (15% vs. 5%; p = 0.013)
    explanation: >-
      Quantifies the greater progression to advanced heart failure symptoms in
      thin-filament HCM (including ACTC1) versus thick-filament disease.
  - reference: PMID:25524337
    reference_title: "Clinical phenotype and outcome of hypertrophic cardiomyopathy associated with thin-filament gene mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "similar rates of malignant ventricular arrhythmias and sudden cardiac death (p = 0.593)"
    explanation: >-
      Establishes that arrhythmic and sudden-death risk in thin-filament HCM is
      comparable to thick-filament disease, an important honesty caveat against
      assuming ACTC1 is lower-risk.
phenotypes:
- name: Hypertrophic Cardiomyopathy
  category: Cardiovascular
  description: >-
    Unexplained left ventricular hypertrophy is the defining feature; in ACTC1
    disease it is often milder and atypically distributed.
  phenotype_term:
    preferred_term: Hypertrophic cardiomyopathy
    term:
      id: HP:0001639
      label: Hypertrophic cardiomyopathy
  frequency: OBLIGATE
  evidence:
  - reference: PMID:28912181
    reference_title: "Hypertrophic Cardiomyopathy: Genetics, Pathogenesis, Clinical Manifestations, Diagnosis, and Therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hypertrophic cardiomyopathy (HCM) is a genetic disorder that is characterized by left ventricular hypertrophy unexplained by secondary causes and a nondilated left ventricle with preserved or increased ejection fraction."
    explanation: >-
      States the defining clinical feature of the disease this ACTC1 form manifests.
- name: Left Ventricular Diastolic Dysfunction
  category: Cardiovascular
  description: >-
    Impaired ventricular relaxation and filling is a prominent feature of
    thin-filament HCM, with a characteristically high burden of restrictive
    filling patterns.
  phenotype_term:
    preferred_term: Left ventricular diastolic dysfunction
    term:
      id: HP:0025168
      label: Left ventricular diastolic dysfunction
  evidence:
  - reference: PMID:25524337
    reference_title: "Clinical phenotype and outcome of hypertrophic cardiomyopathy associated with thin-filament gene mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      higher prevalence of systolic dysfunction or restrictive LV filling at last
      evaluation (20% vs. 9%; p = 0.038)
    explanation: >-
      Documents the greater burden of restrictive filling and systolic dysfunction
      in thin-filament HCM.
- name: Congestive Heart Failure
  category: Cardiovascular
  description: >-
    Progression to advanced heart failure is more common in thin-filament HCM than
    in thick-filament disease.
  phenotype_term:
    preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  evidence:
  - reference: PMID:25524337
    reference_title: "Clinical phenotype and outcome of hypertrophic cardiomyopathy associated with thin-filament gene mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      higher rate of progression to New York Heart Association functional class III
      or IV (15% vs. 5%; p = 0.013)
    explanation: >-
      Quantifies progression to advanced heart failure symptoms in thin-filament
      HCM.
- name: Sudden Cardiac Death
  category: Cardiovascular
  description: >-
    Malignant ventricular arrhythmia on the fibrotic substrate carries a risk of
    sudden cardiac death comparable to thick-filament HCM.
  phenotype_term:
    preferred_term: Sudden cardiac death
    term:
      id: HP:0001645
      label: Sudden cardiac death
  evidence:
  - reference: PMID:25524337
    reference_title: "Clinical phenotype and outcome of hypertrophic cardiomyopathy associated with thin-filament gene mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "similar rates of malignant ventricular arrhythmias and sudden cardiac death (p = 0.593)"
    explanation: >-
      Establishes comparable sudden-death risk in thin-filament HCM, supporting
      this phenotype for the ACTC1 form.
genetic:
- name: ACTC1
  gene_term:
    preferred_term: ACTC1
    term:
      id: hgnc:143
      label: ACTC1
  relationship_type: CAUSATIVE
  frequency: >-
    Definitive but numerically minor cause of hypertrophic cardiomyopathy.
    Thin-filament genes as a class account for up to about 30% of inherited
    cardiomyopathy; ACTC1 is a small share of that class and no ACTC1-specific
    fraction has been reported.
  evidence:
  - reference: CGGV:assertion_2f62793b-0015-46eb-bb51-bddbae25ba0d-2021-06-23T201616.296Z
    reference_title: "ACTC1 / hypertrophic cardiomyopathy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      ACTC1 | HGNC:143 | hypertrophic cardiomyopathy | MONDO:0005045 | AD |
      Definitive
    explanation: >-
      ClinGen's Gene Curation Expert Panel classifies this gene-disease
      relationship as Definitive, which is the authority for curating the gene
      as CAUSATIVE rather than a candidate.
  - reference: PMID:36158814
    reference_title: "Thin filament cardiomyopathies: A review of genetics, disease mechanisms, and emerging therapeutics."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      account for as many as 30% of all cases of inherited cardiomyopathy
    explanation: >-
      The 30% figure is measured over thin-filament genes as a class (ACTC1,
      TNNC1, TNNI3, TNNT2, TPM1) and over inherited cardiomyopathy generally,
      not over ACTC1 in hypertrophic cardiomyopathy. Curated PARTIAL for that
      reason, and no case_fractions record is recorded because neither the
      numerator nor the denominator matches this entry.
treatments:
- name: Implantable Cardioverter-Defibrillator
  description: >-
    An implantable cardioverter-defibrillator provides primary or secondary
    prevention of sudden cardiac death in patients at high arrhythmic risk.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: implantable cardioverter-defibrillator placement
    term:
      id: NCIT:C80435
      label: Implantable Cardioverter-Defibrillator Placement
- name: Heart Failure Pharmacotherapy and Supportive Care
  description: >-
    Management of diastolic dysfunction and heart failure symptoms, which are a
    disproportionate burden in thin-filament HCM, follows standard heart-failure
    and HCM medical therapy.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
references:
- reference: PMID:20301725
  title: Nonsyndromic Hypertrophic Cardiomyopathy Overview.
  tags:
  - GeneReviews
notes: >-
  CMH11 is the ACTC1 (alpha-cardiac actin) member of the sarcomeric HCM series and
  one of the eight ClinGen-definitive HCM genes, added to complete the
  definitive-gene set. It is curated as a thin-filament HCM (with TNNC1/CMH13,
  TNNT2/CMH2, TNNI3/CMH7, TPM1/CMH3), sharing the milder-hypertrophy,
  greater-diastolic-dysfunction, comparable-arrhythmic-risk profile documented for
  the thin-filament class, and conforms to the shared
  cardiomyopathy_maladaptive_remodeling module. ACTC1 is allelically pleiotropic —
  other variants cause dilated cardiomyopathy (ClinGen Moderate), left ventricular
  noncompaction, and atrial septal defect — so this entry is scoped to the
  hypertrophic phenotype.

  GeneReviews scope. The GeneReviews resource applicable to this entry is the
  disease-level "Nonsyndromic Hypertrophic Cardiomyopathy Overview"
  (PMID:20301725), tagged accordingly in `references`. Its indexed PubMed record
  is content_type abstract_only and carries only the chapter's purpose
  statement, not the Clinical Characteristics, Management, or Genetic Counseling
  sections, so section-by-section GeneReviews mining is not possible from the
  cache and no snippet is quoted from it. The clinical-characteristics baseline
  for this entry is therefore built from the primary ACTC1 cohort and pedigree
  literature cited throughout, principally PMID:28912181, PMID:25524337.
📚

References & Deep Research

References

1
PMID:20301725
Nonsyndromic Hypertrophic Cardiomyopathy Overview.
No top-level findings curated for this source.