Hypertrophic cardiomyopathy 1 (CMH1) is the MYH7-related form of familial hypertrophic cardiomyopathy and, with the MYBPC3 form (CMH4), one of the two commonest genetic causes of the disease. MYH7 encodes the beta-cardiac myosin heavy chain (beta-MyHC), the force-generating molecular motor of the cardiac thick filament. CMH1 is historically the founding molecular diagnosis of the entire field: the first mutation ever shown to cause familial hypertrophic cardiomyopathy was the MYH7 Arg403Gln (R403Q) missense change, identified in a large kindred in 1990. Unlike MYBPC3-related disease, where truncating alleles act through haploinsufficiency, the great majority of MYH7 disease alleles are missense variants that are stably expressed and incorporated into the sarcomere as a mutant motor. The operative mechanism is therefore not loss of protein but a gain of contractile function: the mutant myosin destabilizes the folded-back, autoinhibited super-relaxed state of the thick filament, freeing more heads to interact with actin, and often raises the intrinsic force and the energetic cost of each cross-bridge. The net cellular consequence is hypercontractility with impaired relaxation and raised tension cost, which drives the structural remodeling — cardiomyocyte hypertrophy, myofiber disarray, and interstitial fibrosis — that defines the clinical phenotype. Inheritance is autosomal dominant with incomplete, age-related penetrance; MYH7 variants carry a clinically important risk of malignant ventricular arrhythmia and sudden cardiac death, and beta-cardiac myosin is the direct molecular target of the cardiac myosin inhibitors (mavacamten, aficamten) now used to treat obstructive disease.
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name: Hypertrophic Cardiomyopathy 1
creation_date: "2026-08-22T00:00:00Z"
synonyms:
- CMH1
- MYH7 hypertrophic cardiomyopathy
- beta-myosin heavy chain hypertrophic cardiomyopathy
- cardiomyopathy, familial hypertrophic, 1
- familial hypertrophic cardiomyopathy type 1
- hypertrophic cardiomyopathy caused by mutation in MYH7
description: >-
Hypertrophic cardiomyopathy 1 (CMH1) is the MYH7-related form of familial
hypertrophic cardiomyopathy and, with the MYBPC3 form (CMH4), one of the two
commonest genetic causes of the disease. MYH7 encodes the beta-cardiac myosin
heavy chain (beta-MyHC), the force-generating molecular motor of the cardiac
thick filament. CMH1 is historically the founding molecular diagnosis of the
entire field: the first mutation ever shown to cause familial hypertrophic
cardiomyopathy was the MYH7 Arg403Gln (R403Q) missense change, identified in a
large kindred in 1990.
Unlike MYBPC3-related disease, where truncating alleles act through
haploinsufficiency, the great majority of MYH7 disease alleles are missense
variants that are stably expressed and incorporated into the sarcomere as a
mutant motor. The operative mechanism is therefore not loss of protein but a
gain of contractile function: the mutant myosin destabilizes the folded-back,
autoinhibited super-relaxed state of the thick filament, freeing more heads to
interact with actin, and often raises the intrinsic force and the energetic
cost of each cross-bridge. The net cellular consequence is hypercontractility
with impaired relaxation and raised tension cost, which drives the structural
remodeling — cardiomyocyte hypertrophy, myofiber disarray, and interstitial
fibrosis — that defines the clinical phenotype. Inheritance is autosomal
dominant with incomplete, age-related penetrance; MYH7 variants carry a
clinically important risk of malignant ventricular arrhythmia and sudden
cardiac death, and beta-cardiac myosin is the direct molecular target of the
cardiac myosin inhibitors (mavacamten, aficamten) now used to treat obstructive
disease.
category: Genetic
classifications:
harrisons_chapter:
- classification_value: CARDIOVASCULAR
- classification_value: GENETICS_ENVIRONMENT_DISEASE
disease_term:
preferred_term: hypertrophic cardiomyopathy 1
term:
id: MONDO:0008647
label: hypertrophic cardiomyopathy 1
parents:
- Hypertrophic Cardiomyopathy
- Genetic Disorder
inheritance:
- name: Autosomal dominant
description: >-
CMH1 is inherited as an autosomal dominant trait, with a single mutant MYH7
allele producing disease. Penetrance is incomplete and age-related, and a
family history of hypertrophic cardiomyopathy and of sudden cardiac death is
characteristic of sarcomere-variant-positive disease, so cascade screening of
relatives must be longitudinal rather than a single evaluation.
