Hypertrophic Cardiomyopathy 10

Genetic MONDO:0012112 Pathograph 5 Show in embeddings browser Hypertrophic Cardiomyopathy Genetic Disorder

Hypertrophic cardiomyopathy 10 (CMH10) is the MYL2-related form of familial hypertrophic cardiomyopathy. MYL2 encodes the ventricular/slow-twitch regulatory myosin light chain (RLC), which binds the neck (lever-arm) region of the beta-cardiac myosin heavy chain and tunes the force and calcium sensitivity of contraction. It is one of the eight genes with definitive ClinGen gene-disease validity for HCM. Heterozygous missense RLC variants (the archetype being R58Q) produce dominant HCM through a gain of myofilament calcium sensitivity together with impaired force transmission by the lever arm; because MYL2 is expressed in both heart ventricle and slow-twitch skeletal muscle, the same lesion can produce a cardioskeletal phenotype. A distinct severe autosomal recessive form, caused by biallelic loss-of-function (e.g. the IVS6-1 cryptic-splice allele), presents as fatal infantile cardiomyopathy with slow-skeletal fiber hypotrophy.

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2
Inheritance
4
Pathophys.
3
Phenotypes
5
Pathograph
1
Genes
2
Medical Actions
1
References
🏷

Classifications

Harrison's Part
CARDIOVASCULAR GENETICS ENVIRONMENT DISEASE
👪

Inheritance

2
Autosomal dominant (heterozygous missense) HP:0000006
The classic CMH10 presentation is autosomal dominant, caused by a single heterozygous MYL2 missense allele acting on the regulatory light chain, with incomplete, age-related penetrance typical of sarcomeric HCM.
Autosomal dominant inheritance Penetrance: INCOMPLETE
Show evidence (1 reference)
CGGV:assertion_7b25ff6c-3ede-46a3-a637-3eab7aa18569-2026-01-13T170000.000Z SUPPORT Other
"MYL2 | HGNC:7583 | hypertrophic cardiomyopathy | MONDO:0005045 | AD | Definitive"
ClinGen's Hereditary Cardiovascular Disease Gene Curation Expert Panel classifies the MYL2-HCM relationship as Definitive with autosomal dominant inheritance.
Autosomal recessive (biallelic loss of function) HP:0000007
A separate, severe autosomal recessive form results from biallelic loss-of-function MYL2 alleles (e.g. the IVS6-1 cryptic-splice variant), presenting as fatal infantile cardiomyopathy with slow-skeletal muscle fiber hypotrophy.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:27378946 SUPPORT In Vitro
"severely compromising the ability of myosin to develop contractile force and maintain normal systolic and diastolic cardiac function"
Characterises the biallelic IVS6-1 loss-of-function mechanism producing the severe infantile cardioskeletal form.
⚙

