Hypertrophic Cardiomyopathy 13

Genetic MONDO:0013195 Pathograph 6 Show in embeddings browser Hypertrophic Cardiomyopathy Genetic Disorder

Hypertrophic cardiomyopathy 13 (CMH13) is the TNNC1-related form of familial hypertrophic cardiomyopathy. TNNC1 encodes cardiac troponin C (cTnC), the calcium-sensing subunit of the thin-filament troponin complex: calcium binding to its regulatory N-domain is the switch that turns cardiac contraction on. TNNC1 is a rare but ClinGen-definitive HCM gene, and it is the most direct calcium-sensitization lesion in the sarcomere — pathogenic missense variants increase the myofilament calcium sensitivity of contraction, which reconfigures excitation-contraction coupling and predisposes to a hypertrophic, and in some probands strongly arrhythmogenic, phenotype. The founding TNNC1 HCM allele (L29Q) and later variants such as A31S illustrate the spectrum, the latter presenting in childhood with ventricular fibrillation and aborted sudden death. Inheritance is autosomal dominant; other TNNC1 variants cause dilated cardiomyopathy.

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1
Inheritance
5
Pathophys.
3
Phenotypes
6
Pathograph
1
Genes
2
Medical Actions
1
References
🏷

Classifications

Harrison's Part
CARDIOVASCULAR GENETICS ENVIRONMENT DISEASE
👪

Inheritance

1
Autosomal dominant HP:0000006
CMH13 is inherited as an autosomal dominant trait; a single TNNC1 missense allele produces disease, with the incomplete penetrance and familial clustering characteristic of sarcomeric HCM. De novo variants also occur.
Autosomal dominant inheritance Penetrance: INCOMPLETE
Show evidence (1 reference)
CGGV:assertion_5d832673-8acb-4a02-ae34-35e0d9981b70-2023-09-13T160000.000Z SUPPORT Other
"TNNC1 | HGNC:11943 | hypertrophic cardiomyopathy | MONDO:0005045 | AD | Definitive"
ClinGen's Hereditary Cardiovascular Disease Gene Curation Expert Panel classifies the TNNC1-HCM relationship as Definitive with autosomal dominant inheritance.
⚙