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
penetrance: INCOMPLETE
evidence:
- reference: CGGV:assertion_31325c90-05cb-4db0-9372-e4f705cd5c82-2023-07-12T160000.000Z
reference_title: "MYH7 / hypertrophic cardiomyopathy (Definitive)"
supports: SUPPORT
evidence_source: OTHER
snippet: "MYH7 | HGNC:7577 | hypertrophic cardiomyopathy | MONDO:0005045 | AD | Definitive"
explanation: >-
ClinGen's Hereditary Cardiovascular Disease Gene Curation Expert Panel
classifies the MYH7-hypertrophic cardiomyopathy relationship as Definitive
with autosomal dominant inheritance.
- 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: >-
Meta-analysis of 2459 patients documenting the familial, dominantly
inherited pattern of sarcomere-positive HCM, with a positive family history
of both HCM and sudden cardiac death and younger onset than
sarcomere-negative disease.
prevalence:
- population: Worldwide (hypertrophic cardiomyopathy overall)
measure_type: POINT_PREVALENCE
prevalence_class: ABOVE_1_IN_1000
rate_per_100000: 200.0
notes: >-
Clinical prevalence of hypertrophic cardiomyopathy in the general population,
the context for the MYH7 subtype. MYH7-specific population rates are not
separately documented.
evidence:
- reference: PMID:31213605
reference_title: "β-Cardiac myosin hypertrophic cardiomyopathy mutations release sequestered heads and increase enzymatic activity."
supports: SUPPORT
evidence_source: OTHER
snippet: "Hypertrophic cardiomyopathy (HCM) affects 1 in 500 people and leads to hyper-contractility of the heart."
explanation: >-
Gives the ~1 in 500 general-population prevalence of hypertrophic
cardiomyopathy overall. Evidence source is OTHER because this is a
biochemical mechanism paper stating the epidemiological background.
- population: Worldwide (MYH7 share of HCM mutations)
measure_type: UNKNOWN
prevalence_class: NOT_YET_DOCUMENTED
notes: >-
No population-based prevalence estimate exists for the MYH7-specific entity.
MYH7 is, with MYBPC3, one of the two most frequently mutated genes in
hypertrophic cardiomyopathy, accounting for roughly 40% of identified
HCM-causing mutations.
evidence:
- reference: PMID:31213605
reference_title: "β-Cardiac myosin hypertrophic cardiomyopathy mutations release sequestered heads and increase enzymatic activity."
supports: SUPPORT
evidence_source: OTHER
snippet: "Nearly 40 percent of HCM-causing mutations are found in human β-cardiac myosin."
explanation: >-
Quantifies MYH7's share of HCM-causing mutations. Evidence source is OTHER
because this is a biochemical mechanism paper.
pathophysiology:
- name: MYH7 Missense Variant in Beta-Cardiac Myosin Heavy Chain
biological_scale: MOLECULAR
role: trigger
conforms_to: "cardiomyopathy_maladaptive_remodeling#Primary Cardiomyocyte Insult"
description: >-
The initiating lesion in CMH1 is a heterozygous missense variant in MYH7,
the gene encoding the beta-cardiac myosin heavy chain — the ATP-hydrolysing
motor of the sarcomeric thick filament. The founding example, and still the
archetype, is Arg403Gln (R403Q), the first mutation ever linked to familial
hypertrophic cardiomyopathy; R403Q sits in the globular myosin head (S1),
the region responsible for actin interaction and motor function. In contrast
to the truncating, haploinsufficiency mechanism of MYBPC3 disease, most MYH7
alleles are missense changes that are stably expressed and incorporated into
the sarcomere as a mutant motor, so the mutant protein perturbs contraction
directly rather than by its absence.
genes:
- preferred_term: MYH7
term:
id: hgnc:7577
label: MYH7
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:1975517
reference_title: "A molecular basis for familial hypertrophic cardiomyopathy: a beta cardiac myosin heavy chain gene missense mutation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
A point mutation in exon 13 of the beta cardiac myosin heavy chain (MHC)
gene is present in all individuals affected with familial hypertrophic
cardiomyopathy (FHC) from a large kindred. This missense mutation converts
a highly conserved arginine residue (Arg-403) to a glutamine.
explanation: >-
The founding CMH1 report: co-segregation of the MYH7 R403Q missense variant
with familial hypertrophic cardiomyopathy in a large kindred, establishing
the beta-cardiac myosin heavy chain gene as a cause of the disease.
