Hypertrophic Cardiomyopathy 8

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Classifications

Harrison's Part

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Inheritance

2

Autosomal Dominant HP:0000006

Most reported MYL3 hypertrophic cardiomyopathy families segregate a heterozygous missense variant in an autosomal dominant pattern, with incomplete penetrance and late onset described for at least one variant. ClinGen's Hypertrophic Cardiomyopathy Gene Curation Expert Panel classifies the MYL3-hypertrophic cardiomyopathy relationship as Definitive with autosomal dominant inheritance. Penetrance is incomplete, age-dependent, and allele-dependent: a meta-analysis of relatives ascertained by cascade screening puts MYL3 at about 32%, the lowest of the definitive sarcomere genes, while allele-specific pedigree estimates span 40% for p.V79I to 88% for p.R94H. Those three figures are not interchangeable and should not be averaged — the ~32% value is a pooled cross-study estimate for nonproband relatives found by cascade screening, whereas 40% and 88% are single-pedigree, allele-specific values whose spread is itself the finding. Both pedigree estimates are additionally age-confounded: in the p.V79I family the mean age of nonpenetrant carriers was 15 against 47 for penetrant carriers.

Autosomal dominant inheritance Penetrance: INCOMPLETE Penetrance %: 32-88 Expressivity: VARIABLE

Show evidence (5 references)

CGGV:assertion_d74b9d56-4f2a-4479-8913-1d96ddc28592-2021-06-07T145050.605Z SUPPORT Other

ClinGen classifies the MYL3-hypertrophic cardiomyopathy gene-disease relationship as definitive with autosomal dominant inheritance.

PMID:37929589 SUPPORT Human Clinical

"Penetrance varied from ≈32% for MYL3 (myosin light chain 3) to ≈55% for MYBPC3 (myosin-binding protein C3), ≈60% for TNNT2 (troponin T2) and TNNI3 (troponin I3), and ≈65% for MYH7 (myosin heavy chain 7)."

Places MYL3 penetrance at the bottom of the definitive sarcomere genes in a pooled meta-analysis of cascade-screened relatives, moving the estimate beyond the single-pedigree figure previously available.

PMID:37929589 SUPPORT Human Clinical

"The penetrance across all genes in nonproband relatives carrying P/LP variants identified during cascade screening was 57%"

Establishes the ascertainment context of the ~32% MYL3 figure — it is a cascade-screening estimate in nonproband relatives, benchmarked against a 57% all-gene average.

+ 2 more references

Autosomal Recessive HP:0000007

A distinct recessive presentation is documented: three siblings homozygous for MYL3 Glu143Lys developed severe childhood-onset cardiomyopathy with mid-cavitary hypertrophy and restrictive physiology, while family members carrying a single Glu143Lys allele had normal echocardiograms and ECGs even in late adulthood. Distinct variants in the same gene can therefore act dominantly or recessively.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:12021217 SUPPORT Human Clinical

"Family members with one Glu143Lys allele had normal echocardiograms and ECGs, even in late adulthood, whereas those with two mutant alleles developed severe cardiomyopathy in childhood."

Demonstrates a recessive mode of inheritance for the MYL3 Glu143Lys allele, with unaffected heterozygous carriers.

PMID:12021217 SUPPORT Human Clinical

"Distinct mutations affecting the same sarcomeric protein can cause either dominant or recessive cardiomyopathy."

States the allele-dependent dual inheritance mode for the myosin essential light chain.

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Discussions and Knowledge Gaps

4

What is the natural history, penetrance, and sudden-death risk of MYL3-related hypertrophic cardiomyopathy, and does MYL3 genotype modify outcome relative to other sarcomeric genes?

KNOWLEDGE GAP OPEN myl3_natural_history_gap

Attached to

pathophysiology#MYL3 Essential Light Chain Variant — Altered Lever-Arm and Actin Contact phenotypes#Sudden Cardiac Death

MYL3 is a definitive hypertrophic cardiomyopathy gene, but published human data are limited to single families and case reports. Penetrance is the one dimension where this has partly improved: a meta-analysis of cascade-screened nonproband relatives places MYL3 at roughly 32%, the lowest of the definitive sarcomere genes, and allele-specific pedigree estimates run from 40% (p.V79I) to 88% (p.R94H) — so penetrance is now bounded, but only as a pooled cross-study figure plus two single-pedigree values, with no prospective MYL3 cohort behind any of them and a spread wide enough that no single number can be quoted to a family. The rest of the natural history remains genuinely unmeasured: sudden death is asserted as an association without a denominator, no MYL3-stratified outcome cohort exists, and no MYL3-specific survival curve, arrhythmia rate, atrial fibrillation incidence, or stroke rate has been published. Consequently every management recommendation in this entry is extrapolated from hypertrophic cardiomyopathy generally rather than from MYL3 evidence.

Does MYL3 Glu143Lys act through loss of function, as originally proposed from the human recessive pedigree, or through myosin hypercontractility, as characterised in transgenic mice?

CONTROVERSY OPEN myl3_loss_of_function_vs_hypercontractility

Attached to

pathophysiology#Thick Filament Interface Disruption and Loss of Super-Relaxed State genetic#MYL3 Glu143Lys (Recessive Allele)

The human recessive pedigree inferred a loss-of-function mechanism from the requirement for two mutant alleles and the normal phenotype of heterozygotes, and a later study of three consanguineous families found biallelic nonsense and splice-acceptor MYL3 alleles with failure of zebrafish rescue — strong independent support for genuine loss of function in the recessive form. Transgenic E143K mice, by contrast, show increased duty ratio, increased actin affinity, increased actin-activated ATPase and stabilisation of the super-relaxed state — a hypercontractile, not hypomorphic, molecular phenotype. The most likely reconciliation is that MYL3 disease is mechanistically split (dominant missense alleles acting by altered cross-bridge mechanics; recessive null alleles acting by ELC insufficiency), but this has not been shown directly, and it matters because myosin-inhibitor therapy is rational only under the hypercontractility model and could be harmful under the deficiency model.

Show evidence (1 reference)

PMID:33288880 SUPPORT Human Clinical

"There are, however, no reports of DCM associated with MYL3 variants or cardiomyopathy associated with likely ELC deficiency due to nonsense or essential splice acceptor variants in MYL3."

Frames ELC deficiency from null alleles as a mechanism distinct from the previously described missense disease, motivating the two-mechanism reading.

Do the transgenic MYL3 mouse models faithfully reproduce human MYL3 hypertrophic cardiomyopathy, given that Tg-A57G mice develop eccentric hypertrophy with enhanced left ventricular cavity dimension rather than the concentric hypertrophy that defines the human disease?

HUMAN MODEL MISMATCH OPEN myl3_mouse_to_human_fidelity

Attached to

pathophysiology#Cardiomyocyte Hypertrophy, Myocardial Stiffness and Fibrosis phenotypes#Myocardial Fibrosis

Most of the mechanistic content in this entry — super-relaxed state inhibition, calcium sensitisation, fibrosis, progressive remodeling — comes from transgenic mice expressing human MYL3 A57G or E143K. Echocardiography in Tg-A57G mice showed a phenotype of eccentric hypertrophy with enhanced left ventricular cavity dimension and no change in wall thickness, which is not the human hypertrophic cardiomyopathy morphology; and E143K, a recessive allele in humans, is modeled as a dominantly expressed transgene producing restrictive cardiomyopathy. The translational validity of these models for human CMH8 therefore remains an open question rather than an absence of evidence.

Show evidence (1 reference)

PMID:23748425 SUPPORT Model Organism

"Echocardiography examination showed a phenotype of eccentric hypertrophy in Tg-A57G mice, enhanced left ventricular (LV) cavity dimension without changes in LV posterior/anterior wall thickness."

Documents the eccentric, cavity-dilating murine morphology that differs from the concentric hypertrophy of human hypertrophic cardiomyopathy.

Is skeletal myopathy a genuine and generalisable component of MYL3-related disease, or was it specific to the original 1996 kindreds?

KNOWLEDGE GAP OPEN myl3_skeletal_muscle_gap

Attached to

pathophysiology#Skeletal Muscle Involvement phenotypes#Skeletal Myopathy

The founding report described abnormal skeletal muscle alongside cardiac hypertrophy for essential and regulatory light chain mutations together, but later MYL3 case reports and cohort screens are cardiac-only and do not report systematic skeletal muscle evaluation. Whether skeletal involvement is under-ascertained or genuinely absent from most MYL3 genotypes is unknown, and no MYL3 series reports muscle biopsy or CK data.

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Pathophysiology

7

MYL3 Essential Light Chain Variant — Altered Lever-Arm and Actin Contact

MYL3 encodes the ventricular/slow-skeletal myosin essential light chain (ELC), one of the two light-chain pairs of the hexameric muscle myosin. The light chains stabilize the long alpha-helical neck of the myosin head, and the cardiac-specific N-terminal extension of the ELC contacts actin and prepositions the cross-bridge for force production. Missense variants (e.g. Met149Val, Ala57Gly, Glu56Gly, Glu177Gly, Val79Ile, Glu143Lys) substitute residues in the ELC that lie at contact surfaces between the light chain and the myosin lever arm, altering cross-bridge mechanics rather than abolishing the protein. Subtle changes in ELC sequence are sufficient to alter cross-bridge properties and produce a pathological phenotype.

MYL3 hgnc:7584

myosin heavy chain binding GO:0032036 ⚠ ABNORMAL

myosin filament GO:0032982

Myocardium UBERON:0002349

Downstream

Thick Filament Interface Disruption and Loss of Super-Relaxed State

Altered Actomyosin Cross-Bridge Kinetics and Calcium Sensitivity

Skeletal Muscle Involvement MYL3 is expressed in slow skeletal muscle as well as ventricle, so the same variant can produce a skeletal myopathy alongside the cardiac phenotype.

Show evidence (4 references)

PMID:8673105 SUPPORT Human Clinical

"We report here the identification of distinct missense mutations in a skeletal/ventricular ELC and RLC, each of which are associated with a rare variant of cardiac hypertrophy as well as abnormal skeletal muscle."

Original identification of an essential light chain (MYL3) missense mutation as a cause of cardiac hypertrophy.

PMID:8673105 SUPPORT In Vitro

"We show that myosin containing the mutant ELC has abnormal function, map the mutant residues on the three-dimensional structure of myosin and suggest that the mutations disrupt the stretch activation response of the cardiac papillary muscles."

Demonstrates that the mutant essential light chain confers abnormal myosin function and localizes the defect structurally.

PMID:22957257 SUPPORT Human Clinical

"The mutation affects a conserved valine replacing it with a larger isoleucine residue in the region of contact between the light chain and the myosin lever arm."

Locates a pathogenic MYL3 variant at the light chain-lever arm contact surface, supporting the lever-arm mechanism.

+ 1 more reference

Thick Filament Interface Disruption and Loss of Super-Relaxed State

Pathogenic MYL3 variants map onto molecular interfaces of the cardiac thick filament, including interfaces of the myosin interacting-heads motif (IHM) that hold myosin heads in the energy-conserving super-relaxed (SRX) state. Destabilizing these interfaces shifts myosin from SRX toward the disordered relaxed (DRX) state, increasing the number of heads available to interact with actin and raising ATPase activity. In transgenic mice carrying the HCM-associated A57G ELC mutation, the SRX state is inhibited and cross-bridges become hypercontractile; the contrasting RCM-associated E143K ELC mutation instead stabilizes SRX, indicating that MYL3 variants can move the SRX/DRX equilibrium in opposite directions.

ATP hydrolysis activity GO:0016887 ↑ INCREASED

myosin filament GO:0032982

Downstream

Altered Actomyosin Cross-Bridge Kinetics and Calcium Sensitivity

Show evidence (4 references)

PMID:42372158 SUPPORT Computational

"We identified HCM variants residing in 30 molecular interfaces of the complex thick filament interactome, including the two main interfaces of the myosin interacting-heads motif (IHM), and interfaces involving the MHC, essential and regulatory light chains, and cMyBP-C."

Maps pathogenic variants — including MYL3 (essential light chain) variants — onto thick filament and IHM interfaces, supporting interface disruption as the proximal structural lesion.

PMID:42372158 SUPPORT Human Clinical

"We demonstrated earlier disease onset and adverse outcomes in HCM patients with pathogenic variants within vs. outside of molecular interfaces, emphasizing their importance in normal thick filament function and improving risk stratification of patients."

Links interface location of thick filament variants to clinical onset and outcome, giving the structural mechanism clinical traction.

PMID:32034976 SUPPORT Model Organism

"The hypercontractile activity of A57G-ELC cross-bridges was manifested by the inhibition of the SRX state, increased number of myosin heads available for interaction with actin, and higher ATPase activity."

Directly demonstrates SRX destabilization and hypercontractility for an HCM-causing MYL3 (ELC) mutation in transgenic mice.

+ 1 more reference

Altered Actomyosin Cross-Bridge Kinetics and Calcium Sensitivity

MYL3 variants change how the cross-bridge cycles. Recombinant myosin subfragment-1 carrying the cardiomyopathic ELC substitutions E56G, M149V and E177G all significantly increase the calcium sensitivity of thin filament sliding, and M149V additionally upregulates actin-activated ATPase — although the specific effect on actin-myosin interaction differs between variants. In transgenic A57G mice, calcium sensitivity of force is increased with a reduction in maximal force per cross section, alongside a mutation-induced increase in myocardial stiffness. Downstream of the myofilament change, contractility and energetics are dysregulated.

Cardiac muscle cell CL:0000746

regulation of cardiac muscle contraction GO:0055117 ↕ DYSREGULATED muscle filament sliding GO:0030049 ⚠ ABNORMAL

microfilament motor activity GO:0000146 ⚠ ABNORMAL

Myocardium UBERON:0002349

Downstream

Cardiomyocyte Hypertrophy, Myocardial Stiffness and Fibrosis Sustained myofilament dysfunction activates cardiomyopathic signalling and compensatory hypertrophy.

Show evidence (3 references)

PMID:36509720 SUPPORT In Vitro

"All mutations significantly increased the Ca2+-sensitivity of the sliding velocity of thin filaments on the surface with immobilized myosin in the in vitro motility assay"

Shows that three MYL3 cardiomyopathic ELC substitutions increase myofilament calcium sensitivity in a reconstituted motility assay.

PMID:36509720 SUPPORT In Vitro

"Therefore, despite the fact that all studied mutations in ELCv are involved in the development of hypertrophic cardiomyopathy, the mechanisms of their influence on the actin-myosin interaction are different."

Documents variant-specific heterogeneity in how MYL3 mutations perturb the actomyosin interaction.

PMID:23748425 SUPPORT Model Organism

"Compared with the Tg-WT, there was a significant increase in the Ca²⁺ sensitivity of force (ΔpCa₅₀ ≅ 0.1) and an ~1.3-fold decrease in maximal force per cross section of muscle observed in the mutant preparations."

Quantifies the increase in calcium sensitivity and loss of maximal force caused by an HCM-associated MYL3 mutation in transgenic mouse and protein-exchanged muscle preparations.