Pathophysiology

5
TNNC1 Missense Variant in Cardiac Troponin C
The initiating lesion in CMH13 is a heterozygous missense variant in TNNC1, the gene encoding cardiac troponin C (cTnC) — the calcium-sensing subunit of the thin-filament troponin complex whose regulatory N-domain binds calcium to initiate contraction. The founding HCM allele was L29Q, detected in a patient with hypertrophic cardiomyopathy; the mutant cTnC is incorporated into the troponin complex and alters the calcium switch rather than being lost.
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.
TNNC1 hgnc:11943 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves TNNC1 (hgnc:11943). hgnc:11943 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
Troponin complex GO:0005861 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves Troponin complex (GO:0005861). GO:0005861 is a cellular component from the Gene Ontology.
Downstream
Increased Myofilament Calcium Sensitivity The mutant troponin C shifts the calcium responsiveness of the thin-filament regulatory switch.
Show evidence (1 reference)
PMID:16302972 SUPPORT In Vitro
"the first mutation in TNNC1, coding for the calcium-binding subunit (cTnC) of cardiac troponin, which was detected in a patient with hypertrophic cardiomyopathy"
Identifies the founding TNNC1 HCM allele (L29Q) in the calcium-binding subunit of cardiac troponin.
Increased Myofilament Calcium Sensitivity
Cardiac troponin C sets the calcium sensitivity of contraction: calcium binding to its regulatory N-domain relieves troponin-I inhibition and allows cross-bridge cycling. HCM TNNC1 variants directly increase this calcium sensitivity — the A31S allele, for example, increases calcium sensitivity with no change in maximal force. A myofilament that activates at lower calcium reconfigures excitation-contraction coupling and calcium handling, the proximal functional lesion of the disease and the reason cTnC is a target for calcium-sensitivity-modulating drugs.
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.
Regulation of Cardiac Muscle Contraction by Calcium GO:0010882 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased 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. ↑ INCREASED
Downstream
Ventricular Hypertrophy, Myocyte Disarray and Fibrosis Chronic calcium-sensitized, dysregulated contraction drives maladaptive structural remodeling.
Arrhythmogenic Substrate Altered calcium handling from myofilament calcium sensitization contributes to an arrhythmogenic substrate in some TNNC1 probands.
Show evidence (2 references)
PMID:22815480 SUPPORT In Vitro
"increased Ca(2+) sensitivity with no effect on the maximal contractile force generation"
Quantifies the defining functional consequence of an HCM TNNC1 variant — increased myofilament calcium sensitivity without a change in maximal force.
PMID:26232335 SUPPORT Other
"directly impacts the calcium sensitivity of muscle contraction"
Establishes that regulation of cTnC calcium affinity directly sets the calcium sensitivity of contraction, the axis these variants perturb. Evidence source is OTHER because this is a structure-function review.
Ventricular Hypertrophy, Myocyte Disarray and Fibrosis
Sustained calcium-sensitized, dysregulated contraction produces the structural remodeling that defines HCM — cardiomyocyte hypertrophy, myofiber disarray, and interstitial fibrosis. As a thin-filament HCM, TNNC1 disease shares this substrate while tending toward the thin-filament pattern of milder hypertrophy and prominent diastolic dysfunction.
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 (1 reference)
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 that this node represents.
Arrhythmogenic Substrate
Increased myofilament calcium sensitivity alters intracellular calcium handling and, together with the fibrotic tissue substrate, creates a propensity to malignant ventricular arrhythmia. Some TNNC1 probands present with a strongly arrhythmogenic subtype, including childhood ventricular fibrillation and aborted sudden cardiac death, out of proportion to the degree of hypertrophy.
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.
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
Diastolic Dysfunction, Heart Failure and Arrhythmic Risk The arrhythmogenic substrate contributes to the malignant-arrhythmia and sudden-death endpoint.
Show evidence (1 reference)
PMID:22815480 SUPPORT Human Clinical
"identified in a pediatric HCM proband with multiple episodes of ventricular fibrillation and aborted sudden cardiac death"
Documents the arrhythmogenic presentation of a TNNC1 HCM proband — recurrent ventricular fibrillation and aborted sudden death.
Diastolic Dysfunction, Heart Failure and Arrhythmic Risk
The remodelled, fibrotic ventricle and the calcium-sensitized, arrhythmia-prone myocardium produce the clinical endpoints of CMH13: diastolic dysfunction and heart failure, and a risk of malignant ventricular arrhythmia and sudden death that in some TNNC1 probands defines a fatal arrhythmogenic subtype.
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 (1 reference)
PMID:22815480 SUPPORT Human Clinical
"associated with HCM pathogenesis and may predispose to the pathogenesis of a fatal arrhythmogenic subtype of HCM"
Names the fatal arrhythmogenic subtype that constitutes the severe endpoint of TNNC1 HCM.
⬡

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 13 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

3
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 TNNC1 form manifests.
Ventricular Fibrillation Cardiovascular HP:0001663 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ventricular fibrillation (HP:0001663). HP:0001663 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:22815480 SUPPORT Human Clinical
"identified in a pediatric HCM proband with multiple episodes of ventricular fibrillation and aborted sudden cardiac death"
Documents recurrent ventricular fibrillation in a TNNC1 HCM proband.
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:22815480 SUPPORT Human Clinical
"identified in a pediatric HCM proband with multiple episodes of ventricular fibrillation and aborted sudden cardiac death"
Documents aborted sudden cardiac death in a TNNC1 HCM proband.
🧬

Genetic Associations

1
TNNC1
Gene: TNNC1 hgnc:11943 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is TNNC1 (hgnc:11943). hgnc:11943 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
CGGV:assertion_5d832673-8acb-4a02-ae34-35e0d9981b70-2023-09-13T160000.000Z SUPPORT Other
"TNNC1 | HGNC:11943 | 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:22815480 SUPPORT Human Clinical
"Mutations in TNNC1-encoded cardiac troponin C (cTnC) are a relatively rare cause of HCM."
Supports the qualitative frequency band. It carries no denominator, which is why the band is recorded in frequency rather than as a case_fractions record.
💊

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, particularly relevant given the strongly arrhythmogenic subtype of TNNC1 HCM.
HCM 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
Medical management of hypertrophy and heart failure symptoms follows standard HCM therapy.
📊

Prevalence

1
Worldwide (TNNC1 share of HCM)
Unknown Not yet documented
TNNC1 is a definitive but rare cause of HCM; no population-based rate for the TNNC1-specific entity is documented.
Show evidence (1 reference)
PMID:22815480 SUPPORT Human Clinical
"Mutations in TNNC1-encoded cardiac troponin C (cTnC) are a relatively rare cause of HCM."
Establishes TNNC1 as a relatively rare cause of hypertrophic cardiomyopathy.
{ }