- reference: PMID:23798412
reference_title: "Molecular consequences of the R453C hypertrophic cardiomyopathy mutation on human β-cardiac myosin motor function."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
HCM is caused by mutations in the genes encoding the fundamental
force-generating machinery of the cardiac muscle, including β-cardiac
myosin.
explanation: >-
Places the MYH7 lesion in the force-generating machinery of the sarcomere,
the trigger for this entity.
downstream:
- target: Destabilization of the Autoinhibited Super-Relaxed State
causal_link_type: DIRECT
description: >-
The mutant motor, incorporated into the thick filament, destabilizes the
folded-back autoinhibited state that normally sequesters myosin heads.
- name: Destabilization of the Autoinhibited Super-Relaxed State
biological_scale: MOLECULAR
role: amplifier
description: >-
In the resting sarcomere a large fraction of myosin heads occupy the
super-relaxed (SRX) state — folded back against the thick-filament backbone
in the interacting-heads motif (IHM), with very low ATPase activity, forming
an energy-conserving reserve of motors withheld from force generation. Many
MYH7 HCM mutations map to the interfaces that stabilize this folded-back
state (the myosin mesa, the head-head and head-tail contacts), and they
weaken those intramolecular interactions. The result is release of
sequestered heads from the SRX/IHM into the disordered-relaxed state, so more
heads become functionally accessible to actin — the molecular origin of
hypercontractility shared across a large subset of MYH7 alleles.
cell_types:
- preferred_term: Cardiomyocyte
term:
id: CL:0000746
label: cardiac muscle cell
molecular_functions:
- preferred_term: ATP Hydrolysis by Myosin
term:
id: GO:0016887
label: ATP hydrolysis activity
modifier: INCREASED
cellular_components:
- preferred_term: Myosin thick filament
term:
id: GO:0032982
label: myosin filament
evidence:
- reference: PMID:31213605
reference_title: "β-Cardiac myosin hypertrophic cardiomyopathy mutations release sequestered heads and increase enzymatic activity."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
folded-back sequestered state referred to as the interacting heads motif
(IHM) lead to a significant increase in the number of heads functionally
accessible for interaction with actin.
explanation: >-
Direct biochemical evidence that MYH7 HCM mutations at IHM interfaces
release sequestered heads, increasing the number available to interact with
actin.
- reference: PMID:28481356
reference_title: "The myosin mesa and the basis of hypercontractility caused by hypertrophic cardiomyopathy mutations."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
hypercontractility is due to an increase in the number of myosin heads (S1)
that are accessible for force production.
explanation: >-
States the core hypothesis this node captures: HCM hypercontractility
arises from an increase in the number of force-producing heads freed from
the sequestered state.
- reference: PMID:34117120
reference_title: "Hypertrophic cardiomyopathy β-cardiac myosin mutation (P710R) leads to hypercontractility by disrupting super relaxed state."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
destabilized the super relaxed state in longer, two-headed myosin
constructs, freeing more heads to generate force.
explanation: >-
Shows a specific MYH7 mutation (P710R) destabilizing the super-relaxed
state and freeing heads for force generation.
- reference: PMID:40118457
reference_title: "Dynamics of β-cardiac myosin between the super-relaxed and disordered-relaxed states."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Some mutations which cause hypertrophic or dilated cardiomyopathies alter
the SRX-DRX equilibrium, but not all mutations.
explanation: >-
Important caveat curated with the node: SRX-DRX destabilization is a common
but not universal consequence of cardiomyopathy myosin mutations, so this
arm applies to the large subset of alleles that shift the equilibrium
rather than to every MYH7 variant. PARTIAL for that reason.
downstream:
- target: Increased Motor Force and Energetic Cost
causal_link_type: DIRECT
description: >-
Heads released from the super-relaxed reserve, together with allele-specific
changes in the motor stroke, raise ensemble force and the ATP cost of
contraction.
- name: Increased Motor Force and Energetic Cost
biological_scale: MOLECULAR
role: effector
description: >-
Beyond releasing sequestered heads, individual MYH7 missense alleles alter
the mechanochemistry of the motor stroke itself. Single-molecule and
myofibril studies show mutation-specific changes — increased intrinsic force
per cross-bridge, and faster cross-bridge detachment kinetics — that together
raise the force generated by the ensemble of motors and increase the ATP
consumed per unit tension (tension cost). The energetic penalty, measured
directly in human myocardium carrying R403Q, is a distinctive feature of the
beta-myosin motor lesion and links the molecular defect to the myocardial
energy deficit seen in HCM.