Cardiomyocyte Hypertrophy, Myocardial Stiffness and Fibrosis

Chronically altered myofilament function drives compensatory cardiomyocyte hypertrophy with increased passive stiffness and interstitial fibrosis. Transgenic A57G-ELC mice show a high level of fibrosis and hypertrophy with increased heart weight-to-body weight ratio and enlarged myocytes; the E143K-ELC model develops ultrastructural defects and fibrosis that worsen with age together with upregulation of stress-response and collagen genes. In humans, histopathology of an infant with a MYL3 variant contributed to the diagnosis of severe progressive hypertrophic cardiomyopathy.

Cardiac muscle cell CL:0000746 Cardiac fibroblast CL:0002548

cardiac muscle hypertrophy GO:0003300 ↑ INCREASED extracellular matrix organization GO:0030198 ↑ INCREASED

Heart left ventricle UBERON:0002084

Downstream

Diastolic Dysfunction and Restrictive Physiology

Left Ventricular Hypertrophy

Myocardial Fibrosis

Show evidence (3 references)

PMID:23748425 SUPPORT Model Organism

"Consistently, the hearts of Tg-A57G mice demonstrated a high level of fibrosis and hypertrophy manifested by increased heart weight-to-body weight ratios"

Links the MYL3 A57G myofilament lesion to hypertrophy and fibrosis at the tissue level in vivo.

PMID:23748425 SUPPORT Model Organism

"These and other contributing factors such as increased myocardial stiffness and fibrosis most likely activate cardiomyopathic signaling pathways leading to pathologic cardiac remodeling."

States the proposed causal chain from myofilament dysfunction through stiffness and fibrosis to pathological remodeling.

PMID:28371863 SUPPORT Model Organism

"The hearts of mutant-mice demonstrated ultrastructural defects and fibrosis that progressively worsened in senescent animals"

Shows progressive fibrosis and sarcomeric ultrastructural disruption caused by a MYL3 essential light chain mutation.

Diastolic Dysfunction and Restrictive Physiology

Stiff, hypertrophied, fibrotic ventricles impair filling. In the E143K-ELC mouse model, augmented active and passive tension in skinned papillary muscle fibres accompanies stiff ventricles and physiological, morphologic and metabolic remodeling consistent with restrictive cardiomyopathy; in humans, homozygous MYL3 Glu143Lys produced mid-cavitary hypertrophy with restrictive physiology in childhood. In heterozygous adult-onset disease, outflow obstruction and left atrial dilation follow from the same hypertrophic substrate.

Heart UBERON:0000948

Downstream

Congestive Heart Failure

Left Atrial Dilation

Atrial Remodeling and Intracavitary Stasis Impaired filling raises left atrial pressure and dilates the atrium, creating the substrate for atrial fibrillation and stasis-driven thrombus formation.

Show evidence (2 references)

PMID:28371863 SUPPORT Model Organism

"As a result of the E143K-induced myosin hypercontractility, the hearts of RCM mice model exhibited cardiac dysfunction, stiff ventricles and physiological, morphologic, and metabolic remodelling consistent with the development of RCM."

Connects MYL3-driven myosin hypercontractility to ventricular stiffening and restrictive physiology.

PMID:12021217 SUPPORT Human Clinical

"We studied a family with early-onset cardiomyopathy in 3 siblings, characterized by mid-cavitary hypertrophy and restrictive physiology."

Human counterpart of the restrictive phenotype, in siblings homozygous for MYL3 Glu143Lys.

Atrial Remodeling and Intracavitary Stasis

Two stasis-generating substrates converge on cardioembolism in this genotype. Diastolic impairment dilates the left atrium and predisposes to atrial fibrillation, which in the reported MYL3 mid-cavity case proved refractory to both pharmacological and direct-current cardioversion. Independently, the mid-ventricular obstruction characteristic of MYL3 disease can progress to a left ventricular apical aneurysm — a blind, akinetic pouch that is separately recognised as predisposing to thromboembolisation. Both routes generate cardioembolic risk, which is why anticoagulation rather than rhythm control alone is the operative management decision. In the index case the cerebrovascular events were judged cardioembolic and long-term anticoagulation was started, at the cost of a subsequent extra-axial haemorrhage.

Heart left atrium UBERON:0002079

Downstream

Atrial Fibrillation

Cardioembolic Stroke Stasis in a fibrillating atrium or an akinetic apical aneurysm permits thrombus formation and systemic embolization.

Show evidence (2 references)

PMID:35288424 SUPPORT Human Clinical

"The patient had normal epicardial coronary arteries, but presented with recurrent cerebrovascular events."

Documents recurrent cerebrovascular events in a genotyped MYL3 patient with mid-cavity obstruction and apical aneurysm, with coronary disease excluded as the cause.

PMID:35288424 SUPPORT Human Clinical

"The development of LV apical aneurysm may predispose patients to complications involving ventricular tachyarrhythmias, thromboembolisations and ventricular rupture in the context of immature aneurysms."

States the apical aneurysm to thromboembolism link that makes this arm genotype-relevant rather than generic hypertrophic cardiomyopathy context.

Skeletal Muscle Involvement

MYL3 encodes the light chain shared by ventricular and slow skeletal muscle. The founding report of essential light chain disease described the associated hypertrophy as occurring together with abnormal skeletal muscle, making a skeletal myopathy part of the original MYL3 phenotype. This arm is much less well characterised than the cardiac arm and has not been a consistent finding in later MYL3 case reports.

skeletal muscle contraction GO:0003009 ⚠ ABNORMAL

Downstream

Skeletal Myopathy

Show evidence (1 reference)

PMID:8673105 SUPPORT Human Clinical

"a rare variant of cardiac hypertrophy as well as abnormal skeletal muscle"

Skeletal muscle abnormality is reported alongside the cardiac phenotype in the founding essential light chain paper. PARTIAL because the abstract reports ELC and RLC mutations together and does not detail the skeletal findings attributable to MYL3 alone.

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Histopathology

1

Sarcomeric ultrastructural disruption with interstitial and replacement fibrosis

Myocardial fibrosis progressing with age, together with sarcomeric ultrastructural defects, is the tissue-level correlate of MYL3 disease. The direct observations are from transgenic mouse models of the MYL3 A57G and E143K essential light chain mutations; in humans, histopathology contributed to the diagnosis in the infantile MYL3 case, but no published MYL3 series describes the human histological pattern in detail.

Show evidence (2 references)

PMID:28371863 SUPPORT Model Organism

"The hearts of mutant-mice demonstrated ultrastructural defects and fibrosis that progressively worsened in senescent animals"

Direct histological and ultrastructural observation in a MYL3 essential light chain mutant model.

PMID:23594557 SUPPORT Human Clinical

"We report on genetic and histopathological findings in a 3-month-old infant presenting with severe progressive HCM arising from a mutation in the gene encoding the essential light chain of myosin (MYL3)."

Establishes that human MYL3 histopathology has been examined and contributed to a diagnosis. PARTIAL because the abstract states that histopathological findings were obtained without describing them, so it cannot support any specific tissue finding.

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Pathograph

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Phenotypes

14

Cardiovascular 8

Left Ventricular Hypertrophy VERY_FREQUENT HP:0001712

Show evidence (1 reference)

PMID:22957257 SUPPORT Human Clinical

"The patient had HCM with left ventricular hypertrophy (max WT 21 mm), a resting left ventricular outflow gradient of 36 mm Hg, and left atrial dilation (54 mm)."

Documents left ventricular hypertrophy in a genotyped MYL3 p.V79I proband.

Non-Sustained Ventricular Tachycardia HP:0004756

Show evidence (1 reference)

PMID:35288424 SUPPORT Human Clinical

"with Holter monitoring assessment displaying segments of non-sustained ventricular tachycardia"

Documents ventricular arrhythmia in a MYL3 carrier.

Severe Infantile-Onset Hypertrophic Cardiomyopathy VERY_RARE HP:0001639

Course: PROGRESSIVE

Show evidence (2 references)

PMID:23594557 SUPPORT Human Clinical

"We report on genetic and histopathological findings in a 3-month-old infant presenting with severe progressive HCM arising from a mutation in the gene encoding the essential light chain of myosin (MYL3)."

Documents infantile-onset severe hypertrophic cardiomyopathy caused by a MYL3 variant.

PMID:23594557 SUPPORT Human Clinical

"Although, MYL3 mutations have been previously associated with adult-onset HCM, it has not been seen in infantile forms."

Establishes infantile presentation as exceptional against the usual adult-onset MYL3 course.

Atrial Fibrillation HP:0005110

Frequency deliberately omitted — documented in a single genotyped MYL3 case; no MYL3 series reports an atrial fibrillation rate.

Show evidence (1 reference)

PMID:35288424 SUPPORT Human Clinical

"A couple of years later, she was admitted with arrhythmic disturbances consistent with atrial flutter and atrial fibrillation."

Documents atrial fibrillation in a genotyped MYL3 carrier.

Cardioembolic Stroke HP:0001297

Frequency deliberately omitted — a single genotyped MYL3 case. HPO has no cardioembolic-stroke term, so the general Stroke term carries a narrower preferred_term, following the same convention used for non-sustained ventricular tachycardia in this entry.

Show evidence (2 references)

PMID:35288424 SUPPORT Human Clinical

"The patient had normal epicardial coronary arteries, but presented with recurrent cerebrovascular events."

Documents recurrent cerebrovascular events in a MYL3 carrier with coronary disease excluded.

PMID:35288424 SUPPORT Human Clinical

"The pathophysiology of the multiple CVAs were deemed likely to be of cardioembolic origin."

Attributes the cerebrovascular events to a cardioembolic mechanism, which is what makes them a downstream consequence of the atrial and apical substrate rather than incidental comorbidity.

Congestive Heart Failure HP:0001635

Curated from the mouse model plus the general hypertrophic cardiomyopathy course; no MYL3-specific human heart failure incidence has been published.

Show evidence (1 reference)

PMID:28371863 SUPPORT Model Organism

"these changes were hypothesized to contribute to diastolic disturbance and to mild systolic dysfunction"

Supports progression to contractile dysfunction in the MYL3 mutant model. PARTIAL because the mechanism is stated as a hypothesis and the data are murine.

Sudden Cardiac Death HP:0001645

Frequency omitted deliberately: the sources establish the association and document events in specific pedigrees, but no denominator-based MYL3 sudden-death risk estimate exists.

Show evidence (3 references)

PMID:22957257 SUPPORT Human Clinical

"Mutations in MYL3, encoding the essential light chain of myosin, are rare and have been associated with sudden death."

Asserts an association between MYL3 mutations and sudden death. PARTIAL because it is a background statement without a quantified risk.

PMID:33288880 SUPPORT Human Clinical

"Affected individuals presented with hypertrophic or dilated cardiomyopathy of variable severity from infantile- to early adulthood-onset and sudden cardiac death."

Documents sudden cardiac death among affected members of three consanguineous families carrying homozygous MYL3 variants.

PMID:35288424 SUPPORT Human Clinical

"The patient had a positive family history for sudden cardiac death."

Family history of sudden cardiac death in a MYL3-genotyped kindred.

Incomplete Penetrance and Borderline Phenotype in Carriers Hypertrophic cardiomyopathy HP:0001639

Show evidence (2 references)

PMID:22957257 SUPPORT Human Clinical

"Cascade screening revealed a further nine heterozygote mutation carriers, three of whom had ECG and/or echocardiographic abnormalities but did not fulfil diagnostic criteria for HCM."

Documents subdiagnostic phenotypes among MYL3 heterozygotes.

PMID:22957257 SUPPORT Human Clinical

"The penetrance, if we consider this borderline HCM the phenotype of the p.V79I mutation, was 40%, but the mean age of the nonpenetrant mutation carriers is 15, while the mean age of the penetrant mutation carriers is 47."

Quantifies incomplete, age-dependent penetrance for a MYL3 variant.

Musculoskeletal 1

Skeletal Myopathy HP:0003198

Low-confidence phenotype. The founding paper reports ELC and RLC mutations together, so the skeletal muscle finding cannot be cleanly attributed to MYL3 alone from the abstract.

Show evidence (2 references)

PMID:8673105 SUPPORT Human Clinical

"a rare variant of cardiac hypertrophy as well as abnormal skeletal muscle"

Skeletal muscle abnormality accompanies the cardiac phenotype in the original essential/regulatory light chain report.

PMID:33288880 REFUTE Human Clinical

"Affected individuals from the three families showed no evidence of muscle weakness by neurological examination or by history."

Explicitly negative skeletal muscle assessment across three MYL3 cardiomyopathy families, arguing that skeletal myopathy is not a general feature of MYL3 disease and may be specific to the original Poetter kindreds.

Other 5

Left Ventricular Outflow Tract Obstruction HP:0032092

Frequency is deliberately omitted — obstruction is documented in single MYL3 cases, and no MYL3 cohort reports the proportion with obstruction.

Show evidence (1 reference)

PMID:22957257 SUPPORT Human Clinical

"a resting left ventricular outflow gradient of 36 mm Hg"

Records a resting outflow tract gradient in a MYL3 mutation carrier.

Left Atrial Dilation Left atrial enlargement HP:0031295

Show evidence (1 reference)

PMID:22957257 SUPPORT Human Clinical

"left atrial dilation (54 mm)"

Documents left atrial dilation in the MYL3 p.V79I proband.

Restrictive Physiology with Mid-Cavitary Hypertrophy Restrictive cardiomyopathy HP:0001723

Show evidence (1 reference)

PMID:12021217 SUPPORT Human Clinical

"characterized by mid-cavitary hypertrophy and restrictive physiology"

Defines the restrictive, mid-cavitary phenotype of homozygous MYL3 Glu143Lys disease.

Mid-Ventricular Obstruction with Left Ventricular Apical Aneurysm Left ventricular aneurysm HP:6000144

Single case report; frequency deliberately omitted. Mid-cavitary hypertrophy itself is corroborated independently by the recessive Glu143Lys family (PMID:12021217).

Show evidence (2 references)

PMID:35288424 SUPPORT Human Clinical

"Cardiac MRI detected positive features of left ventricular mid-cavity obstruction, left ventricular apical aneurysm and delayed gadolinium enhancement"

Documents mid-cavity obstruction and apical aneurysm in a genotyped MYL3 patient.

PMID:35288424 SUPPORT Human Clinical

"To our knowledge, the presence of a left ventricular apical aneurysm has not been previously reported in literature concerning the MYL3 gene mutation. The presence of this abnormality further increases the risk of sudden cardiac death."

Establishes the apical aneurysm as a novel MYL3 finding and links it to elevated sudden-death risk.

Myocardial Fibrosis HP:0001685

Supporting evidence here is from transgenic mouse models of MYL3 (ELC) mutations, not from human MYL3 carriers; see the HUMAN_MODEL_MISMATCH discussion item.

Show evidence (1 reference)

PMID:28371863 SUPPORT Model Organism

"The hearts of mutant-mice demonstrated ultrastructural defects and fibrosis that progressively worsened in senescent animals"

Progressive myocardial fibrosis in a MYL3 essential light chain mutant mouse model.

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Genetic Associations

3

MYL3 Missense Variants (Pathogenic Variants)

Gene: MYL3 hgnc:7584 relationship_type: CAUSATIVE

Autosomal Dominant

Show evidence (5 references)

CGGV:assertion_d74b9d56-4f2a-4479-8913-1d96ddc28592-2021-06-07T145050.605Z SUPPORT Other

ClinGen gene-disease validity classification for MYL3 and hypertrophic cardiomyopathy.