Source YAML

click to show 
name: Hypertrophic Cardiomyopathy 13
creation_date: "2026-08-22T00:00:00Z"
synonyms:
- CMH13
- TNNC1 hypertrophic cardiomyopathy
- cardiac troponin C hypertrophic cardiomyopathy
- cardiomyopathy, familial hypertrophic, 13
- hypertrophic cardiomyopathy caused by mutation in TNNC1
description: >-
  Hypertrophic cardiomyopathy 13 (CMH13) is the TNNC1-related form of familial
  hypertrophic cardiomyopathy. TNNC1 encodes cardiac troponin C (cTnC), the
  calcium-sensing subunit of the thin-filament troponin complex: calcium binding
  to its regulatory N-domain is the switch that turns cardiac contraction on. TNNC1
  is a rare but ClinGen-definitive HCM gene, and it is the most direct
  calcium-sensitization lesion in the sarcomere — pathogenic missense variants
  increase the myofilament calcium sensitivity of contraction, which reconfigures
  excitation-contraction coupling and predisposes to a hypertrophic, and in some
  probands strongly arrhythmogenic, phenotype. The founding TNNC1 HCM allele (L29Q)
  and later variants such as A31S illustrate the spectrum, the latter presenting in
  childhood with ventricular fibrillation and aborted sudden death. Inheritance is
  autosomal dominant; other TNNC1 variants cause dilated cardiomyopathy.
category: Genetic
classifications:
  harrisons_chapter:
  - classification_value: CARDIOVASCULAR
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
disease_term:
  preferred_term: hypertrophic cardiomyopathy 13
  term:
    id: MONDO:0013195
    label: hypertrophic cardiomyopathy 13
parents:
- Hypertrophic Cardiomyopathy
- Genetic Disorder
inheritance:
- name: Autosomal dominant
  description: >-
    CMH13 is inherited as an autosomal dominant trait; a single TNNC1 missense
    allele produces disease, with the incomplete penetrance and familial clustering
    characteristic of sarcomeric HCM. De novo variants also occur.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  penetrance: INCOMPLETE
  evidence:
  - reference: CGGV:assertion_5d832673-8acb-4a02-ae34-35e0d9981b70-2023-09-13T160000.000Z
    reference_title: "TNNC1 / hypertrophic cardiomyopathy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "TNNC1 | HGNC:11943 | hypertrophic cardiomyopathy | MONDO:0005045 | AD | Definitive"
    explanation: >-
      ClinGen's Hereditary Cardiovascular Disease Gene Curation Expert Panel
      classifies the TNNC1-HCM relationship as Definitive with autosomal dominant
      inheritance.
prevalence:
- population: Worldwide (TNNC1 share of HCM)
  measure_type: UNKNOWN
  prevalence_class: NOT_YET_DOCUMENTED
  notes: >-
    TNNC1 is a definitive but rare cause of HCM; no population-based rate for the
    TNNC1-specific entity is documented.
  evidence:
  - reference: PMID:22815480
    reference_title: "A mutation in TNNC1-encoded cardiac troponin C, TNNC1-A31S, predisposes to hypertrophic cardiomyopathy and ventricular fibrillation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations in TNNC1-encoded cardiac troponin C (cTnC) are a relatively rare cause of HCM."
    explanation: >-
      Establishes TNNC1 as a relatively rare cause of hypertrophic cardiomyopathy.
pathophysiology:
- name: TNNC1 Missense Variant in Cardiac Troponin C
  biological_scale: MOLECULAR
  role: trigger
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Primary Cardiomyocyte Insult"
  description: >-
    The initiating lesion in CMH13 is a heterozygous missense variant in TNNC1,
    the gene encoding cardiac troponin C (cTnC) — the calcium-sensing subunit of
    the thin-filament troponin complex whose regulatory N-domain binds calcium to
    initiate contraction. The founding HCM allele was L29Q, detected in a patient
    with hypertrophic cardiomyopathy; the mutant cTnC is incorporated into the
    troponin complex and alters the calcium switch rather than being lost.
  genes:
  - preferred_term: TNNC1
    term:
      id: hgnc:11943
      label: TNNC1
  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: Troponin complex
    term:
      id: GO:0005861
      label: troponin complex
  evidence:
  - reference: PMID:16302972
    reference_title: "Cardiac troponin C-L29Q, related to hypertrophic cardiomyopathy, hinders the transduction of the protein kinase A dependent phosphorylation signal from cardiac troponin I to C."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      the first mutation in TNNC1, coding for the calcium-binding subunit (cTnC) of
      cardiac troponin, which was detected in a patient with hypertrophic
      cardiomyopathy
    explanation: >-
      Identifies the founding TNNC1 HCM allele (L29Q) in the calcium-binding
      subunit of cardiac troponin.
  downstream:
  - target: Increased Myofilament Calcium Sensitivity
    causal_link_type: DIRECT
    description: >-
      The mutant troponin C shifts the calcium responsiveness of the thin-filament
      regulatory switch.
- name: Increased Myofilament Calcium Sensitivity