cell_types:
- preferred_term: Cardiomyocyte
term:
id: CL:0000746
label: cardiac muscle cell
molecular_functions:
- preferred_term: ATP Hydrolysis by Myosin
term:
id: GO:0016887
label: ATP hydrolysis activity
modifier: INCREASED
biological_processes:
- preferred_term: Actin-Myosin Filament Sliding
term:
id: GO:0033275
label: actin-myosin filament sliding
modifier: ABNORMAL
evidence:
- reference: PMID:23798412
reference_title: "Molecular consequences of the R453C hypertrophic cardiomyopathy mutation on human β-cardiac myosin motor function."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
The major change in the R453C human β-cardiac subfragment 1 is a 50%
increase in the intrinsic force of the motor compared with wild type, with
no appreciable change in the stroke size, as observed with a dual-beam
optical trap.
explanation: >-
Single-molecule optical-trap measurement of a raised intrinsic force for an
MYH7 mutant motor, predicting a hypercontractile ensemble.
- reference: PMID:23798412
reference_title: "Molecular consequences of the R453C hypertrophic cardiomyopathy mutation on human β-cardiac myosin motor function."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Overall, this study suggests that the R453C mutation should result in a
hypercontractile state in the heart muscle.
explanation: >-
States the functional conclusion — a hypercontractile state — that the
motor-level force change produces.
- reference: PMID:24928957
reference_title: "Faster cross-bridge detachment and increased tension cost in human hypertrophic cardiomyopathy with the R403Q MYH7 mutation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
This correlation suggests that faster cross-bridge relaxation kinetics
results in an increase in energetic cost of tension generation in human HCM
with the R403Q mutation compared to HCMsmn.
explanation: >-
Direct measurement in human R403Q myocardium (single myofibrils and muscle
strips) linking faster cross-bridge kinetics to an increased energetic cost
of tension generation, evidence obtained in patient cardiac tissue.
downstream:
- target: Sarcomere Hypercontractility with Impaired Relaxation
causal_link_type: DIRECT
description: >-
Raised ensemble force and disturbed cross-bridge kinetics translate into
cellular hypercontractility with impaired diastolic relaxation.
- name: Sarcomere Hypercontractility with Impaired Relaxation
biological_scale: CELLULAR
role: effector
description: >-
At the cell level the molecular changes converge on hypercontractility:
CRISPR-edited human iPSC-derived cardiomyocytes carrying an MYH7 HCM mutation
generate significantly greater contractile force than isogenic controls.
Because the same lesion disturbs cross-bridge relaxation kinetics, systolic
hypercontraction is accompanied by impaired diastolic relaxation. This
hypercontractile, poorly relaxing cell state — a key pathophysiological
abnormality of HCM and the determinant of dynamic outflow obstruction — is
the cellular phenotype the cardiac myosin inhibitors were designed to
normalize.
cell_types:
- preferred_term: Ventricular cardiomyocyte
term:
id: CL:0002131
label: regular ventricular cardiac myocyte
biological_processes:
- preferred_term: Cardiac Muscle Cell Contraction
term:
id: GO:0086003
label: cardiac muscle cell contraction
modifier: INCREASED
- preferred_term: Regulation of Cardiac Muscle Contraction
term:
id: GO:0055117
label: regulation of cardiac muscle contraction
modifier: ABNORMAL
evidence:
- reference: PMID:34117120
reference_title: "Hypertrophic cardiomyopathy β-cardiac myosin mutation (P710R) leads to hypercontractility by disrupting super relaxed state."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
produced significantly increased force (measured by traction force
microscopy) compared with isogenic control cells.
explanation: >-
Isogenic human iPSC-cardiomyocyte evidence that an MYH7 HCM mutation
increases cellular contractile force.
- reference: PMID:32871100
reference_title: "Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Cardiac muscle hypercontractility is a key pathophysiological abnormality
in hypertrophic cardiomyopathy, and a major determinant of dynamic left
ventricular outflow tract (LVOT) obstruction.
explanation: >-
Confirms hypercontractility as the central pathophysiological abnormality
of HCM and links it to outflow obstruction; PARTIAL because the trial
enrolled obstructive HCM broadly rather than genotyped MYH7 carriers.
downstream:
- target: Cell-to-Cell Contractile Imbalance
causal_link_type: DIRECT
description: >-
Because mutant and wild-type MYH7 alleles are transcribed in variable
proportions between neighboring myocytes, hypercontractility is unevenly
distributed across the myocardium.
- target: Ventricular Hypertrophy, Myocyte Disarray and Fibrosis
causal_link_type: DIRECT
description: >-
Sustained hypercontractility with raised energetic cost drives the
structural remodeling of the ventricle.