PMID:30681346 SUPPORT Human Clinical

"Of 33 HCM genes, only 8 (24%) were categorized as definitive ( MYBPC3, MYH7, TNNT2, TNNI3, TPM1, ACTC1, MYL2, and MYL3)"

Independent systematic gene-disease validity curation placing MYL3 among the eight definitive hypertrophic cardiomyopathy genes.

PMID:22957257 SUPPORT Human Clinical

"Genotyping revealed heterozygosity for a novel missense mutation, p.V79I, in MYL3. The mutation was not found in 300 controls, and the patient had no mutations in 10 sarcomere genes."

Illustrates the missense, heterozygous, control-absent variant pattern typical of MYL3 hypertrophic cardiomyopathy.

+ 2 more references

MYL3 Glu143Lys (Recessive Allele) (Pathogenic Variants)

Gene: MYL3 hgnc:7584 relationship_type: CAUSATIVE

Autosomal Recessive

Show evidence (2 references)

PMID:12021217 SUPPORT Human Clinical

"Sequencing showed that these individuals were homozygous for a Glu143Lys substitution of a highly conserved amino acid that was absent in 150 controls."

Establishes the homozygous MYL3 Glu143Lys genotype in the affected siblings.

PMID:12021217 SUPPORT Human Clinical

"These findings, coupled with previous studies of myosin light chain structure and function in the heart, suggest a loss-of-function disease mechanism."

Records the loss-of-function interpretation offered for the recessive MYL3 allele.

MYL3 Biallelic Loss-of-Function Variants (Pathogenic Variants)

Gene: MYL3 hgnc:7584 relationship_type: CAUSATIVE

Autosomal Recessive

Show evidence (3 references)

PMID:33288880 SUPPORT Human Clinical

"and a presumable homozygous essential splice acceptor variant (c.482-1G>A, predicted to result in skipping of exon 5)."

Identifies a biallelic essential splice-acceptor MYL3 allele alongside a homozygous nonsense allele, extending the mutational spectrum beyond missense. (The nonsense and missense alleles are named in the same sentence; this bracket-free portion is quoted because the validator normalises square-bracketed protein nomenclature.)

PMID:33288880 SUPPORT Model Organism

"Morpholino knockdown of the MYL3 orthologue in zebrafish, cmlc1, resulted in compromised cardiac function, which could not be rescued by reintroduction of MYL3 carrying either the nonsense c.106G>T or the missense c.170C>A variants."

Zebrafish rescue failure provides functional support that these alleles are loss-of-function.

PMID:33288880 SUPPORT Human Clinical

"Our data demonstrate that homozygous MYL3 loss-of-function variants can cause of recessive cardiomyopathy and occurrence of sudden cardiac death, most likely due to impaired or loss of myosin essential light chain function."

States the loss-of-function conclusion for biallelic MYL3 disease.

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Medical Actions

7

Beta-Blocker and Other Negative Inotropic Pharmacotherapy

Action: Pharmacotherapy NCIT:C15986

Symptomatic management of obstructive and diastolic disease follows general hypertrophic cardiomyopathy practice — beta-blockers, non-dihydropyridine calcium channel blockers, and disopyramide. No MYL3-specific trial or cohort evidence exists; treatment is extrapolated from hypertrophic cardiomyopathy as a whole.

Cardiac Myosin Inhibition

Action: Pharmacotherapy NCIT:C15986

Agent: mavacamten aficamten CHEBI:747213

Cardiac myosin inhibitors (mavacamten) reduce the fraction of myosin heads in the disordered relaxed state and restore the super-relaxed state. This is the direct pharmacological counterpart of the MYL3 A57G lesion, which inhibits the super-relaxed state and increases the number of myosin heads available for actin interaction; the mouse work explicitly proposes normalizing myosin motor function with myosin-specific therapeutics to avert the hypercontractile state. Whether this benefit is realised in MYL3 carriers has not been tested clinically.

Mechanism Target:

INHIBITS Thick Filament Interface Disruption and Loss of Super-Relaxed State — Cardiac myosin inhibitors act on the same super-relaxed/disordered-relaxed equilibrium that MYL3 variants perturb.

Show evidence (3 references)

PMID:32871100 SUPPORT Human Clinical

"45 (37%) of 123 patients on mavacamten versus 22 (17%) of 128 on placebo met the primary endpoint"

Randomised phase 3 evidence that cardiac myosin inhibition improves exercise capacity and symptoms in obstructive hypertrophic cardiomyopathy. Enrolment was not stratified by genotype, so this establishes the drug class, not a MYL3-specific effect.

PMID:38739079 SUPPORT Human Clinical

"The results for all 10 secondary end points were significantly improved with aficamten as compared with placebo."

Independent randomised phase 3 confirmation of the myosin-inhibitor class effect with a second agent (aficamten, SEQUOIA-HCM). Also not MYL3-stratified.

PMID:28371863 SUPPORT Model Organism

"Future efforts should be directed toward normalization of myosin motor function and the use of myosin-specific therapeutics to avert the hypercontractile state of E143K-myosin and prevent pathological cardiac remodelling."

Provides the mechanistic rationale for myosin-targeted therapy in MYL3 disease. PARTIAL because it is a proposal from a mouse study, not clinical evidence of benefit in MYL3 carriers.

Implantable Cardioverter Defibrillator

Action: Implantable cardioverter-defibrillator placement Ontology label: Implantable Cardioverter-Defibrillator Placement NCIT:C80435

ICD implantation for primary or secondary prevention of sudden cardiac death in patients meeting general hypertrophic cardiomyopathy risk criteria. MYL3 genotype is not itself an established risk modifier.

Show evidence (1 reference)

PMID:35288424 SUPPORT Human Clinical

"Risk stratification for an implantable cardioverter defibrillator (ICD) was conducted due to the presence of an LV apical aneurysm, NSVT, LVSD, late gadolinium enhancement (LGE) on CMR and SCD in first-degree relatives."

Records the risk-marker set that drove the ICD decision in a genotyped MYL3 patient — general hypertrophic cardiomyopathy criteria applied to a MYL3 carrier, with the apical aneurysm as the genotype-relevant addition.

Extended Mid-Ventricular Septal Myectomy

Action: Myectomy NCIT:C51591

Surgical septal reduction for drug-refractory obstruction. This is the treatment where MYL3 morphology changes the operation rather than merely the indication: because the obstruction in this genotype is mid-cavitary rather than subaortic, relief requires an extended mid-ventricular myectomy, with papillary muscle reorientation where the papillary muscles contribute to the obstruction — not a standard subaortic myectomy. Alcohol septal ablation, the usual catheter-based alternative, is generally unsuitable here, since the septal perforator territory it targets does not supply the mid-ventricular hypertrophy.

Show evidence (2 references)

PMID:12021217 SUPPORT Human Clinical

"characterized by mid-cavitary hypertrophy and restrictive physiology"

Establishes the mid-cavitary rather than subaortic location of the obstruction, which is the anatomical premise for choosing an extended mid-ventricular myectomy. PARTIAL because the source documents the morphology, not the operation or its outcome.

PMID:35288424 SUPPORT Human Clinical

"TTE identified biatrial dilation, LV hypertrophy predominantly in the mid-ventricular segments, mid-cavitary rest gradient of 33 mm Hg, mild-to-moderate LV systolic dysfunction, grade II diastolic dysfunction and no evidence of LVOTO or SAM of the mitral valve at rest."

Independently documents a mid-cavitary gradient with explicitly absent outflow tract obstruction in a genotyped MYL3 patient. PARTIAL for the same reason — it corroborates the anatomy that dictates the procedure choice, not the procedure itself.

Heart Transplantation

Action: Heart transplantation Ontology label: Heart Transplantation NCIT:C15246

Transplantation for end-stage disease, and the marker of how severe the recessive loss-of-function form can be: the proband homozygous for the MYL3 p.Glu36Ter nonsense allele was diagnosed with dilated cardiomyopathy at age 6 and transplanted soon after, while his brother died of sudden cardiac death at age 2.

Show evidence (1 reference)

PMID:33288880 SUPPORT Human Clinical

"He underwent heart transplantation soon after diagnosis."

Documents transplantation in a genotyped biallelic MYL3 patient, the only MYL3 case in the literature to reach transplant.

Oral Anticoagulation

Action: Pharmacotherapy NCIT:C15986

Agent: anticoagulant agent NCIT:C263

Anticoagulation for cardioembolic stroke prevention, indicated by atrial fibrillation and — independently — by an akinetic left ventricular apical aneurysm with thrombus risk. In the reported MYL3 case long-term anticoagulation was started after recurrent cardioembolic cerebrovascular events, and the entry records the trade-off honestly: an extra-axial haemorrhage extending into the posterior fossa was observed and attributed to it.

Mechanism Target:

INHIBITS Atrial Remodeling and Intracavitary Stasis — Anticoagulation does not remove the stasis substrate; it blocks the thrombus-formation step that converts stasis into systemic embolization.

Show evidence (2 references)

PMID:35288424 SUPPORT Human Clinical

"Long-term anticoagulation was initiated 2 years later when the patient was admitted to a specialist stroke unit for a left corona radiata infarct."

Documents initiation of long-term anticoagulation in a genotyped MYL3 patient for cardioembolic stroke.

PMID:35288424 SUPPORT Human Clinical

"Concurrent extra-axial haemorrhage extension into the posterior fossa, potentially secondary to long-term anticoagulation, was also observed."

Records the bleeding harm attributed to the same therapy. PARTIAL because the source itself hedges the attribution ("potentially secondary to").

Genetic Counseling and Cascade Screening

Action: Genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Family evaluation is central. Cascade screening in a MYL3 family identified nine further heterozygous carriers, several with subdiagnostic ECG or echocardiographic findings, and recessive inheritance in children with cardiomyopathy must be recognised for correct family counseling.

Show evidence (2 references)

PMID:12021217 SUPPORT Human Clinical

"Recognizing recessive inheritance in children with cardiomyopathy is essential for appropriate family counseling."

Directly supports genetic counseling, and specifically recognition of recessive MYL3 inheritance, as a management action.

PMID:22957257 SUPPORT Human Clinical

"Cascade screening revealed a further nine heterozygote mutation carriers"

Demonstrates the yield of cascade family screening in a MYL3 family.

🔬

Diagnosis

4

Cardiac magnetic resonance imaging with late gadolinium enhancement

The genotype-relevant imaging study. MYL3 disease favours mid-ventricular rather than basal septal hypertrophy, and the resulting mid-cavity obliteration and apical aneurysm sit in exactly the segments echocardiography images worst. In the reported MYL3 case, cardiac MRI was what established the apical aneurysm and the delayed gadolinium enhancement, both of which then drove the ICD decision.

Cardiac magnetic resonance imaging with late gadolinium enhancement NCIT:C16809

Results: Mid-cavity obstruction, left ventricular apical aneurysm and diffuse delayed gadolinium enhancement; enhancement burden and aneurysm are themselves sudden-death risk markers.

Show evidence (1 reference)

PMID:35288424 SUPPORT Human Clinical

"Cardiac MRI detected positive features of left ventricular mid-cavity obstruction, left ventricular apical aneurysm and delayed gadolinium enhancement"

Documents the diagnostic yield of cardiac MRI in a genotyped MYL3 patient, including the two findings that changed management.

Transthoracic echocardiography with attention to mid-ventricular segments

First-line imaging, but it must be read with the MYL3 morphology in mind: the gradient to look for is mid-cavitary, and its absence at the outflow tract is not reassurance. In the reported case echocardiography found a mid-cavitary resting gradient with explicitly no outflow tract obstruction and no systolic anterior motion. Serial studies are warranted because the intracavitary gradient is documented to progress.

Transthoracic echocardiography NCIT:C16525

Results: Mid-ventricular-predominant hypertrophy, mid-cavitary resting gradient, biatrial dilation and diastolic dysfunction, typically without left ventricular outflow tract obstruction or systolic anterior motion.

Show evidence (1 reference)

PMID:35288424 SUPPORT Human Clinical

"TTE identified biatrial dilation, LV hypertrophy predominantly in the mid-ventricular segments, mid-cavitary rest gradient of 33 mm Hg, mild-to-moderate LV systolic dysfunction, grade II diastolic dysfunction and no evidence of LVOTO or SAM of the mitral valve at rest."

Records the echocardiographic pattern in a genotyped MYL3 patient, including the diagnostically important absence of outflow obstruction.

Ambulatory (Holter) electrocardiographic monitoring

Arrhythmia surveillance for sudden-death risk stratification. Detection of non-sustained ventricular tachycardia is one of the risk markers that determined the ICD recommendation in the reported MYL3 patient.

Holter monitoring NCIT:C38064

Results: Runs of non-sustained ventricular tachycardia; a positive result contributes to the sudden-death risk-marker count.

Show evidence (1 reference)

PMID:35288424 SUPPORT Human Clinical

"with Holter monitoring assessment displaying segments of non-sustained ventricular tachycardia"

Documents the arrhythmia yield of Holter monitoring in a MYL3 carrier.

Multigene hypertrophic cardiomyopathy panel testing

MYL3 is one of only eight genes with definitive evidence for hypertrophic cardiomyopathy and is on essentially all clinical panels, so a standard multigene panel — not single-gene MYL3 testing — is the appropriate first genetic test. Single-gene MYL3 testing is appropriate only for site-specific cascade testing of relatives once a familial variant is known. In consanguineous families the panel must be interpreted with recessive inheritance in mind, or a homozygous MYL3 genotype will be misread as uninformative heterozygosity.

Multigene hypertrophic cardiomyopathy panel testing NCIT:C15709

Results: Identification of a pathogenic MYL3 variant establishes the molecular diagnosis and enables cascade testing; a homozygous or compound genotype changes both the prognosis and the recurrence risk given to the family.

Deliberately omitted from this section: chromosomal microarray, karyotype, FISH, mitochondrial DNA and repeat-expansion testing. There is no copy-number or repeat mechanism in MYL3 disease (ClinGen dosage score 0), so those tests belong to the differential-diagnosis workup of syndromic or mitochondrial left ventricular hypertrophy, not to a MYL3 diagnosis.

Show evidence (2 references)

PMID:30681346 SUPPORT Human Clinical

"Of 33 HCM genes, only 8 (24%) were categorized as definitive ( MYBPC3, MYH7, TNNT2, TNNI3, TPM1, ACTC1, MYL2, and MYL3)"

Justifies including MYL3 on, and restricting testing to, the definitive-evidence gene set rather than an oversized panel.

PMID:33288880 SUPPORT Human Clinical

"and a presumable homozygous essential splice acceptor variant (c.482-1G>A, predicted to result in skipping of exon 5)."

Illustrates the biallelic genotypes that exome-scale testing in consanguineous families is needed to detect, and that a dominant-inheritance reading of a panel would miss.

📊

Prevalence

2

Hypertrophic cardiomyopathy probands (Caucasian, clinically characterised)

Unknown Ultra Rare

MYL3 is a definitive hypertrophic cardiomyopathy gene but an uncommon cause. Myosin light chain mutations (MYL2 and MYL3 together) were estimated to account for about 1% of hypertrophic cardiomyopathy; in a systematic screen of 186 unrelated HCM probands, no MYL3 mutation was found at all. No population prevalence estimate specific to MYL3-related hypertrophic cardiomyopathy is available, so a numeric rate is deliberately omitted.