  biological_scale: MOLECULAR
  role: effector
  description: >-
    Cardiac troponin C sets the calcium sensitivity of contraction: calcium binding
    to its regulatory N-domain relieves troponin-I inhibition and allows
    cross-bridge cycling. HCM TNNC1 variants directly increase this calcium
    sensitivity — the A31S allele, for example, increases calcium sensitivity with
    no change in maximal force. A myofilament that activates at lower calcium
    reconfigures excitation-contraction coupling and calcium handling, the proximal
    functional lesion of the disease and the reason cTnC is a target for
    calcium-sensitivity-modulating drugs.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: Regulation of Cardiac Muscle Contraction by Calcium
    term:
      id: GO:0010882
      label: regulation of cardiac muscle contraction by calcium ion signaling
    modifier: INCREASED
  evidence:
  - reference: PMID:22815480
    reference_title: "A mutation in TNNC1-encoded cardiac troponin C, TNNC1-A31S, predisposes to hypertrophic cardiomyopathy and ventricular fibrillation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "increased Ca(2+) sensitivity with no effect on the maximal contractile force generation"
    explanation: >-
      Quantifies the defining functional consequence of an HCM TNNC1 variant —
      increased myofilament calcium sensitivity without a change in maximal force.
  - reference: PMID:26232335
    reference_title: "Structure and function of cardiac troponin C (TNNC1): Implications for heart failure, cardiomyopathies, and troponin modulating drugs."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "directly impacts the calcium sensitivity of muscle contraction"
    explanation: >-
      Establishes that regulation of cTnC calcium affinity directly sets the
      calcium sensitivity of contraction, the axis these variants perturb. Evidence
      source is OTHER because this is a structure-function review.
  downstream:
  - target: Ventricular Hypertrophy, Myocyte Disarray and Fibrosis
    causal_link_type: DIRECT
    description: >-
      Chronic calcium-sensitized, dysregulated contraction drives maladaptive
      structural remodeling.
  - target: Arrhythmogenic Substrate
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Altered calcium handling from myofilament calcium sensitization contributes
      to an arrhythmogenic substrate in some TNNC1 probands.
- name: Ventricular Hypertrophy, Myocyte Disarray and Fibrosis
  biological_scale: TISSUE
  role: central_effector
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Ventricular Remodeling"
  description: >-
    Sustained calcium-sensitized, dysregulated contraction produces the structural
    remodeling that defines HCM — cardiomyocyte hypertrophy, myofiber disarray, and
    interstitial fibrosis. As a thin-filament HCM, TNNC1 disease shares this
    substrate while tending toward the thin-filament pattern of milder hypertrophy
    and prominent diastolic dysfunction.
  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 that this node represents.
  downstream:
  - target: Diastolic Dysfunction, Heart Failure and Arrhythmic Risk
    causal_link_type: DIRECT
- name: Arrhythmogenic Substrate
  biological_scale: CELLULAR
  role: amplifier
  description: >-
    Increased myofilament calcium sensitivity alters intracellular calcium
    handling and, together with the fibrotic tissue substrate, creates a
    propensity to malignant ventricular arrhythmia. Some TNNC1 probands present
    with a strongly arrhythmogenic subtype, including childhood ventricular
    fibrillation and aborted sudden cardiac death, out of proportion to the degree
    of hypertrophy.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - 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:22815480
    reference_title: "A mutation in TNNC1-encoded cardiac troponin C, TNNC1-A31S, predisposes to hypertrophic cardiomyopathy and ventricular fibrillation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "identified in a pediatric HCM proband with multiple episodes of ventricular fibrillation and aborted sudden cardiac death"
    explanation: >-
      Documents the arrhythmogenic presentation of a TNNC1 HCM proband —
      recurrent ventricular fibrillation and aborted sudden death.
  downstream:
  - target: Diastolic Dysfunction, Heart Failure and Arrhythmic Risk
    causal_link_type: DIRECT
    description: >-
      The arrhythmogenic substrate contributes to the malignant-arrhythmia and
      sudden-death endpoint.
- 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 and the calcium-sensitized, arrhythmia-prone
    myocardium produce the clinical endpoints of CMH13: diastolic dysfunction and
    heart failure, and a risk of malignant ventricular arrhythmia and sudden death
    that in some TNNC1 probands defines a fatal arrhythmogenic subtype.