Pathophysiology

4
MYL2 Variant in Ventricular Regulatory Myosin Light Chain
The initiating lesion in CMH10 is a variant in MYL2, encoding the ventricular regulatory myosin light chain (RLC) that binds the lever-arm region of beta-cardiac myosin. In the common dominant form the variant is a missense change (archetype R58Q) incorporated into the sarcomere; in the rare severe recessive form biallelic loss-of-function abolishes normal RLC. Either way the lesion perturbs how the myosin lever arm transmits force and how the myofilament responds to calcium.
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.
MYL2 hgnc:7583 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves MYL2 (hgnc:7583). hgnc:7583 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
Myosin thick filament GO:0032982 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves Myosin thick filament, annotated with myosin filament (GO:0032982). GO:0032982 is a cellular component from the Gene Ontology.
Downstream
Impaired Lever-Arm Function and Myofilament Calcium Sensitization The abnormal regulatory light chain disturbs lever-arm force transmission and shifts myofilament calcium sensitivity.
Show evidence (1 reference)
PMID:30365366 SUPPORT Model Organism
"MYL2 mutated models of hypertrophic cardiomyopathy may be useful research tools to study the molecular, structural, and energetic mechanisms of cardioskeletal myopathy associated with myosin RLC"
Establishes MYL2/regulatory-light-chain variants as a cause of hypertrophic cardiomyopathy with an associated cardioskeletal component, in a transgenic model of the R58Q allele.
Impaired Lever-Arm Function and Myofilament Calcium Sensitization
The regulatory light chain stabilizes the myosin lever arm and modulates the calcium responsiveness of contraction. MYL2 disease variants reduce maximal contractile force while increasing myofilament calcium sensitivity — the two functional signatures repeatedly observed for HCM-associated MYL2 mutations. In transgenic RLC-mutant hearts and slow-twitch muscle, contractile force is lower than wild type, consistent with defective force transmission by the mutant lever arm.
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 GO:0055117 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Regulation of Cardiac Muscle Contraction (GO:0055117). GO:0055117 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 maladaptive structural remodeling.
Show evidence (2 references)
PMID:27378946 SUPPORT In Vitro
"a significant decrease in maximal contractile force and a significantly increased Ca(2+) sensitivity, both hallmarks of hypertrophic cardiomyopathy-associated mutations in MYL2"
States the two canonical functional consequences of HCM MYL2 mutations — reduced maximal force and increased myofilament calcium sensitivity.
PMID:30365366 SUPPORT Model Organism
"Skinned SOL muscles and ventricular PMs of R58Q animals exhibited lower contractile force"
Confirms reduced contractile force in ventricular papillary muscle of an R58Q RLC transgenic model, the in vivo correlate of the force deficit.
Ventricular Hypertrophy, Myocyte Disarray and Fibrosis
Sustained sarcomeric dysfunction produces the structural remodeling that defines HCM — cardiomyocyte hypertrophy, myofiber disarray, and interstitial fibrosis. RLC-mutant HCM classically involves mid-ventricular and papillary muscle hypertrophy, but the disarray-and-fibrosis substrate is shared with the other sarcomeric forms.
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.
Diastolic Dysfunction, Heart Failure and Arrhythmic Risk
The remodelled, stiff, fibrotic ventricle produces the clinical endpoints of CMH10: diastolic dysfunction, heart failure, and a risk of malignant ventricular arrhythmia and sudden death. As with sarcomeric HCM generally, a positive family history of HCM and of sudden cardiac death is common. The severe recessive infantile form fails systolically and diastolically together and is fatal in infancy.
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:23674365 SUPPORT Human Clinical
"The presence of any sarcomere gene mutation was associated with a younger age at presentation (38.4 vs 46.0 years, p<0.0005), a family history of HCM (50.6% vs 23.1%, p<0.0005), a family history of SCD (27.0% vs 14.9%, p<0.0005) and greater MLVWT (21.0 vs 19.3 mm, p=0.03)."
Places the MYL2 sarcomeric form within the familial, younger-onset, sudden-death-associated clinical pattern of sarcomere-positive HCM.
PMID:27378946 SUPPORT In Vitro
"severely compromising the ability of myosin to develop contractile force and maintain normal systolic and diastolic cardiac function"
Documents the severe systolic-and-diastolic failure of the biallelic infantile form.
⬡

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 10 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 MYL2 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:27378946 SUPPORT In Vitro
"severely compromising the ability of myosin to develop contractile force and maintain normal systolic and diastolic cardiac function"
Links the MYL2 lesion to impaired systolic and diastolic cardiac function.
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:27378946 SUPPORT In Vitro
"severely compromising the ability of myosin to develop contractile force and maintain normal systolic and diastolic cardiac function"
Supports heart failure as an endpoint, most severe in the biallelic form.
🧬

Genetic Associations

1
MYL2
Gene: MYL2 hgnc:7583 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is MYL2 (hgnc:7583). hgnc:7583 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
CGGV:assertion_7b25ff6c-3ede-46a3-a637-3eab7aa18569-2026-01-13T170000.000Z SUPPORT Other
"MYL2 | HGNC:7583 | 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:27378946 SUPPORT In Vitro
"severely compromising the ability of myosin to develop contractile force and maintain normal systolic and diastolic cardiac function"
Characterizes the functional consequence of the biallelic loss-of-function allele class, which is the second, recessive arm of this gene-disease relationship and is distinct from the dominant missense arm.
💊

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 and HCM Pharmacotherapy
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, outflow obstruction, and heart failure symptoms follows standard HCM and heart-failure therapy.
📊

Prevalence

1
Worldwide (MYL2 share of HCM)
Unknown Not yet documented
MYL2 is a definitive but numerically minor HCM gene; no population-based rate for the MYL2-specific entity is documented.
{ }