Show evidence (2 references)

PMID:12404107 SUPPORT Human Clinical

"Two MYL2 missense mutations were identified in two Caucasian families while no mutation was found in MYL3."

A systematic screen of 186 unrelated HCM probands for both ventricular myosin light chain genes found no MYL3 mutation, establishing that MYL3 is a rare cause of hypertrophic cardiomyopathy.

PMID:12404107 SUPPORT Human Clinical

"In conclusion, myosin light chain mutations are a very rare cause of HCM responsible for about 1% of cases."

Quantifies the combined contribution of the two ventricular myosin light chain genes. PARTIAL because the ~1% figure covers MYL2 and MYL3 together, not MYL3 alone.

Worldwide (derived order-of-magnitude estimate)

Point Prevalence 1.5 per 100,000 (1.0–2.0) 1–9 per 100,000

DERIVED, NOT PUBLISHED. No prevalence estimate specific to MYL3-related hypertrophic cardiomyopathy exists. This record is an explicit order-of-magnitude derivation from two published quantities: hypertrophic cardiomyopathy point prevalence of about 1 in 500 (200 per 100,000), and the myosin light chain genes (MYL2 and MYL3 together) accounting for about 1% of hypertrophic cardiomyopathy. Attributing roughly half of that 1% to MYL3 gives 1-2 per 100,000. The two supporting citations below each attest one input to the derivation; neither states a MYL3 prevalence, so both are PARTIAL. Treat the class band as the usable signal and the numeric rate as an approximation.

Show evidence (2 references)

PMID:25814232 SUPPORT Human Clinical

"For the past 20 years, most data have supported the occurrence of HCM at about 1 in 500."

Supplies the hypertrophic cardiomyopathy denominator used in the derivation. PARTIAL because it concerns hypertrophic cardiomyopathy as a whole, not MYL3, and the same source argues the true figure is higher once genotype-positive/phenotype-negative individuals are counted.

PMID:12404107 SUPPORT Human Clinical

"In conclusion, myosin light chain mutations are a very rare cause of HCM responsible for about 1% of cases."

Supplies the myosin-light-chain fraction used in the derivation. PARTIAL because the 1% covers MYL2 and MYL3 jointly, so the MYL3-only share is an assumption, not a measurement.

🔬

Clinical Trials

3

NCT03470545 PHASE_III COMPLETED

EXPLORER-HCM. Randomised, double-blind, placebo-controlled trial of mavacamten in adults with symptomatic obstructive hypertrophic cardiomyopathy. The pivotal trial establishing cardiac myosin inhibition as a disease-directed therapy class — the class whose molecular target is the super-relaxed/disordered-relaxed equilibrium that MYL3 variants perturb.

Target Phenotypes: Left ventricular outflow tract obstruction HP:0032092

Show evidence (1 reference)

clinicaltrials:NCT03470545 SUPPORT Human Clinical

"This is a multicenter, international, double-blind study of the administration of mavacamten in participants with symptomatic obstructive HCM (oHCM)."

Confirms the design and population of the trial underpinning the cardiac myosin inhibition treatment entry.

NCT04349072 PHASE_III COMPLETED

VALOR-HCM. Randomised, double-blind, placebo-controlled trial of mavacamten in patients already eligible for septal reduction therapy, testing whether pharmacological myosin inhibition can avert the procedure. Directly relevant to this entry because septal reduction in MYL3 disease means an extended mid-ventricular myectomy, a higher-complexity operation than the standard subaortic one.

Show evidence (1 reference)

clinicaltrials:NCT04349072 SUPPORT Human Clinical

"will evaluate the effect of mavacamten treatment on reducing the number of septal reduction therapy (SRT) procedures performed in subjects with symptomatic obstructive hypertrophic cardiomyopathy"

Establishes the trial's septal-reduction-avoidance endpoint, which is the link between the pharmacotherapy and surgical arms of this entry.

NCT05186818 PHASE_III COMPLETED

SEQUOIA-HCM. Randomised, double-blind, placebo-controlled trial of aficamten, a second-generation selective cardiac myosin inhibitor, in symptomatic obstructive hypertrophic cardiomyopathy. Provides independent confirmation of the drug class with a second agent.

Target Phenotypes: Left ventricular outflow tract obstruction HP:0032092

Show evidence (1 reference)

clinicaltrials:NCT05186818 SUPPORT Human Clinical

"The purpose of this study is to evaluate the efficacy and safety of aficamten (CK-3773274) versus placebo in adults with symptomatic hypertrophic cardiomyopathy (HCM) and left ventricular outflow tract obstruction."

Confirms the design and population of the aficamten trial cited in the cardiac myosin inhibition treatment entry.