- name: Cell-to-Cell Contractile Imbalance
biological_scale: CELLULAR
role: amplifier
description: >-
A mechanism specific to the missense/poison-peptide biology of MYH7 disease.
Because the mutant and wild-type MYH7 alleles are transcribed in a random,
burst-like fashion and independently of one another, the fraction of mutant
beta-myosin varies markedly from cardiomyocyte to cardiomyocyte within a
single patient's myocardium. This produces much greater cell-to-cell
variability of contractile function than in control hearts. The resulting
mechanical mismatch between adjacent, differently loaded myocytes is proposed
to drive the myofiber disarray and interstitial fibrosis that are hallmarks
of HCM, providing a route from the molecular lesion to the tissue phenotype
that does not depend on the average level of hypercontractility alone.
cell_types:
- preferred_term: Cardiomyocyte
term:
id: CL:0000746
label: cardiac muscle cell
biological_processes:
- preferred_term: Cardiac Muscle Cell Contraction
term:
id: GO:0086003
label: cardiac muscle cell contraction
modifier: ABNORMAL
evidence:
- reference: PMID:30740621
reference_title: "Altered force generation and cell-to-cell contractile imbalance in hypertrophic cardiomyopathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
substantial contractile variability from cardiomyocyte to cardiomyocyte
within a patient's myocardium, much higher than in controls.
explanation: >-
Documents the cell-to-cell contractile variability in beta-MyHC-mutant
patient myocardium that this node captures.
- reference: PMID:30740621
reference_title: "Altered force generation and cell-to-cell contractile imbalance in hypertrophic cardiomyopathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
contractile imbalance due to unequal fractions of mutated and wildtype
protein among individual cardiomyocytes over time will induce cardiomyocyte
disarray and fibrosis, hallmarks of HCM.
explanation: >-
States the contractile-imbalance hypothesis linking unequal mutant-allele
expression to disarray and fibrosis, the hallmarks of HCM.
downstream:
- target: Ventricular Hypertrophy, Myocyte Disarray and Fibrosis
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Mechanical mismatch between neighboring myocytes promotes disarray and
fibrotic remodeling.
- name: Ventricular Hypertrophy, Myocyte Disarray and Fibrosis
biological_scale: TISSUE
role: central_effector
conforms_to: "cardiomyopathy_maladaptive_remodeling#Ventricular Remodeling"
description: >-
Chronic hypercontractility with raised energetic cost, amplified by
cell-to-cell contractile imbalance, drives the structural remodeling that
defines the clinical phenotype: cardiomyocyte hypertrophy — typically
asymmetric and septal-predominant — together with myofiber disarray and
interstitial and replacement fibrosis. Pro-hypertrophic growth signalling
contributes: in an MYH7-mutant human iPSC-cardiomyocyte model, cellular
hypertrophy was prevented by inhibition of ERK or Akt, implicating those
pathways downstream of the mechanical stimulus. Fibrosis provides the
substrate for both diastolic dysfunction and re-entrant arrhythmia.
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 — myocyte hypertrophy, disarray, and
interstitial fibrosis — that this node represents.
- reference: PMID:34117120
reference_title: "Hypertrophic cardiomyopathy β-cardiac myosin mutation (P710R) leads to hypercontractility by disrupting super relaxed state."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Cellular hypertrophy was prevented in the P710R cells by inhibition of ERK or Akt."
explanation: >-
Implicates ERK and Akt growth signalling downstream of the MYH7 mechanical
lesion in producing the cellular hypertrophy of this node.
- reference: PMID:30740621
reference_title: "Altered force generation and cell-to-cell contractile imbalance in hypertrophic cardiomyopathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
contractile imbalance due to unequal fractions of mutated and wildtype
protein among individual cardiomyocytes over time will induce cardiomyocyte
disarray and fibrosis, hallmarks of HCM.
explanation: >-
Ties the upstream contractile imbalance to the disarray and fibrosis of
this tissue node.
downstream:
- target: Diastolic Dysfunction, Outflow Obstruction, Heart Failure and Arrhythmic Risk
causal_link_type: DIRECT
- name: Diastolic Dysfunction, Outflow Obstruction, Heart Failure and Arrhythmic Risk
biological_scale: ORGANISM
role: consequence
conforms_to: "cardiomyopathy_maladaptive_remodeling#Structural Cardiac Impairment and Heart Failure"
description: >-
The hypertrophied, disarrayed and fibrotic ventricle produces the clinical
endpoints of CMH1. Hypercontractility with septal hypertrophy generates
dynamic left ventricular outflow tract obstruction in a subset of patients;
the stiff, poorly relaxing ventricle causes diastolic dysfunction; and the
fibrotic, electrically heterogeneous substrate carries a risk of malignant
ventricular arrhythmia and sudden cardiac death that is clinically important
for MYH7 variants. Sarcomere-positive disease, of which MYH7 is a leading
cause, presents younger and with a stronger family history of sudden death
than sarcomere-negative HCM.