  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:22815480
    reference_title: "A mutation in TNNC1-encoded cardiac troponin C, TNNC1-A31S, predisposes to hypertrophic cardiomyopathy and ventricular fibrillation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "associated with HCM pathogenesis and may predispose to the pathogenesis of a fatal arrhythmogenic subtype of HCM"
    explanation: >-
      Names the fatal arrhythmogenic subtype that constitutes the severe endpoint
      of TNNC1 HCM.
phenotypes:
- name: Hypertrophic Cardiomyopathy
  category: Cardiovascular
  description: >-
    Unexplained left ventricular hypertrophy is the defining feature of CMH13.
  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 TNNC1 form manifests.
- name: Ventricular Fibrillation
  category: Cardiovascular
  description: >-
    A fatal arrhythmogenic subtype of TNNC1 HCM presents with ventricular
    fibrillation, sometimes in childhood and out of proportion to hypertrophy.
  phenotype_term:
    preferred_term: Ventricular fibrillation
    term:
      id: HP:0001663
      label: Ventricular fibrillation
  evidence:
  - reference: PMID:22815480
    reference_title: "A mutation in TNNC1-encoded cardiac troponin C, TNNC1-A31S, predisposes to hypertrophic cardiomyopathy and ventricular fibrillation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "identified in a pediatric HCM proband with multiple episodes of ventricular fibrillation and aborted sudden cardiac death"
    explanation: >-
      Documents recurrent ventricular fibrillation in a TNNC1 HCM proband.
- name: Sudden Cardiac Death
  category: Cardiovascular
  description: >-
    Aborted and completed sudden cardiac death occur in the arrhythmogenic TNNC1
    subtype.
  phenotype_term:
    preferred_term: Sudden cardiac death
    term:
      id: HP:0001645
      label: Sudden cardiac death
  evidence:
  - reference: PMID:22815480
    reference_title: "A mutation in TNNC1-encoded cardiac troponin C, TNNC1-A31S, predisposes to hypertrophic cardiomyopathy and ventricular fibrillation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "identified in a pediatric HCM proband with multiple episodes of ventricular fibrillation and aborted sudden cardiac death"
    explanation: >-
      Documents aborted sudden cardiac death in a TNNC1 HCM proband.
genetic:
- name: TNNC1
  gene_term:
    preferred_term: TNNC1
    term:
      id: hgnc:11943
      label: TNNC1
  relationship_type: CAUSATIVE
  frequency: >-
    Rare cause of hypertrophic cardiomyopathy; described as relatively rare in
    the literature, with no case fraction reported in a screened cohort.
  evidence:
  - reference: CGGV:assertion_5d832673-8acb-4a02-ae34-35e0d9981b70-2023-09-13T160000.000Z
    reference_title: "TNNC1 / hypertrophic cardiomyopathy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      TNNC1 | HGNC:11943 | 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:22815480
    reference_title: "A mutation in TNNC1-encoded cardiac troponin C, TNNC1-A31S, predisposes to hypertrophic cardiomyopathy and ventricular fibrillation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutations in TNNC1-encoded cardiac troponin C (cTnC) are a relatively
      rare cause of HCM.
    explanation: >-
      Supports the qualitative frequency band. It carries no denominator,
      which is why the band is recorded in frequency rather than as a
      case_fractions record.
treatments:
- name: Implantable Cardioverter-Defibrillator
  description: >-
    An implantable cardioverter-defibrillator provides primary or secondary
    prevention of sudden cardiac death, particularly relevant given the strongly
    arrhythmogenic subtype of TNNC1 HCM.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: implantable cardioverter-defibrillator placement
    term:
      id: NCIT:C80435
      label: Implantable Cardioverter-Defibrillator Placement
- name: HCM Pharmacotherapy and Supportive Care
  description: >-
    Medical management of hypertrophy and heart failure symptoms follows standard
    HCM 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: >-
  CMH13 is the TNNC1 (cardiac troponin C) member of the sarcomeric HCM series and
  a ClinGen-definitive HCM gene, added to complete the definitive thin-filament
  gene set (with ACTC1/CMH11, TNNT2/CMH2, TNNI3/CMH7, TPM1/CMH3). It is the most
  direct myofilament calcium-sensitization lesion in the sarcomere and conforms to
  the shared cardiomyopathy_maladaptive_remodeling module. A parallel
  arrhythmogenic-substrate node captures the fatal arrhythmogenic subtype reported
  for TNNC1. TNNC1 is allelically pleiotropic — other variants cause dilated
  cardiomyopathy (ClinGen Definitive) — 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 TNNC1 cohort and pedigree
  literature cited throughout, principally PMID:28912181, PMID:22815480.
📚

References & Deep Research

References

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