Source YAML

click to show 
name: Hypertrophic Cardiomyopathy 10
creation_date: "2026-08-22T00:00:00Z"
synonyms:
- CMH10
- MYL2 hypertrophic cardiomyopathy
- ventricular regulatory myosin light chain hypertrophic cardiomyopathy
- cardiomyopathy, familial hypertrophic, 10
- hypertrophic cardiomyopathy caused by mutation in MYL2
description: >-
  Hypertrophic cardiomyopathy 10 (CMH10) is the MYL2-related form of familial
  hypertrophic cardiomyopathy. MYL2 encodes the ventricular/slow-twitch regulatory
  myosin light chain (RLC), which binds the neck (lever-arm) region of the
  beta-cardiac myosin heavy chain and tunes the force and calcium sensitivity of
  contraction. It is one of the eight genes with definitive ClinGen gene-disease
  validity for HCM. Heterozygous missense RLC variants (the archetype being R58Q)
  produce dominant HCM through a gain of myofilament calcium sensitivity together
  with impaired force transmission by the lever arm; because MYL2 is expressed in
  both heart ventricle and slow-twitch skeletal muscle, the same lesion can produce
  a cardioskeletal phenotype. A distinct severe autosomal recessive form, caused by
  biallelic loss-of-function (e.g. the IVS6-1 cryptic-splice allele), presents as
  fatal infantile cardiomyopathy with slow-skeletal fiber hypotrophy.
category: Genetic
classifications:
  harrisons_chapter:
  - classification_value: CARDIOVASCULAR
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
disease_term:
  preferred_term: hypertrophic cardiomyopathy 10
  term:
    id: MONDO:0012112
    label: hypertrophic cardiomyopathy 10
parents:
- Hypertrophic Cardiomyopathy
- Genetic Disorder
inheritance:
- name: Autosomal dominant (heterozygous missense)
  description: >-
    The classic CMH10 presentation is autosomal dominant, caused by a single
    heterozygous MYL2 missense allele acting on the regulatory light chain, with
    incomplete, age-related penetrance typical of sarcomeric HCM.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  penetrance: INCOMPLETE
  evidence:
  - reference: CGGV:assertion_7b25ff6c-3ede-46a3-a637-3eab7aa18569-2026-01-13T170000.000Z
    reference_title: "MYL2 / hypertrophic cardiomyopathy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MYL2 | HGNC:7583 | hypertrophic cardiomyopathy | MONDO:0005045 | AD | Definitive"
    explanation: >-
      ClinGen's Hereditary Cardiovascular Disease Gene Curation Expert Panel
      classifies the MYL2-HCM relationship as Definitive with autosomal dominant
      inheritance.
- name: Autosomal recessive (biallelic loss of function)
  description: >-
    A separate, severe autosomal recessive form results from biallelic
    loss-of-function MYL2 alleles (e.g. the IVS6-1 cryptic-splice variant),
    presenting as fatal infantile cardiomyopathy with slow-skeletal muscle fiber
    hypotrophy.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:27378946
    reference_title: "Molecular and Functional Effects of a Splice Site Mutation in the MYL2 Gene Associated with Cardioskeletal Myopathy and Early Cardiac Death in Infants."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      severely compromising the ability of myosin to develop contractile force and
      maintain normal systolic and diastolic cardiac function
    explanation: >-
      Characterises the biallelic IVS6-1 loss-of-function mechanism producing the
      severe infantile cardioskeletal form.
prevalence:
- population: Worldwide (MYL2 share of HCM)
  measure_type: UNKNOWN
  prevalence_class: NOT_YET_DOCUMENTED
  notes: >-
    MYL2 is a definitive but numerically minor HCM gene; no population-based rate
    for the MYL2-specific entity is documented.
pathophysiology:
- name: MYL2 Variant in Ventricular Regulatory Myosin Light Chain
  biological_scale: MOLECULAR
  role: trigger
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Primary Cardiomyocyte Insult"
  description: >-
    The initiating lesion in CMH10 is a variant in MYL2, encoding the ventricular
    regulatory myosin light chain (RLC) that binds the lever-arm region of
    beta-cardiac myosin. In the common dominant form the variant is a missense
    change (archetype R58Q) incorporated into the sarcomere; in the rare severe
    recessive form biallelic loss-of-function abolishes normal RLC. Either way the
    lesion perturbs how the myosin lever arm transmits force and how the myofilament
    responds to calcium.
  genes:
  - preferred_term: MYL2
    term:
      id: hgnc:7583
      label: MYL2
  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: Myosin thick filament
    term:
      id: GO:0032982
      label: myosin filament
  evidence:
  - reference: PMID:30365366