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: >-
There were no differences when the two most frequently affected genes,
MYBPC3 and MYH7, were compared.
explanation: >-
Records the important nuance that, at the cohort level, MYH7 and MYBPC3 do
not differ significantly across the pooled clinical features, so MYH7 is
not simply a uniformly more severe genotype than MYBPC3; it is one of the
two commonest sarcomeric causes.
- reference: PMID:39681440
reference_title: "[Correlation between genotype and clinical phenotype in hypertrophic cardiomyopathy families with MYH7-R453C mutation]."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In the five families with HCM carrying MYH7-R453C mutations, genotype is
highly correlated with clinical phenotype, and patients have a high risk of
sudden death and poor prognosis.
explanation: >-
A family study of a specific MYH7 variant documenting high sudden-death
risk and poor prognosis, the arrhythmic endpoint of this node.
phenotypes:
- name: Hypertrophic Cardiomyopathy
category: Cardiovascular
description: >-
Unexplained left ventricular hypertrophy, not accounted for by abnormal
loading conditions, is the defining feature of CMH1.
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 — unexplained left ventricular
hypertrophy with a nondilated ventricle — of the disease this MYH7 form
manifests.
- name: Asymmetric Septal Hypertrophy
category: Cardiovascular
description: >-
Asymmetric, septal-predominant left ventricular hypertrophy is the classic
morphological pattern of MYH7-related hypertrophic cardiomyopathy.
phenotype_term:
preferred_term: Asymmetric septal hypertrophy
term:
id: HP:0001670
label: Asymmetric septal hypertrophy
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: >-
Sarcomere-positive HCM, of which MYH7 is a leading cause, shows greater
maximum left ventricular wall thickness than sarcomere-negative disease,
supporting the pronounced hypertrophy of this member.
- name: Left Ventricular Outflow Tract Obstruction
category: Cardiovascular
description: >-
Dynamic obstruction of the left ventricular outflow tract arises from
hypercontractility combined with septal hypertrophy and systolic anterior
motion of the mitral valve, defining the obstructive phenotype targeted by
myosin inhibitors and septal reduction therapy.
phenotype_term:
preferred_term: Left ventricular outflow tract obstruction
term:
id: HP:0032092
label: Left ventricular outflow tract obstruction
evidence:
- reference: PMID:32871100
reference_title: "Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Cardiac muscle hypercontractility is a key pathophysiological abnormality
in hypertrophic cardiomyopathy, and a major determinant of dynamic left
ventricular outflow tract (LVOT) obstruction.
explanation: >-
Links hypercontractility to dynamic LVOT obstruction; PARTIAL because the
trial population is obstructive HCM broadly rather than genotyped MYH7
carriers.
- name: Left Ventricular Diastolic Dysfunction
category: Cardiovascular
description: >-
Impaired relaxation and increased chamber stiffness produce diastolic
dysfunction, an early and characteristic functional consequence of the
hypercontractile, poorly relaxing myocardium.
phenotype_term:
preferred_term: Left ventricular diastolic dysfunction
term:
id: HP:0025168
label: Left ventricular diastolic dysfunction
evidence:
- reference: PMID:24928957
reference_title: "Faster cross-bridge detachment and increased tension cost in human hypertrophic cardiomyopathy with the R403Q MYH7 mutation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Cross-bridge slow relaxation kinetics in single R403Q myofibrils was
significantly higher (P < 0.0001) than in HCMsmn myofibrils
explanation: >-
Documents disturbed cross-bridge relaxation kinetics in human R403Q
myocardium, the molecular basis of the impaired relaxation underlying
diastolic dysfunction.
- name: Sudden Cardiac Death
category: Cardiovascular
description: >-
Malignant ventricular arrhythmia on the fibrotic, hypertrophied substrate
can cause sudden cardiac death, sometimes as the presenting event; the risk
is clinically important for MYH7 variants and family history of sudden death
is characteristic.
phenotype_term:
preferred_term: Sudden cardiac death
term:
id: HP:0001645
label: Sudden cardiac death
evidence:
- reference: PMID:39681440
reference_title: "[Correlation between genotype and clinical phenotype in hypertrophic cardiomyopathy families with MYH7-R453C mutation]."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In the five families with HCM carrying MYH7-R453C mutations, genotype is
highly correlated with clinical phenotype, and patients have a high risk of
sudden death and poor prognosis.
explanation: >-
A family study of an MYH7 variant documenting a high risk of sudden death.