{ }

Source YAML

click to show

name: Hypertrophic Cardiomyopathy 8
creation_date: "2026-08-01T00:00:00Z"
description: >-
  Hypertrophic cardiomyopathy 8 (CMH8; OMIM 608751) is the form of familial
  hypertrophic cardiomyopathy caused by variants in MYL3, the gene encoding the
  ventricular/slow-skeletal myosin essential light chain (ELC). The ELC is a
  structural component of the actomyosin cross-bridge that stabilizes the long
  alpha-helical neck (lever arm) of the myosin head and, through its
  cardiac-specific N-terminal extension, contacts actin. MYL3 was one of the
  first two myosin light chain genes implicated in cardiac hypertrophy, in a
  1996 report describing a rare variant of cardiac hypertrophy accompanied by
  abnormal skeletal muscle. MYL3 is a definitive-evidence hypertrophic
  cardiomyopathy gene but an uncommon one: myosin light chain variants together
  account for roughly 1% of hypertrophic cardiomyopathy, and a systematic
  screen of 186 unrelated probands found no MYL3 mutation at all. Reported
  presentations span late-onset, low-expressivity heterozygous disease through
  severe infantile-onset hypertrophic cardiomyopathy, and a homozygous MYL3
  Glu143Lys genotype causing early-onset, mid-cavitary, restrictive-physiology
  cardiomyopathy in which heterozygous relatives were unaffected. Because the
  MYL3-specific literature is thin, most management is extrapolated from
  hypertrophic cardiomyopathy generally.
category: Mendelian
parents:
- Hypertrophic Cardiomyopathy
synonyms:
- CMH8
- MYL3 hypertrophic cardiomyopathy
- cardiomyopathy, familial hypertrophic, 8
disease_term:
  preferred_term: hypertrophic cardiomyopathy 8
  term:
    id: MONDO:0012111
    label: hypertrophic cardiomyopathy 8
references:
- reference: PMID:20301725
  title: "Nonsyndromic Hypertrophic Cardiomyopathy Overview"
  tags:
  - GeneReviews
notes: >-
  The GeneReviews chapter listed under `references` (PMID:20301725) is carried
  for provenance only and is deliberately not mined for evidence items: its
  PubMed record is a purpose statement ("The purpose of this overview is to: 1.
  Define the clinical characteristics...") with no clinical, diagnostic,
  management or counseling text, so no snippet can be quoted from it without
  misrepresenting the cached source. This is a recorded scoping decision, not an
  oversight.
prevalence:
- population: Hypertrophic cardiomyopathy probands (Caucasian, clinically characterised)
  measure_type: UNKNOWN
  prevalence_class: ULTRA_RARE
  notes: >-
    MYL3 is a definitive hypertrophic cardiomyopathy gene but an uncommon cause.
    Myosin light chain mutations (MYL2 and MYL3 together) were estimated to
    account for about 1% of hypertrophic cardiomyopathy; in a systematic screen
    of 186 unrelated HCM probands, no MYL3 mutation was found at all. No
    population prevalence estimate specific to MYL3-related hypertrophic
    cardiomyopathy is available, so a numeric rate is deliberately omitted.
  evidence:
  - reference: PMID:12404107
    reference_title: "Systematic analysis of the regulatory and essential myosin light chain genes: genetic variants and mutations in hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two MYL2 missense mutations were identified in two Caucasian families
      while no mutation was found in MYL3.
    explanation: >-
      A systematic screen of 186 unrelated HCM probands for both ventricular
      myosin light chain genes found no MYL3 mutation, establishing that MYL3
      is a rare cause of hypertrophic cardiomyopathy.
  - reference: PMID:12404107
    reference_title: "Systematic analysis of the regulatory and essential myosin light chain genes: genetic variants and mutations in hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In conclusion, myosin light chain mutations are a very rare cause of HCM
      responsible for about 1% of cases.
    explanation: >-
      Quantifies the combined contribution of the two ventricular myosin light
      chain genes. PARTIAL because the ~1% figure covers MYL2 and MYL3
      together, not MYL3 alone.
- population: Worldwide (derived order-of-magnitude estimate)
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_9_PER_100000
  rate_per_100000: 1.5
  rate_low: 1.0
  rate_high: 2.0
  notes: >-
    DERIVED, NOT PUBLISHED. No prevalence estimate specific to MYL3-related
    hypertrophic cardiomyopathy exists. This record is an explicit
    order-of-magnitude derivation from two published quantities: hypertrophic
    cardiomyopathy point prevalence of about 1 in 500 (200 per 100,000), and the
    myosin light chain genes (MYL2 and MYL3 together) accounting for about 1% of
    hypertrophic cardiomyopathy. Attributing roughly half of that 1% to MYL3
    gives 1-2 per 100,000. The two supporting citations below each attest one
    input to the derivation; neither states a MYL3 prevalence, so both are
    PARTIAL. Treat the class band as the usable signal and the numeric rate as
    an approximation.
  evidence:
  - reference: PMID:25814232
    reference_title: "New perspectives on the prevalence of hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      For the past 20 years, most data have supported the occurrence of HCM at
      about 1 in 500.
    explanation: >-
      Supplies the hypertrophic cardiomyopathy denominator used in the
      derivation. PARTIAL because it concerns hypertrophic cardiomyopathy as a
      whole, not MYL3, and the same source argues the true figure is higher once
      genotype-positive/phenotype-negative individuals are counted.
  - reference: PMID:12404107
    reference_title: "Systematic analysis of the regulatory and essential myosin light chain genes: genetic variants and mutations in hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In conclusion, myosin light chain mutations are a very rare cause of HCM
      responsible for about 1% of cases.
    explanation: >-
      Supplies the myosin-light-chain fraction used in the derivation. PARTIAL
      because the 1% covers MYL2 and MYL3 jointly, so the MYL3-only share is an
      assumption, not a measurement.
inheritance:
- name: Autosomal Dominant
  description: >-
    Most reported MYL3 hypertrophic cardiomyopathy families segregate a
    heterozygous missense variant in an autosomal dominant pattern, with
    incomplete penetrance and late onset described for at least one variant.
    ClinGen's Hypertrophic Cardiomyopathy Gene Curation Expert Panel classifies
    the MYL3-hypertrophic cardiomyopathy relationship as Definitive with
    autosomal dominant inheritance. Penetrance is incomplete, age-dependent, and
    allele-dependent: a meta-analysis of relatives ascertained by cascade
    screening puts MYL3 at about 32%, the lowest of the definitive sarcomere
    genes, while allele-specific pedigree estimates span 40% for p.V79I to 88%
    for p.R94H. Those three figures are not interchangeable and should not be
    averaged — the ~32% value is a pooled cross-study estimate for nonproband
    relatives found by cascade screening, whereas 40% and 88% are
    single-pedigree, allele-specific values whose spread is itself the finding.
    Both pedigree estimates are additionally age-confounded: in the p.V79I
    family the mean age of nonpenetrant carriers was 15 against 47 for penetrant
    carriers.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  penetrance: INCOMPLETE
  penetrance_percentage: "32-88"
  expressivity: VARIABLE
  evidence:
  - reference: CGGV:assertion_d74b9d56-4f2a-4479-8913-1d96ddc28592-2021-06-07T145050.605Z
    reference_title: "MYL3 / hypertrophic cardiomyopathy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MYL3 | HGNC:7584 | hypertrophic cardiomyopathy | MONDO:0005045 | AD | Definitive"
    explanation: >-
      ClinGen classifies the MYL3-hypertrophic cardiomyopathy gene-disease
      relationship as definitive with autosomal dominant inheritance.
  - reference: PMID:37929589
    reference_title: "Meta-Analysis of Penetrance and Systematic Review on Transition to Disease in Genetic Hypertrophic Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Penetrance varied from ≈32% for MYL3 (myosin light chain 3) to ≈55% for
      MYBPC3 (myosin-binding protein C3), ≈60% for TNNT2 (troponin T2) and
      TNNI3 (troponin I3), and ≈65% for MYH7 (myosin heavy chain 7).
    explanation: >-
      Places MYL3 penetrance at the bottom of the definitive sarcomere genes in
      a pooled meta-analysis of cascade-screened relatives, moving the estimate
      beyond the single-pedigree figure previously available.
  - reference: PMID:37929589
    reference_title: "Meta-Analysis of Penetrance and Systematic Review on Transition to Disease in Genetic Hypertrophic Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The penetrance across all genes in nonproband relatives carrying P/LP
      variants identified during cascade screening was 57%
    explanation: >-
      Establishes the ascertainment context of the ~32% MYL3 figure — it is a
      cascade-screening estimate in nonproband relatives, benchmarked against a
      57% all-gene average.
  - reference: PMID:26443374
    reference_title: "Whole exome sequencing combined with integrated variant annotation prediction identifies a causative myosin essential light chain variant in hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Serial assessments of the variant carriers revealed the following
      phenotypic characteristics: (1) disease-penetrance of 88%
    explanation: >-
      Allele-specific high-penetrance counterpoint (MYL3 p.R94H) to the 40%
      p.V79I estimate, establishing that penetrance in MYL3 is allele-dependent
      rather than a single gene-level constant.
  - reference: PMID:22957257
    reference_title: "A novel Myosin essential light chain mutation causes hypertrophic cardiomyopathy with late onset and low expressivity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The penetrance, if we consider this borderline HCM the phenotype of the
      p.V79I mutation, was 40%, but the mean age of the nonpenetrant mutation
      carriers is 15, while the mean age of the penetrant mutation carriers is
      47.
    explanation: >-
      The low-penetrance allele-specific estimate, and the source of the
      age-dependence caveat.
- name: Autosomal Recessive
  description: >-
    A distinct recessive presentation is documented: three siblings homozygous
    for MYL3 Glu143Lys developed severe childhood-onset cardiomyopathy with
    mid-cavitary hypertrophy and restrictive physiology, while family members
    carrying a single Glu143Lys allele had normal echocardiograms and ECGs even
    in late adulthood. Distinct variants in the same gene can therefore act
    dominantly or recessively.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:12021217
    reference_title: "Myosin light chain mutation causes autosomal recessive cardiomyopathy with mid-cavitary hypertrophy and restrictive physiology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Family members with one Glu143Lys allele had normal echocardiograms and
      ECGs, even in late adulthood, whereas those with two mutant alleles
      developed severe cardiomyopathy in childhood.
    explanation: >-
      Demonstrates a recessive mode of inheritance for the MYL3 Glu143Lys
      allele, with unaffected heterozygous carriers.
  - reference: PMID:12021217
    reference_title: "Myosin light chain mutation causes autosomal recessive cardiomyopathy with mid-cavitary hypertrophy and restrictive physiology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Distinct mutations affecting the same sarcomeric protein can cause either
      dominant or recessive cardiomyopathy.
    explanation: >-
      States the allele-dependent dual inheritance mode for the myosin
      essential light chain.
pathophysiology:
- name: MYL3 Essential Light Chain Variant — Altered Lever-Arm and Actin Contact
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Primary Cardiomyocyte Insult"
  biological_scale: MOLECULAR
  description: >-
    MYL3 encodes the ventricular/slow-skeletal myosin essential light chain
    (ELC), one of the two light-chain pairs of the hexameric muscle myosin. The
    light chains stabilize the long alpha-helical neck of the myosin head, and
    the cardiac-specific N-terminal extension of the ELC contacts actin and
    prepositions the cross-bridge for force production. Missense variants
    (e.g. Met149Val, Ala57Gly, Glu56Gly, Glu177Gly, Val79Ile, Glu143Lys)
    substitute residues in the ELC that lie at contact surfaces between the
    light chain and the myosin lever arm, altering cross-bridge mechanics
    rather than abolishing the protein. Subtle changes in ELC sequence are
    sufficient to alter cross-bridge properties and produce a pathological
    phenotype.
  genes:
  - preferred_term: MYL3
    term:
      id: hgnc:7584
      label: MYL3
  molecular_functions:
  - preferred_term: myosin heavy chain binding
    term:
      id: GO:0032036
      label: myosin heavy chain binding
    modifier: ABNORMAL
  cellular_components:
  - preferred_term: myosin filament
    term:
      id: GO:0032982
      label: myosin filament
  locations:
  - preferred_term: Myocardium
    term:
      id: UBERON:0002349
      label: myocardium
  evidence:
  - reference: PMID:8673105
    reference_title: "Mutations in either the essential or regulatory light chains of myosin are associated with a rare myopathy in human heart and skeletal muscle."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report here the identification of distinct missense mutations in a
      skeletal/ventricular ELC and RLC, each of which are associated with a
      rare variant of cardiac hypertrophy as well as abnormal skeletal muscle.
    explanation: >-
      Original identification of an essential light chain (MYL3) missense
      mutation as a cause of cardiac hypertrophy.
  - reference: PMID:8673105
    reference_title: "Mutations in either the essential or regulatory light chains of myosin are associated with a rare myopathy in human heart and skeletal muscle."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We show that myosin containing the mutant ELC has abnormal function, map
      the mutant residues on the three-dimensional structure of myosin and
      suggest that the mutations disrupt the stretch activation response of the
      cardiac papillary muscles.
    explanation: >-
      Demonstrates that the mutant essential light chain confers abnormal
      myosin function and localizes the defect structurally.
  - reference: PMID:22957257
    reference_title: "A novel Myosin essential light chain mutation causes hypertrophic cardiomyopathy with late onset and low expressivity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The mutation affects a conserved valine replacing it with a larger
      isoleucine residue in the region of contact between the light chain and
      the myosin lever arm.
    explanation: >-
      Locates a pathogenic MYL3 variant at the light chain-lever arm contact
      surface, supporting the lever-arm mechanism.
  - reference: PMID:21885653
    reference_title: "Structural and functional aspects of the myosin essential light chain in cardiac muscle contraction."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      These results support an important role for the N-terminal ELC extension
      in prepositioning the cross-bridge for optimal force production. Subtle
      changes in the ELC sequence were sufficient to alter cross-bridge
      properties and lead to pathological phenotypes.
    explanation: >-
      Establishes the mechanistic role of the ELC N-terminal extension and that
      small sequence changes suffice to cause disease.
  downstream:
  - target: Thick Filament Interface Disruption and Loss of Super-Relaxed State
    causal_link_type: DIRECT
  - target: Altered Actomyosin Cross-Bridge Kinetics and Calcium Sensitivity
    causal_link_type: DIRECT
  - target: Skeletal Muscle Involvement
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      MYL3 is expressed in slow skeletal muscle as well as ventricle, so the
      same variant can produce a skeletal myopathy alongside the cardiac
      phenotype.
- name: Thick Filament Interface Disruption and Loss of Super-Relaxed State
  biological_scale: MOLECULAR
  description: >-
    Pathogenic MYL3 variants map onto molecular interfaces of the cardiac thick
    filament, including interfaces of the myosin interacting-heads motif (IHM)
    that hold myosin heads in the energy-conserving super-relaxed (SRX) state.
    Destabilizing these interfaces shifts myosin from SRX toward the disordered
    relaxed (DRX) state, increasing the number of heads available to interact
    with actin and raising ATPase activity. In transgenic mice carrying the
    HCM-associated A57G ELC mutation, the SRX state is inhibited and
    cross-bridges become hypercontractile; the contrasting RCM-associated
    E143K ELC mutation instead stabilizes SRX, indicating that MYL3 variants
    can move the SRX/DRX equilibrium in opposite directions.
  molecular_functions:
  - preferred_term: ATP hydrolysis activity
    term:
      id: GO:0016887
      label: ATP hydrolysis activity
    modifier: INCREASED
  cellular_components:
  - preferred_term: myosin filament
    term:
      id: GO:0032982
      label: myosin filament
  evidence:
  - reference: PMID:42372158
    reference_title: "Thick filament molecular interfaces play a critical role in the pathogenesis of hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      We identified HCM variants residing in 30 molecular interfaces of the
      complex thick filament interactome, including the two main interfaces of
      the myosin interacting-heads motif (IHM), and interfaces involving the
      MHC, essential and regulatory light chains, and cMyBP-C.
    explanation: >-
      Maps pathogenic variants — including MYL3 (essential light chain)
      variants — onto thick filament and IHM interfaces, supporting interface
      disruption as the proximal structural lesion.
  - reference: PMID:42372158
    reference_title: "Thick filament molecular interfaces play a critical role in the pathogenesis of hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We demonstrated earlier disease onset and adverse outcomes in HCM
      patients with pathogenic variants within vs. outside of molecular
      interfaces, emphasizing their importance in normal thick filament
      function and improving risk stratification of patients.
    explanation: >-
      Links interface location of thick filament variants to clinical onset and
      outcome, giving the structural mechanism clinical traction.
  - reference: PMID:32034976
    reference_title: "Ablation of the N terminus of cardiac essential light chain promotes the super-relaxed state of myosin and counteracts hypercontractility in hypertrophic cardiomyopathy mutant mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The hypercontractile activity of A57G-ELC cross-bridges was manifested by
      the inhibition of the SRX state, increased number of myosin heads
      available for interaction with actin, and higher ATPase activity.
    explanation: >-
      Directly demonstrates SRX destabilization and hypercontractility for an
      HCM-causing MYL3 (ELC) mutation in transgenic mice.
  - reference: PMID:34014247
    reference_title: "Cardiomyopathic mutations in essential light chain reveal mechanisms regulating the super relaxed state of myosin."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The HCM-A57G and RCM-E143K mutations had antagonistic effects on the
      ATP-dependent myosin energetic states, with HCM-A57G cross-bridges
      fostering the disordered relaxed (DRX) state and the RCM-E143K model
      favoring the energy-conserving SRX state.
    explanation: >-
      Shows that two MYL3 variants shift the SRX/DRX equilibrium in opposite
      directions, mechanistically separating the hypertrophic from the
      restrictive presentation.
  downstream:
  - target: Altered Actomyosin Cross-Bridge Kinetics and Calcium Sensitivity
    causal_link_type: DIRECT
- name: Altered Actomyosin Cross-Bridge Kinetics and Calcium Sensitivity
  biological_scale: CELLULAR
  description: >-
    MYL3 variants change how the cross-bridge cycles. Recombinant myosin
    subfragment-1 carrying the cardiomyopathic ELC substitutions E56G, M149V
    and E177G all significantly increase the calcium sensitivity of thin