    reference_title: "Slow-twitch skeletal muscle defects accompany cardiac dysfunction in transgenic mice with a mutation in the myosin regulatory light chain."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      MYL2 mutated models of hypertrophic cardiomyopathy may be useful research
      tools to study the molecular, structural, and energetic mechanisms of
      cardioskeletal myopathy associated with myosin RLC
    explanation: >-
      Establishes MYL2/regulatory-light-chain variants as a cause of hypertrophic
      cardiomyopathy with an associated cardioskeletal component, in a transgenic
      model of the R58Q allele.
  downstream:
  - target: Impaired Lever-Arm Function and Myofilament Calcium Sensitization
    causal_link_type: DIRECT
    description: >-
      The abnormal regulatory light chain disturbs lever-arm force transmission and
      shifts myofilament calcium sensitivity.
- name: Impaired Lever-Arm Function and Myofilament Calcium Sensitization
  biological_scale: MOLECULAR
  role: effector
  description: >-
    The regulatory light chain stabilizes the myosin lever arm and modulates the
    calcium responsiveness of contraction. MYL2 disease variants reduce maximal
    contractile force while increasing myofilament calcium sensitivity — the two
    functional signatures repeatedly observed for HCM-associated MYL2 mutations.
    In transgenic RLC-mutant hearts and slow-twitch muscle, contractile force is
    lower than wild type, consistent with defective force transmission by the
    mutant lever arm.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: Regulation of Cardiac Muscle Contraction
    term:
      id: GO:0055117
      label: regulation of cardiac muscle contraction
    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:27378946
    reference_title: "Molecular and Functional Effects of a Splice Site Mutation in the MYL2 Gene Associated with Cardioskeletal Myopathy and Early Cardiac Death in Infants."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      a significant decrease in maximal contractile force and a significantly
      increased Ca(2+) sensitivity, both hallmarks of hypertrophic
      cardiomyopathy-associated mutations in MYL2
    explanation: >-
      States the two canonical functional consequences of HCM MYL2 mutations —
      reduced maximal force and increased myofilament calcium sensitivity.
  - reference: PMID:30365366
    reference_title: "Slow-twitch skeletal muscle defects accompany cardiac dysfunction in transgenic mice with a mutation in the myosin regulatory light chain."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Skinned SOL muscles and ventricular PMs of R58Q animals exhibited lower contractile force"
    explanation: >-
      Confirms reduced contractile force in ventricular papillary muscle of an
      R58Q RLC transgenic model, the in vivo correlate of the force deficit.
  downstream:
  - target: Ventricular Hypertrophy, Myocyte Disarray and Fibrosis
    causal_link_type: DIRECT
    description: >-
      Chronic sarcomeric dysfunction drives maladaptive structural remodeling.
- 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. RLC-mutant HCM classically involves mid-ventricular and papillary
    muscle hypertrophy, but the disarray-and-fibrosis substrate is shared with the
    other sarcomeric forms.
  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: 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, stiff, fibrotic ventricle produces the clinical endpoints of
    CMH10: diastolic dysfunction, heart failure, and a risk of malignant
    ventricular arrhythmia and sudden death. As with sarcomeric HCM generally,
    a positive family history of HCM and of sudden cardiac death is common. The
    severe recessive infantile form fails systolically and diastolically together
    and is fatal in infancy.
  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:23674365
    reference_title: "A systematic review and meta-analysis of genotype-phenotype associations in patients with hypertrophic cardiomyopathy caused by sarcomeric protein mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The presence of any sarcomere gene mutation was associated with a younger
      age at presentation (38.4 vs 46.0 years, p<0.0005), a family history of HCM
      (50.6% vs 23.1%, p<0.0005), a family history of SCD (27.0% vs 14.9%,
      p<0.0005) and greater MLVWT (21.0 vs 19.3 mm, p=0.03).
    explanation: >-
      Places the MYL2 sarcomeric form within the familial, younger-onset,
      sudden-death-associated clinical pattern of sarcomere-positive HCM.
  - reference: PMID:27378946
    reference_title: "Molecular and Functional Effects of a Splice Site Mutation in the MYL2 Gene Associated with Cardioskeletal Myopathy and Early Cardiac Death in Infants."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      severely compromising the ability of myosin to develop contractile force and