- name: Ventricular Arrhythmia
category: Cardiovascular
description: >-
The electrically heterogeneous, fibrotic myocardium supports malignant
ventricular arrhythmia, the proximate cause of sudden cardiac death in this
disease.
phenotype_term:
preferred_term: Ventricular arrhythmia
term:
id: HP:0004308
label: Ventricular arrhythmia
evidence:
- reference: PMID:39681440
reference_title: "[Correlation between genotype and clinical phenotype in hypertrophic cardiomyopathy families with MYH7-R453C mutation]."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
2 experienced (F1Ⅲ1, F3Ⅲ3) events of sudden cardiac death survival
explanation: >-
Aborted sudden cardiac death (survived cardiac arrest) in MYH7-R453C
carriers evidences the malignant ventricular arrhythmia of this node.
- name: Congestive Heart Failure
category: Cardiovascular
description: >-
Progressive diastolic dysfunction, and in a minority progression toward
systolic impairment or an end-stage phase, produces heart failure symptoms.
phenotype_term:
preferred_term: Congestive heart failure
term:
id: HP:0001635
label: Congestive heart failure
evidence:
- reference: PMID:39681440
reference_title: "[Correlation between genotype and clinical phenotype in hypertrophic cardiomyopathy families with MYH7-R453C mutation]."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
2(F1Ⅱ2, F3Ⅱ1) died from heart failure during the follow-up period.
explanation: >-
Deaths from heart failure among MYH7-R453C carriers evidence heart failure
as a clinical endpoint of the disease.
genetic:
- name: MYH7
gene_term:
preferred_term: MYH7
term:
id: hgnc:7577
label: MYH7
relationship_type: CAUSATIVE
frequency: >-
With MYBPC3, one of the two commonest genetic causes of hypertrophic
cardiomyopathy: nearly 40% of identified HCM-causing mutations fall in
beta-cardiac myosin.
case_fractions:
- population: Identified HCM-causing mutations (genotyped probands)
case_fraction_percent: 40.0
notes: >-
This is a share of identified HCM-causing mutations, not a share of all
hypertrophic cardiomyopathy cases. The two differ because a substantial
fraction of clinically diagnosed HCM is genotype-negative, so the figure
overstates the share of the whole disease population and is recorded
with that denominator named explicitly.
evidence:
- reference: PMID:31213605
reference_title: "β-Cardiac myosin hypertrophic cardiomyopathy mutations release sequestered heads and increase enzymatic activity."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Nearly 40 percent of HCM-causing mutations are found in human
β-cardiac myosin.
explanation: >-
Directly states the beta-cardiac myosin share of HCM-causing
mutations.
evidence:
- reference: CGGV:assertion_31325c90-05cb-4db0-9372-e4f705cd5c82-2023-07-12T160000.000Z
reference_title: "MYH7 / hypertrophic cardiomyopathy (Definitive)"
supports: SUPPORT
evidence_source: OTHER
snippet: >-
MYH7 | HGNC:7577 | 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: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: >-
The cohort is sarcomere-mutation carriers across genes rather than MYH7
carriers, so this is class-level evidence that a sarcomere genotype
shifts age at presentation and family history. Curated PARTIAL for that
reason; the same study's finding of no outcome difference between MYH7
and MYBPC3 carriers is recorded in this entry's pathophysiology.
treatments:
- name: Mavacamten (Cardiac Myosin Inhibitor)
description: >-
Mavacamten is a small-molecule allosteric inhibitor of cardiac myosin ATPase
that reduces the number of force-generating actin-myosin cross-bridges,
stabilizing myosin in the energy-sparing super-relaxed state. It directly
counteracts the hypercontractility that is the central abnormality of HCM, and
is approved for symptomatic obstructive hypertrophic cardiomyopathy; because
beta-cardiac myosin is the MYH7 gene product, the drug acts on the same motor
that carries the CMH1 lesion.