    filament sliding, and M149V additionally upregulates actin-activated
    ATPase — although the specific effect on actin-myosin interaction differs
    between variants. In transgenic A57G mice, calcium sensitivity of force is
    increased with a reduction in maximal force per cross section, alongside a
    mutation-induced increase in myocardial stiffness. Downstream of the
    myofilament change, contractility and energetics are dysregulated.
  cell_types:
  - preferred_term: Cardiac muscle cell
    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: DYSREGULATED
  - preferred_term: muscle filament sliding
    term:
      id: GO:0030049
      label: muscle filament sliding
    modifier: ABNORMAL
  molecular_functions:
  - preferred_term: microfilament motor activity
    term:
      id: GO:0000146
      label: microfilament motor activity
    modifier: ABNORMAL
  locations:
  - preferred_term: Myocardium
    term:
      id: UBERON:0002349
      label: myocardium
  evidence:
  - reference: PMID:36509720
    reference_title: "Properties of Cardiac Myosin with Cardiomyopathic Mutations in Essential Light Chains."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      All mutations significantly increased the Ca2+-sensitivity of the sliding
      velocity of thin filaments on the surface with immobilized myosin in the
      in vitro motility assay
    explanation: >-
      Shows that three MYL3 cardiomyopathic ELC substitutions increase
      myofilament calcium sensitivity in a reconstituted motility assay.
  - reference: PMID:36509720
    reference_title: "Properties of Cardiac Myosin with Cardiomyopathic Mutations in Essential Light Chains."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Therefore, despite the fact that all studied mutations in ELCv are
      involved in the development of hypertrophic cardiomyopathy, the
      mechanisms of their influence on the actin-myosin interaction are
      different.
    explanation: >-
      Documents variant-specific heterogeneity in how MYL3 mutations perturb
      the actomyosin interaction.
  - reference: PMID:23748425
    reference_title: "Discrete effects of A57G-myosin essential light chain mutation associated with familial hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Compared with the Tg-WT, there was a significant increase in the Ca²⁺
      sensitivity of force (ΔpCa₅₀ ≅ 0.1) and an ~1.3-fold decrease in maximal
      force per cross section of muscle observed in the mutant preparations.
    explanation: >-
      Quantifies the increase in calcium sensitivity and loss of maximal force
      caused by an HCM-associated MYL3 mutation in transgenic mouse and
      protein-exchanged muscle preparations.
  downstream:
  - target: Cardiomyocyte Hypertrophy, Myocardial Stiffness and Fibrosis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Sustained myofilament dysfunction activates cardiomyopathic signalling
      and compensatory hypertrophy.
- name: Cardiomyocyte Hypertrophy, Myocardial Stiffness and Fibrosis
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Ventricular Remodeling"
  biological_scale: TISSUE
  description: >-
    Chronically altered myofilament function drives compensatory cardiomyocyte
    hypertrophy with increased passive stiffness and interstitial fibrosis.
    Transgenic A57G-ELC mice show a high level of fibrosis and hypertrophy with
    increased heart weight-to-body weight ratio and enlarged myocytes; the
    E143K-ELC model develops ultrastructural defects and fibrosis that worsen
    with age together with upregulation of stress-response and collagen genes.
    In humans, histopathology of an infant with a MYL3 variant contributed to
    the diagnosis of severe progressive hypertrophic cardiomyopathy.
  cell_types:
  - preferred_term: Cardiac muscle cell
    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
    term:
      id: GO:0003300
      label: cardiac muscle hypertrophy
    modifier: INCREASED
  - preferred_term: extracellular matrix organization
    term:
      id: GO:0030198
      label: extracellular matrix organization
    modifier: INCREASED
  locations:
  - preferred_term: Heart left ventricle
    term:
      id: UBERON:0002084
      label: heart left ventricle
  evidence:
  - reference: PMID:23748425
    reference_title: "Discrete effects of A57G-myosin essential light chain mutation associated with familial hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Consistently, the hearts of Tg-A57G mice demonstrated a high level of
      fibrosis and hypertrophy manifested by increased heart weight-to-body
      weight ratios
    explanation: >-
      Links the MYL3 A57G myofilament lesion to hypertrophy and fibrosis at the
      tissue level in vivo.
  - reference: PMID:23748425
    reference_title: "Discrete effects of A57G-myosin essential light chain mutation associated with familial hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      These and other contributing factors such as increased myocardial
      stiffness and fibrosis most likely activate cardiomyopathic signaling
      pathways leading to pathologic cardiac remodeling.
    explanation: >-
      States the proposed causal chain from myofilament dysfunction through
      stiffness and fibrosis to pathological remodeling.
  - reference: PMID:28371863
    reference_title: "Hypercontractile mutant of ventricular myosin essential light chain leads to disruption of sarcomeric structure and function and results in restrictive cardiomyopathy in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The hearts of mutant-mice demonstrated ultrastructural defects and
      fibrosis that progressively worsened in senescent animals
    explanation: >-
      Shows progressive fibrosis and sarcomeric ultrastructural disruption
      caused by a MYL3 essential light chain mutation.
  downstream:
  - target: Diastolic Dysfunction and Restrictive Physiology
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Left Ventricular Hypertrophy
    causal_link_type: DIRECT
  - target: Myocardial Fibrosis
    causal_link_type: DIRECT
- name: Diastolic Dysfunction and Restrictive Physiology
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Progressive Contractile Dysfunction"
  biological_scale: ORGANISM
  description: >-
    Stiff, hypertrophied, fibrotic ventricles impair filling. In the E143K-ELC
    mouse model, augmented active and passive tension in skinned papillary
    muscle fibres accompanies stiff ventricles and physiological, morphologic
    and metabolic remodeling consistent with restrictive cardiomyopathy; in
    humans, homozygous MYL3 Glu143Lys produced mid-cavitary hypertrophy with
    restrictive physiology in childhood. In heterozygous adult-onset disease,
    outflow obstruction and left atrial dilation follow from the same
    hypertrophic substrate.
  locations:
  - preferred_term: Heart
    term:
      id: UBERON:0000948
      label: heart
  evidence:
  - reference: PMID:28371863
    reference_title: "Hypercontractile mutant of ventricular myosin essential light chain leads to disruption of sarcomeric structure and function and results in restrictive cardiomyopathy in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      As a result of the E143K-induced myosin hypercontractility, the hearts of
      RCM mice model exhibited cardiac dysfunction, stiff ventricles and
      physiological, morphologic, and metabolic remodelling consistent with the
      development of RCM.
    explanation: >-
      Connects MYL3-driven myosin hypercontractility to ventricular stiffening
      and restrictive physiology.
  - reference: PMID:12021217
    reference_title: "Myosin light chain mutation causes autosomal recessive cardiomyopathy with mid-cavitary hypertrophy and restrictive physiology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We studied a family with early-onset cardiomyopathy in 3 siblings,
      characterized by mid-cavitary hypertrophy and restrictive physiology.
    explanation: >-
      Human counterpart of the restrictive phenotype, in siblings homozygous
      for MYL3 Glu143Lys.
  downstream:
  - target: Congestive Heart Failure
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Left Atrial Dilation
    causal_link_type: DIRECT
  - target: Atrial Remodeling and Intracavitary Stasis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Impaired filling raises left atrial pressure and dilates the atrium,
      creating the substrate for atrial fibrillation and stasis-driven
      thrombus formation.
- name: Atrial Remodeling and Intracavitary Stasis
  biological_scale: ORGANISM
  description: >-
    Two stasis-generating substrates converge on cardioembolism in this
    genotype. Diastolic impairment dilates the left atrium and predisposes to
    atrial fibrillation, which in the reported MYL3 mid-cavity case proved
    refractory to both pharmacological and direct-current cardioversion.
    Independently, the mid-ventricular obstruction characteristic of MYL3
    disease can progress to a left ventricular apical aneurysm — a blind,
    akinetic pouch that is separately recognised as predisposing to
    thromboembolisation. Both routes generate cardioembolic risk, which is why
    anticoagulation rather than rhythm control alone is the operative
    management decision. In the index case the cerebrovascular events were
    judged cardioembolic and long-term anticoagulation was started, at the cost
    of a subsequent extra-axial haemorrhage.
  locations:
  - preferred_term: Heart left atrium
    term:
      id: UBERON:0002079
      label: left cardiac atrium
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:35288424
    reference_title: "Mutation of the MYL3 gene in a patient with mid-ventricular obstructive hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient had normal epicardial coronary arteries, but presented with
      recurrent cerebrovascular events.
    explanation: >-
      Documents recurrent cerebrovascular events in a genotyped MYL3 patient
      with mid-cavity obstruction and apical aneurysm, with coronary disease
      excluded as the cause.
  - reference: PMID:35288424
    reference_title: "Mutation of the MYL3 gene in a patient with mid-ventricular obstructive hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The development of LV apical aneurysm may predispose patients to
      complications involving ventricular tachyarrhythmias, thromboembolisations
      and ventricular rupture in the context of immature aneurysms.
    explanation: >-
      States the apical aneurysm to thromboembolism link that makes this arm
      genotype-relevant rather than generic hypertrophic cardiomyopathy context.
  notes: >-
    Mechanism confidence is PROVISIONAL: the whole arm rests on a single
    genotyped MYL3 case report plus the general hypertrophic cardiomyopathy
    apical-aneurysm literature. No MYL3 series reports atrial fibrillation
    incidence or stroke rates, so no frequency is asserted anywhere in this arm.
  downstream:
  - target: Atrial Fibrillation
    causal_link_type: DIRECT
  - target: Cardioembolic Stroke
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Stasis in a fibrillating atrium or an akinetic apical aneurysm permits
      thrombus formation and systemic embolization.
- name: Skeletal Muscle Involvement
  biological_scale: TISSUE
  description: >-
    MYL3 encodes the light chain shared by ventricular and slow skeletal
    muscle. The founding report of essential light chain disease described the
    associated hypertrophy as occurring together with abnormal skeletal muscle,
    making a skeletal myopathy part of the original MYL3 phenotype. This arm is
    much less well characterised than the cardiac arm and has not been a
    consistent finding in later MYL3 case reports.
  biological_processes:
  - preferred_term: skeletal muscle contraction
    term:
      id: GO:0003009
      label: skeletal muscle contraction
    modifier: ABNORMAL
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:8673105
    reference_title: "Mutations in either the essential or regulatory light chains of myosin are associated with a rare myopathy in human heart and skeletal muscle."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a rare variant of cardiac hypertrophy as well as abnormal skeletal muscle
    explanation: >-
      Skeletal muscle abnormality is reported alongside the cardiac phenotype
      in the founding essential light chain paper. PARTIAL because the abstract
      reports ELC and RLC mutations together and does not detail the skeletal
      findings attributable to MYL3 alone.
  downstream:
  - target: Skeletal Myopathy
    causal_link_type: DIRECT
phenotypes:
- category: Cardiovascular
  name: Left Ventricular Hypertrophy
  frequency: VERY_FREQUENT
  description: >-
    Unexplained left ventricular hypertrophy is the defining feature. Reported
    MYL3 probands include an asymptomatic 38-year-old male with a maximal wall
    thickness of 21 mm, and a 3-month-old infant with severe progressive
    hypertrophic cardiomyopathy.
  phenotype_term:
    preferred_term: Left ventricular hypertrophy
    term:
      id: HP:0001712
      label: Left ventricular hypertrophy
  evidence:
  - reference: PMID:22957257
    reference_title: "A novel Myosin essential light chain mutation causes hypertrophic cardiomyopathy with late onset and low expressivity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient had HCM with left ventricular hypertrophy (max WT 21 mm), a
      resting left ventricular outflow gradient of 36 mm Hg, and left atrial
      dilation (54 mm).
    explanation: >-
      Documents left ventricular hypertrophy in a genotyped MYL3 p.V79I
      proband.
- category: Cardiovascular
  name: Left Ventricular Outflow Tract Obstruction
  description: >-
    A resting left ventricular outflow gradient was documented in the MYL3
    p.V79I proband, indicating obstructive physiology in at least some
    heterozygous carriers.
  phenotype_term:
    preferred_term: Left ventricular outflow tract obstruction
    term:
      id: HP:0032092
      label: Left ventricular outflow tract obstruction
  notes: >-
    Frequency is deliberately omitted — obstruction is documented in single
    MYL3 cases, and no MYL3 cohort reports the proportion with obstruction.
  evidence:
  - reference: PMID:22957257
    reference_title: "A novel Myosin essential light chain mutation causes hypertrophic cardiomyopathy with late onset and low expressivity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a resting left ventricular outflow gradient of 36 mm Hg
    explanation: >-
      Records a resting outflow tract gradient in a MYL3 mutation carrier.
- category: Cardiovascular
  name: Left Atrial Dilation
  description: >-
    Left atrial enlargement accompanies the impaired diastolic filling produced
    by the hypertrophic, stiff ventricle.
  phenotype_term:
    preferred_term: Left atrial enlargement
    term:
      id: HP:0031295
      label: Left atrial enlargement
  evidence:
  - reference: PMID:22957257
    reference_title: "A novel Myosin essential light chain mutation causes hypertrophic cardiomyopathy with late onset and low expressivity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      left atrial dilation (54 mm)
    explanation: >-
      Documents left atrial dilation in the MYL3 p.V79I proband.
- category: Cardiovascular
  name: Restrictive Physiology with Mid-Cavitary Hypertrophy
  description: >-
    In the homozygous MYL3 Glu143Lys siblings the hypertrophy was mid-cavitary
    rather than septal, and physiology was restrictive rather than obstructive
    — a distinctive MYL3 presentation. The E143K substitution is also the
    variant modeled as restrictive cardiomyopathy in transgenic mice.
  phenotype_term:
    preferred_term: Restrictive cardiomyopathy
    term:
      id: HP:0001723
      label: Restrictive cardiomyopathy
  evidence:
  - reference: PMID:12021217
    reference_title: "Myosin light chain mutation causes autosomal recessive cardiomyopathy with mid-cavitary hypertrophy and restrictive physiology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      characterized by mid-cavitary hypertrophy and restrictive physiology
    explanation: >-
      Defines the restrictive, mid-cavitary phenotype of homozygous MYL3
      Glu143Lys disease.
- category: Cardiovascular
  name: Mid-Ventricular Obstruction with Left Ventricular Apical Aneurysm
  description: >-
    Mid-ventricular (rather than basal septal) hypertrophy producing a
    mid-cavitary gradient is a recurring MYL3 morphology. In one reported
    patient this progressed to a left ventricular apical aneurysm with delayed
    gadolinium enhancement and recurrent cerebrovascular events — the first
    apical aneurysm reported for MYL3, and an adverse risk marker.
  phenotype_term:
    preferred_term: Left ventricular aneurysm
    term:
      id: HP:6000144
      label: Left ventricular aneurysm
  notes: >-
    Single case report; frequency deliberately omitted. Mid-cavitary
    hypertrophy itself is corroborated independently by the recessive
    Glu143Lys family (PMID:12021217).
  evidence:
  - reference: PMID:35288424
    reference_title: "Mutation of the MYL3 gene in a patient with mid-ventricular obstructive hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cardiac MRI detected positive features of left ventricular mid-cavity
      obstruction, left ventricular apical aneurysm and delayed gadolinium
      enhancement
    explanation: >-
      Documents mid-cavity obstruction and apical aneurysm in a genotyped MYL3
      patient.
  - reference: PMID:35288424
    reference_title: "Mutation of the MYL3 gene in a patient with mid-ventricular obstructive hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      To our knowledge, the presence of a left ventricular apical aneurysm has
      not been previously reported in literature concerning the MYL3 gene
      mutation. The presence of this abnormality further increases the risk of
      sudden cardiac death.
    explanation: >-
      Establishes the apical aneurysm as a novel MYL3 finding and links it to
      elevated sudden-death risk.
- category: Cardiovascular
  name: Non-Sustained Ventricular Tachycardia
  description: >-
    Holter monitoring in a MYL3 patient with mid-cavity obstruction and apical
    aneurysm showed non-sustained ventricular tachycardia, prompting referral
    for an implantable cardioverter defibrillator.
  phenotype_term:
    preferred_term: Non-sustained ventricular tachycardia
    term:
      id: HP:0004756
      label: Ventricular tachycardia
  evidence:
  - reference: PMID:35288424
    reference_title: "Mutation of the MYL3 gene in a patient with mid-ventricular obstructive hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      with Holter monitoring assessment displaying segments of non-sustained
      ventricular tachycardia
    explanation: >-
      Documents ventricular arrhythmia in a MYL3 carrier.
- category: Cardiovascular
  name: Severe Infantile-Onset Hypertrophic Cardiomyopathy
  frequency: VERY_RARE
  description: >-
    MYL3 disease is usually adult-onset, but a 3-month-old infant with a
    paternally inherited pathogenic MYL3 variant presented with severe
    progressive hypertrophic cardiomyopathy and a fatal outcome, while the
    father remained asymptomatic — an extreme illustration of the variable
    expressivity of this gene.
  phenotype_term:
    preferred_term: Hypertrophic cardiomyopathy
    term:
      id: HP:0001639
      label: Hypertrophic cardiomyopathy
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:23594557
    reference_title: "Infantile hypertrophic cardiomyopathy associated with a novel MYL3 mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report on genetic and histopathological findings in a 3-month-old
      infant presenting with severe progressive HCM arising from a mutation in
      the gene encoding the essential light chain of myosin (MYL3).
    explanation: >-
      Documents infantile-onset severe hypertrophic cardiomyopathy caused by a
      MYL3 variant.
  - reference: PMID:23594557
    reference_title: "Infantile hypertrophic cardiomyopathy associated with a novel MYL3 mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although, MYL3 mutations have been previously associated with
      adult-onset HCM, it has not been seen in infantile forms.
    explanation: >-