      maintain normal systolic and diastolic cardiac function
    explanation: >-
      Documents the severe systolic-and-diastolic failure of the biallelic
      infantile form.
phenotypes:
- name: Hypertrophic Cardiomyopathy
  category: Cardiovascular
  description: >-
    Unexplained left ventricular hypertrophy is the defining feature; RLC-mutant
    disease classically involves mid-ventricular and papillary muscle hypertrophy.
  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 MYL2 form manifests.
- name: Left Ventricular Diastolic Dysfunction
  category: Cardiovascular
  description: >-
    Increased myofilament calcium sensitivity and a stiff, hypertrophied ventricle
    impair relaxation and filling.
  phenotype_term:
    preferred_term: Left ventricular diastolic dysfunction
    term:
      id: HP:0025168
      label: Left ventricular diastolic dysfunction
  evidence:
  - reference: PMID:27378946
    reference_title: "Molecular and Functional Effects of a Splice Site Mutation in the MYL2 Gene Associated with Cardioskeletal Myopathy and Early Cardiac Death in Infants."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      severely compromising the ability of myosin to develop contractile force and
      maintain normal systolic and diastolic cardiac function
    explanation: >-
      Links the MYL2 lesion to impaired systolic and diastolic cardiac function.
- name: Congestive Heart Failure
  category: Cardiovascular
  description: >-
    Heart failure develops from progressive diastolic dysfunction; the recessive
    infantile form presents with fatal heart failure in the first months of life.
  phenotype_term:
    preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  evidence:
  - reference: PMID:27378946
    reference_title: "Molecular and Functional Effects of a Splice Site Mutation in the MYL2 Gene Associated with Cardioskeletal Myopathy and Early Cardiac Death in Infants."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      severely compromising the ability of myosin to develop contractile force and
      maintain normal systolic and diastolic cardiac function
    explanation: >-
      Supports heart failure as an endpoint, most severe in the biallelic form.
genetic:
- name: MYL2
  gene_term:
    preferred_term: MYL2
    term:
      id: hgnc:7583
      label: MYL2
  relationship_type: CAUSATIVE
  frequency: >-
    Definitive but numerically minor cause of hypertrophic cardiomyopathy; no
    case fraction has been reported in a screened cohort.
  evidence:
  - reference: CGGV:assertion_7b25ff6c-3ede-46a3-a637-3eab7aa18569-2026-01-13T170000.000Z
    reference_title: "MYL2 / hypertrophic cardiomyopathy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      MYL2 | HGNC:7583 | 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:27378946
    reference_title: "Molecular and Functional Effects of a Splice Site Mutation in the MYL2 Gene Associated with Cardioskeletal Myopathy and Early Cardiac Death in Infants."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      severely compromising the ability of myosin to develop contractile force
      and maintain normal systolic and diastolic cardiac function
    explanation: >-
      Characterizes the functional consequence of the biallelic
      loss-of-function allele class, which is the second, recessive arm of
      this gene-disease relationship and is distinct from the dominant
      missense arm.
  notes: >-
    Both the dominant heterozygous missense arm and the recessive biallelic
    loss-of-function arm are curated on this one gene record, because the
    gene-disease relationship is single and it is the allele class and dose
    that differ.
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 and HCM Pharmacotherapy
  description: >-
    Medical management of hypertrophy, outflow obstruction, and heart failure
    symptoms follows standard HCM and heart-failure 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: >-
  CMH10 is the MYL2 (ventricular regulatory myosin light chain) member of the
  sarcomeric HCM series and one of the eight ClinGen-definitive HCM genes, added to
  complete the definitive-gene set. It conforms to the shared
  cardiomyopathy_maladaptive_remodeling module. Two inheritance modes are curated:
  the common autosomal dominant missense form (R58Q archetype) and a severe
  autosomal recessive infantile cardioskeletal form from biallelic loss of
  function (IVS6-1). Because MYL2 is expressed in slow-twitch skeletal muscle as
  well as ventricle, a cardioskeletal component can accompany the cardiomyopathy.

  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 MYL2 cohort and pedigree
  literature cited throughout, principally PMID:28912181, PMID:27378946.
📚

References & Deep Research

References

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