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: mavacamten
term:
id: CHEBI:756998
label: mavacamten
target_mechanisms:
- target: Destabilization of the Autoinhibited Super-Relaxed State
treatment_effect: INHIBITS
description: >-
Mavacamten stabilizes the super-relaxed state and reduces the number of
heads available for force generation, directly opposing the SRX
destabilization that drives hypercontractility.
evidence:
- reference: PMID:40118457
reference_title: "Dynamics of β-cardiac myosin between the super-relaxed and disordered-relaxed states."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
cardiac myosin inhibitor mavacamten slows nucleotide release by an equal
factor for both heavy meromyosin and subfragment 1, thus only indirectly
influencing the occupancy time of the SRX state.
explanation: >-
Establishes mavacamten's biochemical action on beta-cardiac myosin
nucleotide handling and its effect on SRX-state occupancy, the node it
targets.
evidence:
- reference: PMID:32871100
reference_title: "Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Cardiac muscle hypercontractility is a key pathophysiological abnormality
in hypertrophic cardiomyopathy, and a major determinant of dynamic left
ventricular outflow tract (LVOT) obstruction.
explanation: >-
The pivotal phase 3 trial establishing the rationale and use of a cardiac
myosin inhibitor targeting hypercontractility in obstructive HCM.
- name: Septal Reduction (Surgical Myectomy)
description: >-
Surgical septal myectomy relieves severe drug-refractory left ventricular
outflow tract obstruction by resecting hypertrophied basal septal muscle.
therapeutic_modality: SURGERY
treatment_term:
preferred_term: septal myectomy
term:
id: NCIT:C51591
label: Myectomy
- name: Implantable Cardioverter-Defibrillator
description: >-
An implantable cardioverter-defibrillator provides secondary or primary
prevention of sudden cardiac death in patients judged to be at high arrhythmic
risk, terminating malignant ventricular arrhythmia.
therapeutic_modality: DEVICE
treatment_term:
preferred_term: implantable cardioverter-defibrillator placement
term:
id: NCIT:C80435
label: Implantable Cardioverter-Defibrillator Placement
clinical_trials:
- name: NCT01912534
phase: PHASE_II
status: COMPLETED
description: >-
VANISH (Valsartan for Attenuating Disease Evolution in Early Sarcomeric
Hypertrophic Cardiomyopathy) tested whether the angiotensin receptor blocker
valsartan can modify disease progression in young carriers of sarcomeric gene
mutations, including MYH7, with early-stage HCM.
target_phenotypes:
- preferred_term: Hypertrophic cardiomyopathy
term:
id: HP:0001639
label: Hypertrophic cardiomyopathy
evidence:
- reference: PMID:31813281
reference_title: "Baseline Characteristics of the VANISH Cohort."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
targeted young sarcomeric gene mutation carriers with early-stage
hypertrophic cardiomyopathy (HCM) to test whether valsartan can modify
disease progression.
explanation: >-
Describes the VANISH trial's design and its enrollment of young sarcomeric
(including MYH7) mutation carriers with early HCM.
references:
- reference: PMID:20301725
title: Nonsyndromic Hypertrophic Cardiomyopathy Overview.
tags:
- GeneReviews
notes: >-
Scope and mechanism contrast with CMH4 (MYBPC3). CMH1 is curated as the
MYH7/beta-cardiac myosin form because MYH7 is, with MYBPC3, one of the two
commonest genetic causes of HCM and was the founding molecular diagnosis of the
field (R403Q, 1990). It is deliberately contrasted with the MYBPC3 entry: MYBPC3
disease is predominantly truncating and acts by haploinsufficiency (loss of the
cMyBP-C brake), whereas MYH7 disease is predominantly missense and acts by a
gain of contractile function in a stably expressed mutant motor (super-relaxed
state destabilization, raised intrinsic force, increased tension cost). Both
converge on the same maladaptive-remodeling module.
Allele-heterogeneity caveat preserved on the pathograph: not every MYH7 mutation
shifts the SRX-DRX equilibrium (PMID:40118457), so the super-relaxed-state arm
is curated as the mechanism of a large subset of alleles rather than a universal
one, and the motor-force arm (intrinsic force, tension cost) is curated
separately. At the cohort level MYH7 and MYBPC3 do not differ significantly
across pooled clinical features (PMID:23674365), so the entry does not assert
MYH7 as a uniformly more severe genotype.
Curating this entry deletes the stub stubs/Hypertrophic_Cardiomyopathy_1.yaml
and closes the highest-value gap named in the Familial Hypertrophic
Cardiomyopathy grouping notes. This entry is added as a member of that grouping.
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 MYH7 cohort and pedigree
literature cited throughout, principally PMID:28912181, PMID:23674365,
PMID:32871100, PMID:24928957, PMID:39681440.