      Establishes infantile presentation as exceptional against the usual
      adult-onset MYL3 course.
- category: Cardiovascular
  name: Atrial Fibrillation
  description: >-
    Atrial fibrillation and flutter developed in the reported MYL3 mid-cavity
    obstruction patient and were refractory to both pharmacological and
    direct-current cardioversion. Atrial fibrillation is the expected
    consequence of the left atrial dilation this genotype produces, and it is
    the trigger for anticoagulation rather than for rate control alone.
  phenotype_term:
    preferred_term: Atrial fibrillation
    term:
      id: HP:0005110
      label: Atrial fibrillation
  notes: >-
    Frequency deliberately omitted — documented in a single genotyped MYL3 case;
    no MYL3 series reports an atrial fibrillation rate.
  evidence:
  - reference: PMID:35288424
    reference_title: "Mutation of the MYL3 gene in a patient with mid-ventricular obstructive hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A couple of years later, she was admitted with arrhythmic disturbances
      consistent with atrial flutter and atrial fibrillation.
    explanation: >-
      Documents atrial fibrillation in a genotyped MYL3 carrier.
- category: Cardiovascular
  name: Cardioembolic Stroke
  description: >-
    Recurrent cerebrovascular events of cardioembolic origin occurred in the
    MYL3 mid-cavity obstruction patient, with normal epicardial coronary
    arteries excluding an ischaemic-cardiomyopathy explanation for the apical
    aneurysm. The events comprised a transient ischaemic attack with retinal
    artery occlusion, a left gangliocapsular infarct and a left corona radiata
    infarct, and prompted long-term anticoagulation.
  phenotype_term:
    preferred_term: Cardioembolic stroke
    term:
      id: HP:0001297
      label: Stroke
  notes: >-
    Frequency deliberately omitted — a single genotyped MYL3 case. HPO has no
    cardioembolic-stroke term, so the general Stroke term carries a narrower
    preferred_term, following the same convention used for non-sustained
    ventricular tachycardia in this entry.
  evidence:
  - reference: PMID:35288424
    reference_title: "Mutation of the MYL3 gene in a patient with mid-ventricular obstructive hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient had normal epicardial coronary arteries, but presented with
      recurrent cerebrovascular events.
    explanation: >-
      Documents recurrent cerebrovascular events in a MYL3 carrier with coronary
      disease excluded.
  - reference: PMID:35288424
    reference_title: "Mutation of the MYL3 gene in a patient with mid-ventricular obstructive hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The pathophysiology of the multiple CVAs were deemed likely to be of
      cardioembolic origin.
    explanation: >-
      Attributes the cerebrovascular events to a cardioembolic mechanism, which
      is what makes them a downstream consequence of the atrial and apical
      substrate rather than incidental comorbidity.
- category: Cardiovascular
  name: Myocardial Fibrosis
  description: >-
    Interstitial fibrosis is a consistent feature of MYL3 mutant mouse hearts
    and part of the substrate for diastolic dysfunction and arrhythmia. Direct
    human histological quantification specific to MYL3 carriers is not
    available.
  phenotype_term:
    preferred_term: Myocardial fibrosis
    term:
      id: HP:0001685
      label: Myocardial fibrosis
  notes: >-
    Supporting evidence here is from transgenic mouse models of MYL3 (ELC)
    mutations, not from human MYL3 carriers; see the HUMAN_MODEL_MISMATCH
    discussion item.
  evidence:
  - reference: PMID:28371863
    reference_title: "Hypercontractile mutant of ventricular myosin essential light chain leads to disruption of sarcomeric structure and function and results in restrictive cardiomyopathy in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The hearts of mutant-mice demonstrated ultrastructural defects and
      fibrosis that progressively worsened in senescent animals
    explanation: >-
      Progressive myocardial fibrosis in a MYL3 essential light chain mutant
      mouse model.
- category: Cardiovascular
  name: Congestive Heart Failure
  description: >-
    Progressive cardiac dysfunction is the end point of the remodeling cascade.
    In the E143K MYL3 mouse model this manifests as cardiac dysfunction with
    diastolic disturbance and mild systolic dysfunction.
  phenotype_term:
    preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  notes: >-
    Curated from the mouse model plus the general hypertrophic cardiomyopathy
    course; no MYL3-specific human heart failure incidence has been published.
  evidence:
  - reference: PMID:28371863
    reference_title: "Hypercontractile mutant of ventricular myosin essential light chain leads to disruption of sarcomeric structure and function and results in restrictive cardiomyopathy in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      these changes were hypothesized to contribute to diastolic disturbance
      and to mild systolic dysfunction
    explanation: >-
      Supports progression to contractile dysfunction in the MYL3 mutant model.
      PARTIAL because the mechanism is stated as a hypothesis and the data are
      murine.
- category: Cardiovascular
  name: Sudden Cardiac Death
  description: >-
    MYL3 mutations have been associated with sudden death, though the
    MYL3-specific risk has not been quantified in a cohort. Risk stratification
    in practice follows general hypertrophic cardiomyopathy criteria.
  phenotype_term:
    preferred_term: Sudden cardiac death
    term:
      id: HP:0001645
      label: Sudden cardiac death
  notes: >-
    Frequency omitted deliberately: the sources establish the association and
    document events in specific pedigrees, but no denominator-based MYL3
    sudden-death risk estimate exists.
  evidence:
  - reference: PMID:22957257
    reference_title: "A novel Myosin essential light chain mutation causes hypertrophic cardiomyopathy with late onset and low expressivity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutations in MYL3, encoding the essential light chain of myosin, are rare
      and have been associated with sudden death.
    explanation: >-
      Asserts an association between MYL3 mutations and sudden death. PARTIAL
      because it is a background statement without a quantified risk.
  - reference: PMID:33288880
    reference_title: "Autosomal recessive cardiomyopathy and sudden cardiac death associated with variants in MYL3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Affected individuals presented with hypertrophic or dilated
      cardiomyopathy of variable severity from infantile- to early
      adulthood-onset and sudden cardiac death.
    explanation: >-
      Documents sudden cardiac death among affected members of three
      consanguineous families carrying homozygous MYL3 variants.
  - reference: PMID:35288424
    reference_title: "Mutation of the MYL3 gene in a patient with mid-ventricular obstructive hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient had a positive family history for sudden cardiac death.
    explanation: >-
      Family history of sudden cardiac death in a MYL3-genotyped kindred.
- category: Musculoskeletal
  name: Skeletal Myopathy
  description: >-
    Abnormal skeletal muscle was described together with the cardiac
    hypertrophy in the founding report of myosin light chain disease, in
    keeping with expression of MYL3 in slow skeletal muscle as well as
    ventricle. It is not a consistently reported feature of later MYL3 cases.
  phenotype_term:
    preferred_term: Myopathy
    term:
      id: HP:0003198
      label: Myopathy
  notes: >-
    Low-confidence phenotype. The founding paper reports ELC and RLC mutations
    together, so the skeletal muscle finding cannot be cleanly attributed to
    MYL3 alone from the abstract.
  evidence:
  - reference: PMID:8673105
    reference_title: "Mutations in either the essential or regulatory light chains of myosin are associated with a rare myopathy in human heart and skeletal muscle."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a rare variant of cardiac hypertrophy as well as abnormal skeletal muscle
    explanation: >-
      Skeletal muscle abnormality accompanies the cardiac phenotype in the
      original essential/regulatory light chain report.
  - reference: PMID:33288880
    reference_title: "Autosomal recessive cardiomyopathy and sudden cardiac death associated with variants in MYL3."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Affected individuals from the three families showed no evidence of muscle
      weakness by neurological examination or by history.
    explanation: >-
      Explicitly negative skeletal muscle assessment across three MYL3
      cardiomyopathy families, arguing that skeletal myopathy is not a general
      feature of MYL3 disease and may be specific to the original Poetter
      kindreds.
- category: Cardiovascular
  name: Incomplete Penetrance and Borderline Phenotype in Carriers
  description: >-
    Cascade screening of a MYL3 p.V79I family found nine further heterozygous
    carriers, of whom three had ECG and/or echocardiographic abnormalities that
    did not meet diagnostic criteria for hypertrophic cardiomyopathy. Penetrance
    counting borderline disease as affected was 40%, and unaffected carriers
    were substantially younger than affected ones — an age-dependent
    penetrance pattern.
  phenotype_term:
    preferred_term: Hypertrophic cardiomyopathy
    term:
      id: HP:0001639
      label: Hypertrophic cardiomyopathy
  evidence:
  - reference: PMID:22957257
    reference_title: "A novel Myosin essential light chain mutation causes hypertrophic cardiomyopathy with late onset and low expressivity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cascade screening revealed a further nine heterozygote mutation carriers,
      three of whom had ECG and/or echocardiographic abnormalities but did not
      fulfil diagnostic criteria for HCM.
    explanation: >-
      Documents subdiagnostic phenotypes among MYL3 heterozygotes.
  - reference: PMID:22957257
    reference_title: "A novel Myosin essential light chain mutation causes hypertrophic cardiomyopathy with late onset and low expressivity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The penetrance, if we consider this borderline HCM the phenotype of the
      p.V79I mutation, was 40%, but the mean age of the nonpenetrant mutation
      carriers is 15, while the mean age of the penetrant mutation carriers is
      47.
    explanation: >-
      Quantifies incomplete, age-dependent penetrance for a MYL3 variant.
genetic:
- name: MYL3 Missense Variants
  association: Pathogenic Variants
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: MYL3
    term:
      id: hgnc:7584
      label: MYL3
  features: >-
    Pathogenic MYL3 variants are missense substitutions affecting conserved
    residues of the ventricular essential light chain, including those at the
    light chain-lever arm contact surface (V79I), in the N-terminal region
    (A57G, E56G), and at M149 and E177. Most act dominantly with incomplete,
    age-dependent penetrance and low expressivity; the E143K allele is
    recessive. MYL3 is one of only eight genes with definitive evidence of
    causing hypertrophic cardiomyopathy. Penetrance is an allele property here,
    not a gene constant: p.V79I reached only 40% counting borderline disease in
    its pedigree, whereas p.R94H reached 88% in a Japanese registry family, and
    the pooled cross-study estimate for MYL3 as a whole is about 32% — the
    lowest of the definitive sarcomere genes. The p.R94H carriers were also
    morphologically atypical for this entry's mid-cavity theme, showing
    asymmetric septal hypertrophy without obstruction, which is a further
    reminder that MYL3 morphology is allele-dependent.
  inheritance:
  - name: Autosomal Dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
    penetrance: INCOMPLETE
    penetrance_percentage: "40-88"
    expressivity: VARIABLE
  evidence:
  - reference: CGGV:assertion_d74b9d56-4f2a-4479-8913-1d96ddc28592-2021-06-07T145050.605Z
    reference_title: "MYL3 / hypertrophic cardiomyopathy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MYL3 | HGNC:7584 | hypertrophic cardiomyopathy | MONDO:0005045 | AD | Definitive"
    explanation: >-
      ClinGen gene-disease validity classification for MYL3 and hypertrophic
      cardiomyopathy.
  - reference: PMID:30681346
    reference_title: "Evaluating the Clinical Validity of Hypertrophic Cardiomyopathy Genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of 33 HCM genes, only 8 (24%) were categorized as definitive ( MYBPC3,
      MYH7, TNNT2, TNNI3, TPM1, ACTC1, MYL2, and MYL3)
    explanation: >-
      Independent systematic gene-disease validity curation placing MYL3 among
      the eight definitive hypertrophic cardiomyopathy genes.
  - reference: PMID:22957257
    reference_title: "A novel Myosin essential light chain mutation causes hypertrophic cardiomyopathy with late onset and low expressivity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Genotyping revealed heterozygosity for a novel missense mutation, p.V79I,
      in MYL3. The mutation was not found in 300 controls, and the patient had
      no mutations in 10 sarcomere genes.
    explanation: >-
      Illustrates the missense, heterozygous, control-absent variant pattern
      typical of MYL3 hypertrophic cardiomyopathy.
  - reference: PMID:26443374
    reference_title: "Whole exome sequencing combined with integrated variant annotation prediction identifies a causative myosin essential light chain variant in hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Using CADD score and HHE gene data, the number of candidates was reduced
      to one, a variant in the myosin essential light chain (MYL3,
      NM_000258.2:c.281G>A, p.Arg94His) that was shared by the five affected
      subjects.
    explanation: >-
      Adds p.R94H to the curated missense spectrum, with segregation across five
      affected family members plus two further registry carriers.
  - reference: PMID:26443374
    reference_title: "Whole exome sequencing combined with integrated variant annotation prediction identifies a causative myosin essential light chain variant in hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      all clinically affected carriers exhibited asymmetric septal hypertrophy
      with a substantial maximum left ventricular wall thickness of 18±3mm
      without any obstruction
    explanation: >-
      Records the p.R94H morphology — asymmetric septal hypertrophy without
      obstruction — which differs from the mid-cavitary pattern seen with other
      MYL3 alleles and supports treating MYL3 morphology as allele-dependent.
- name: MYL3 Glu143Lys (Recessive Allele)
  association: Pathogenic Variants
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: MYL3
    term:
      id: hgnc:7584
      label: MYL3
  features: >-
    Homozygosity for the Glu143Lys substitution of a highly conserved residue,
    absent from 150 controls, caused severe childhood-onset cardiomyopathy in
    three siblings; single-allele carriers were unaffected into late adulthood.
    The original report proposed a loss-of-function mechanism, whereas
    subsequent transgenic mouse work characterised E143K myosin as
    hypercontractile — an unresolved mechanistic tension recorded in the
    discussions block.
  inheritance:
  - name: Autosomal Recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:12021217
    reference_title: "Myosin light chain mutation causes autosomal recessive cardiomyopathy with mid-cavitary hypertrophy and restrictive physiology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sequencing showed that these individuals were homozygous for a Glu143Lys
      substitution of a highly conserved amino acid that was absent in 150
      controls.
    explanation: >-
      Establishes the homozygous MYL3 Glu143Lys genotype in the affected
      siblings.
  - reference: PMID:12021217
    reference_title: "Myosin light chain mutation causes autosomal recessive cardiomyopathy with mid-cavitary hypertrophy and restrictive physiology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These findings, coupled with previous studies of myosin light chain
      structure and function in the heart, suggest a loss-of-function disease
      mechanism.
    explanation: >-
      Records the loss-of-function interpretation offered for the recessive
      MYL3 allele.
- name: MYL3 Biallelic Loss-of-Function Variants
  association: Pathogenic Variants
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: MYL3
    term:
      id: hgnc:7584
      label: MYL3
  features: >-
    Exome sequencing of three consanguineous Iranian families identified
    homozygous MYL3 variants that go beyond missense: a nonsense allele
    (c.106G>T, p.Glu36Ter), an essential splice-acceptor allele (c.482-1G>A
    predicted to skip exon 5 and disrupt the EF-hand calcium-binding domains),
    and a missense allele (c.170C>A, p.Ala57Asp). Phenotypes ranged from
    infantile- to early-adulthood-onset hypertrophic or dilated cardiomyopathy
    with sudden cardiac death. Morpholino knockdown of the zebrafish MYL3
    orthologue cmlc1 impaired cardiac function and was not rescued by the
    mutant alleles, providing functional support for a true loss-of-function
    mechanism in the recessive form.
  inheritance:
  - name: Autosomal Recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:33288880
    reference_title: "Autosomal recessive cardiomyopathy and sudden cardiac death associated with variants in MYL3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      and a presumable homozygous essential splice acceptor variant (c.482-1G>A,
      predicted to result in skipping of exon 5).
    explanation: >-
      Identifies a biallelic essential splice-acceptor MYL3 allele alongside a
      homozygous nonsense allele, extending the mutational spectrum beyond
      missense. (The nonsense and missense alleles are named in the same
      sentence; this bracket-free portion is quoted because the validator
      normalises square-bracketed protein nomenclature.)
  - reference: PMID:33288880
    reference_title: "Autosomal recessive cardiomyopathy and sudden cardiac death associated with variants in MYL3."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Morpholino knockdown of the MYL3 orthologue in zebrafish, cmlc1, resulted
      in compromised cardiac function, which could not be rescued by
      reintroduction of MYL3 carrying either the nonsense c.106G>T or the
      missense c.170C>A variants.
    explanation: >-
      Zebrafish rescue failure provides functional support that these alleles
      are loss-of-function.
  - reference: PMID:33288880
    reference_title: "Autosomal recessive cardiomyopathy and sudden cardiac death associated with variants in MYL3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our data demonstrate that homozygous MYL3 loss-of-function variants can
      cause of recessive cardiomyopathy and occurrence of sudden cardiac death,
      most likely due to impaired or loss of myosin essential light chain
      function.
    explanation: >-
      States the loss-of-function conclusion for biallelic MYL3 disease.
diagnosis:
- name: Cardiac magnetic resonance imaging with late gadolinium enhancement
  diagnosis_term:
    preferred_term: Cardiac magnetic resonance imaging with late gadolinium enhancement
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  description: >-
    The genotype-relevant imaging study. MYL3 disease favours mid-ventricular
    rather than basal septal hypertrophy, and the resulting mid-cavity
    obliteration and apical aneurysm sit in exactly the segments
    echocardiography images worst. In the reported MYL3 case, cardiac MRI was
    what established the apical aneurysm and the delayed gadolinium enhancement,
    both of which then drove the ICD decision.
  results: >-
    Mid-cavity obstruction, left ventricular apical aneurysm and diffuse delayed
    gadolinium enhancement; enhancement burden and aneurysm are themselves
    sudden-death risk markers.
  evidence:
  - reference: PMID:35288424
    reference_title: "Mutation of the MYL3 gene in a patient with mid-ventricular obstructive hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cardiac MRI detected positive features of left ventricular mid-cavity
      obstruction, left ventricular apical aneurysm and delayed gadolinium
      enhancement
    explanation: >-
      Documents the diagnostic yield of cardiac MRI in a genotyped MYL3 patient,
      including the two findings that changed management.
- name: Transthoracic echocardiography with attention to mid-ventricular segments
  diagnosis_term:
    preferred_term: Transthoracic echocardiography
    term:
      id: NCIT:C16525
      label: Echocardiography Test
  description: >-
    First-line imaging, but it must be read with the MYL3 morphology in mind:
    the gradient to look for is mid-cavitary, and its absence at the outflow
    tract is not reassurance. In the reported case echocardiography found a
    mid-cavitary resting gradient with explicitly no outflow tract obstruction
    and no systolic anterior motion. Serial studies are warranted because the
    intracavitary gradient is documented to progress.
  results: >-
    Mid-ventricular-predominant hypertrophy, mid-cavitary resting gradient,
    biatrial dilation and diastolic dysfunction, typically without left
    ventricular outflow tract obstruction or systolic anterior motion.
  evidence:
  - reference: PMID:35288424
    reference_title: "Mutation of the MYL3 gene in a patient with mid-ventricular obstructive hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      TTE identified biatrial dilation, LV hypertrophy predominantly in the
      mid-ventricular segments, mid-cavitary rest gradient of 33 mm Hg,
      mild-to-moderate LV systolic dysfunction, grade II diastolic dysfunction
      and no evidence of LVOTO or SAM of the mitral valve at rest.
    explanation: >-
      Records the echocardiographic pattern in a genotyped MYL3 patient,
      including the diagnostically important absence of outflow obstruction.
- name: Ambulatory (Holter) electrocardiographic monitoring
  diagnosis_term:
    preferred_term: Holter monitoring
    term:
      id: NCIT:C38064
      label: Holter Monitoring
  description: >-
    Arrhythmia surveillance for sudden-death risk stratification. Detection of
    non-sustained ventricular tachycardia is one of the risk markers that
    determined the ICD recommendation in the reported MYL3 patient.
  results: >-
    Runs of non-sustained ventricular tachycardia; a positive result contributes
    to the sudden-death risk-marker count.
  evidence:
  - reference: PMID:35288424
    reference_title: "Mutation of the MYL3 gene in a patient with mid-ventricular obstructive hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      with Holter monitoring assessment displaying segments of non-sustained
      ventricular tachycardia
    explanation: >-
      Documents the arrhythmia yield of Holter monitoring in a MYL3 carrier.
- name: Multigene hypertrophic cardiomyopathy panel testing
  diagnosis_term:
    preferred_term: Multigene hypertrophic cardiomyopathy panel testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  description: >-
    MYL3 is one of only eight genes with definitive evidence for hypertrophic
    cardiomyopathy and is on essentially all clinical panels, so a standard
    multigene panel — not single-gene MYL3 testing — is the appropriate first
    genetic test. Single-gene MYL3 testing is appropriate only for site-specific
    cascade testing of relatives once a familial variant is known. In
    consanguineous families the panel must be interpreted with recessive
    inheritance in mind, or a homozygous MYL3 genotype will be misread as
    uninformative heterozygosity.
  results: >-
    Identification of a pathogenic MYL3 variant establishes the molecular
    diagnosis and enables cascade testing; a homozygous or compound genotype
    changes both the prognosis and the recurrence risk given to the family.
  evidence:
  - reference: PMID:30681346
    reference_title: "Evaluating the Clinical Validity of Hypertrophic Cardiomyopathy Genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of 33 HCM genes, only 8 (24%) were categorized as definitive ( MYBPC3,
      MYH7, TNNT2, TNNI3, TPM1, ACTC1, MYL2, and MYL3)
    explanation: >-
      Justifies including MYL3 on, and restricting testing to, the
      definitive-evidence gene set rather than an oversized panel.
  - reference: PMID:33288880
    reference_title: "Autosomal recessive cardiomyopathy and sudden cardiac death associated with variants in MYL3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      and a presumable homozygous essential splice acceptor variant (c.482-1G>A,
      predicted to result in skipping of exon 5).
    explanation: >-
      Illustrates the biallelic genotypes that exome-scale testing in
      consanguineous families is needed to detect, and that a
      dominant-inheritance reading of a panel would miss.
  notes: >-
    Deliberately omitted from this section: chromosomal microarray, karyotype,
    FISH, mitochondrial DNA and repeat-expansion testing. There is no copy-number
    or repeat mechanism in MYL3 disease (ClinGen dosage score 0), so those tests
    belong to the differential-diagnosis workup of syndromic or mitochondrial
    left ventricular hypertrophy, not to a MYL3 diagnosis.
treatments:
- name: Beta-Blocker and Other Negative Inotropic Pharmacotherapy
  description: >-
    Symptomatic management of obstructive and diastolic disease follows general
    hypertrophic cardiomyopathy practice — beta-blockers, non-dihydropyridine
    calcium channel blockers, and disopyramide. No MYL3-specific trial or
    cohort evidence exists; treatment is extrapolated from hypertrophic
    cardiomyopathy as a whole.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  notes: >-
    Unsourced at the MYL3 level by design: no publication reports outcomes of
    negative inotropic therapy in MYL3 carriers specifically.
- name: Cardiac Myosin Inhibition
  description: >-
    Cardiac myosin inhibitors (mavacamten) reduce the fraction of myosin heads
    in the disordered relaxed state and restore the super-relaxed state. This is
    the direct pharmacological counterpart of the MYL3 A57G lesion, which
    inhibits the super-relaxed state and increases the number of myosin heads
    available for actin interaction; the mouse work explicitly proposes
    normalizing myosin motor function with myosin-specific therapeutics to avert
    the hypercontractile state. Whether this benefit is realised in MYL3
    carriers has not been tested clinically.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: mavacamten
    - preferred_term: aficamten
      term:
        id: CHEBI:747213
        label: aficamten
  target_mechanisms:
  - target: Thick Filament Interface Disruption and Loss of Super-Relaxed State
    treatment_effect: INHIBITS
    description: >-
      Cardiac myosin inhibitors act on the same super-relaxed/disordered-relaxed
      equilibrium that MYL3 variants perturb.
  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: >-
      45 (37%) of 123 patients on mavacamten versus 22 (17%) of 128 on placebo
      met the primary endpoint
    explanation: >-
      Randomised phase 3 evidence that cardiac myosin inhibition improves
      exercise capacity and symptoms in obstructive hypertrophic cardiomyopathy.
      Enrolment was not stratified by genotype, so this establishes the drug
      class, not a MYL3-specific effect.
  - reference: PMID:38739079
    reference_title: "Aficamten for Symptomatic Obstructive Hypertrophic Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The results for all 10 secondary end points were significantly improved
      with aficamten as compared with placebo.
    explanation: >-
      Independent randomised phase 3 confirmation of the myosin-inhibitor class
      effect with a second agent (aficamten, SEQUOIA-HCM). Also not
      MYL3-stratified.
  - reference: PMID:28371863
    reference_title: "Hypercontractile mutant of ventricular myosin essential light chain leads to disruption of sarcomeric structure and function and results in restrictive cardiomyopathy in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Future efforts should be directed toward normalization of myosin motor
      function and the use of myosin-specific therapeutics to avert the
      hypercontractile state of E143K-myosin and prevent pathological cardiac
      remodelling.
    explanation: >-
      Provides the mechanistic rationale for myosin-targeted therapy in MYL3
      disease. PARTIAL because it is a proposal from a mouse study, not
      clinical evidence of benefit in MYL3 carriers.
  notes: >-
    Mavacamten and aficamten are both approved/late-phase for symptomatic
    obstructive hypertrophic cardiomyopathy generally. No
    MYL3-genotype-stratified efficacy data exist for either agent; the
    genotype-specific argument here is mechanistic (the SRX/DRX equilibrium
    these drugs act on is the one MYL3 variants perturb), not clinical.
    Mavacamten is deliberately left without an ontology term: NCIT:C174901
    Mavacamten exists but sits under Inotropic Support rather than Pharmacologic
    Substance, so it is not reachable from the ChemicalEntityTerm enum roots and
    would fail term validation, and CHEBI has no mavacamten term. Aficamten
    carries CHEBI:747213. Do not "fix" the missing mavacamten term by
    substituting a poorly fitting one.
    A caution that follows from the two-mechanism controversy recorded in the
    discussions block: myosin inhibition is rational under the
    hypercontractility model but would be expected to worsen disease under the
    ELC-deficiency model that applies to the recessive loss-of-function alleles.
- name: Implantable Cardioverter Defibrillator
  description: >-
    ICD implantation for primary or secondary prevention of sudden cardiac
    death in patients meeting general hypertrophic cardiomyopathy risk criteria.
    MYL3 genotype is not itself an established risk modifier.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: Implantable cardioverter-defibrillator placement
    term:
      id: NCIT:C80435
      label: Implantable Cardioverter-Defibrillator Placement
  evidence:
  - reference: PMID:35288424
    reference_title: "Mutation of the MYL3 gene in a patient with mid-ventricular obstructive hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Risk stratification for an implantable cardioverter defibrillator (ICD)
      was conducted due to the presence of an LV apical aneurysm, NSVT, LVSD,
      late gadolinium enhancement (LGE) on CMR and SCD in first-degree
      relatives.
    explanation: >-
      Records the risk-marker set that drove the ICD decision in a genotyped
      MYL3 patient — general hypertrophic cardiomyopathy criteria applied to a
      MYL3 carrier, with the apical aneurysm as the genotype-relevant addition.
  notes: >-
    No MYL3-specific sudden-death risk stratification data are available; see
    the knowledge gap on MYL3 natural history. The evidence here documents that
    general risk criteria were applied in one MYL3 case, not that MYL3 genotype
    modifies the indication.
- name: Extended Mid-Ventricular Septal Myectomy
  description: >-
    Surgical septal reduction for drug-refractory obstruction. This is the
    treatment where MYL3 morphology changes the operation rather than merely
    the indication: because the obstruction in this genotype is mid-cavitary
    rather than subaortic, relief requires an extended mid-ventricular myectomy,
    with papillary muscle reorientation where the papillary muscles contribute
    to the obstruction — not a standard subaortic myectomy. Alcohol septal
    ablation, the usual catheter-based alternative, is generally unsuitable
    here, since the septal perforator territory it targets does not supply the
    mid-ventricular hypertrophy.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Myectomy
    term:
      id: NCIT:C51591
      label: Myectomy
  evidence:
  - reference: PMID:12021217
    reference_title: "Myosin light chain mutation causes autosomal recessive cardiomyopathy with mid-cavitary hypertrophy and restrictive physiology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      characterized by mid-cavitary hypertrophy and restrictive physiology
    explanation: >-
      Establishes the mid-cavitary rather than subaortic location of the
      obstruction, which is the anatomical premise for choosing an extended
      mid-ventricular myectomy. PARTIAL because the source documents the
      morphology, not the operation or its outcome.
  - reference: PMID:35288424
    reference_title: "Mutation of the MYL3 gene in a patient with mid-ventricular obstructive hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      TTE identified biatrial dilation, LV hypertrophy predominantly in the
      mid-ventricular segments, mid-cavitary rest gradient of 33 mm Hg,
      mild-to-moderate LV systolic dysfunction, grade II diastolic dysfunction
      and no evidence of LVOTO or SAM of the mitral valve at rest.
    explanation: >-
      Independently documents a mid-cavitary gradient with explicitly absent
      outflow tract obstruction in a genotyped MYL3 patient. PARTIAL for the
      same reason — it corroborates the anatomy that dictates the procedure
      choice, not the procedure itself.
  notes: >-
    Deliberately unsourced at the level of MYL3 surgical outcomes: no published
    series reports septal reduction therapy in MYL3 carriers, and neither cited
    patient underwent myectomy. The evidence attests the mid-cavitary anatomy;
    the procedural inference from that anatomy is guideline-level hypertrophic
    cardiomyopathy practice, not a MYL3 finding. The contrast with alcohol
    septal ablation is stated for the same reason and carries no MYL3-specific
    evidence.
- name: Heart Transplantation
  description: >-
    Transplantation for end-stage disease, and the marker of how severe the
    recessive loss-of-function form can be: the proband homozygous for the MYL3
    p.Glu36Ter nonsense allele was diagnosed with dilated cardiomyopathy at age
    6 and transplanted soon after, while his brother died of sudden cardiac
    death at age 2.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Heart transplantation
    term:
      id: NCIT:C15246
      label: Heart Transplantation
  evidence:
  - reference: PMID:33288880
    reference_title: "Autosomal recessive cardiomyopathy and sudden cardiac death associated with variants in MYL3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He underwent heart transplantation soon after diagnosis.
    explanation: >-
      Documents transplantation in a genotyped biallelic MYL3 patient, the only
      MYL3 case in the literature to reach transplant.
  notes: >-
    A single case. Transplantation is recorded here because it is documented in
    a MYL3 genotype, not because MYL3 carries a published transplant rate.
- name: Oral Anticoagulation
  description: >-
    Anticoagulation for cardioembolic stroke prevention, indicated by atrial
    fibrillation and — independently — by an akinetic left ventricular apical
    aneurysm with thrombus risk. In the reported MYL3 case long-term
    anticoagulation was started after recurrent cardioembolic cerebrovascular
    events, and the entry records the trade-off honestly: an extra-axial
    haemorrhage extending into the posterior fossa was observed and attributed
    to it.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: anticoagulant agent
      term:
        id: NCIT:C263
        label: Anticoagulant Agent
  target_mechanisms:
  - target: Atrial Remodeling and Intracavitary Stasis
    treatment_effect: INHIBITS
    description: >-
      Anticoagulation does not remove the stasis substrate; it blocks the
      thrombus-formation step that converts stasis into systemic embolization.
  evidence:
  - reference: PMID:35288424
    reference_title: "Mutation of the MYL3 gene in a patient with mid-ventricular obstructive hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Long-term anticoagulation was initiated 2 years later when the patient was
      admitted to a specialist stroke unit for a left corona radiata infarct.
    explanation: >-
      Documents initiation of long-term anticoagulation in a genotyped MYL3
      patient for cardioembolic stroke.
  - reference: PMID:35288424
    reference_title: "Mutation of the MYL3 gene in a patient with mid-ventricular obstructive hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Concurrent extra-axial haemorrhage extension into the posterior fossa,
      potentially secondary to long-term anticoagulation, was also observed.
    explanation: >-
      Records the bleeding harm attributed to the same therapy. PARTIAL because
      the source itself hedges the attribution ("potentially secondary to").
  notes: >-
    No specific agent is named: the cited case does not state whether a vitamin K
    antagonist or a direct oral anticoagulant was used, so the therapeutic_agent
    is bound at the class level rather than inventing a drug identity.
- name: Genetic Counseling and Cascade Screening
  description: >-
    Family evaluation is central. Cascade screening in a MYL3 family identified
    nine further heterozygous carriers, several with subdiagnostic ECG or
    echocardiographic findings, and recessive inheritance in children with
    cardiomyopathy must be recognised for correct family counseling.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:12021217
    reference_title: "Myosin light chain mutation causes autosomal recessive cardiomyopathy with mid-cavitary hypertrophy and restrictive physiology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Recognizing recessive inheritance in children with cardiomyopathy is
      essential for appropriate family counseling.
    explanation: >-
      Directly supports genetic counseling, and specifically recognition of
      recessive MYL3 inheritance, as a management action.
  - reference: PMID:22957257
    reference_title: "A novel Myosin essential light chain mutation causes hypertrophic cardiomyopathy with late onset and low expressivity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cascade screening revealed a further nine heterozygote mutation carriers
    explanation: >-
      Demonstrates the yield of cascade family screening in a MYL3 family.
  notes: >-
    Because penetrance is age-dependent, young genotype-positive relatives
    require ongoing serial evaluation rather than a single normal study.
clinical_trials:
- name: NCT03470545
  phase: PHASE_III
  status: COMPLETED
  description: >-
    EXPLORER-HCM. Randomised, double-blind, placebo-controlled trial of
    mavacamten in adults with symptomatic obstructive hypertrophic
    cardiomyopathy. The pivotal trial establishing cardiac myosin inhibition as
    a disease-directed therapy class — the class whose molecular target is the
    super-relaxed/disordered-relaxed equilibrium that MYL3 variants perturb.
  target_phenotypes:
  - preferred_term: Left ventricular outflow tract obstruction
    term:
      id: HP:0032092
      label: Left ventricular outflow tract obstruction
  evidence:
  - reference: clinicaltrials:NCT03470545
    reference_title: "A Randomized, Double Blind, Placebo Controlled Clinical Study to Evaluate Mavacamten (MYK-461) in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This is a multicenter, international, double-blind study of the
      administration of mavacamten in participants with symptomatic obstructive
      HCM (oHCM).
    explanation: >-
      Confirms the design and population of the trial underpinning the cardiac
      myosin inhibition treatment entry.
  notes: >-
    Not MYL3-stratified. Enrolment was by phenotype (symptomatic obstructive
    disease), not genotype, and no MYL3 subgroup was reported. Recorded as
    disease-class context for the myosin-inhibitor rationale, not as evidence of
    benefit in MYL3 carriers.
- name: NCT04349072
  phase: PHASE_III
  status: COMPLETED
  description: >-
    VALOR-HCM. Randomised, double-blind, placebo-controlled trial of mavacamten
    in patients already eligible for septal reduction therapy, testing whether
    pharmacological myosin inhibition can avert the procedure. Directly relevant
    to this entry because septal reduction in MYL3 disease means an extended
    mid-ventricular myectomy, a higher-complexity operation than the standard
    subaortic one.
  evidence:
  - reference: clinicaltrials:NCT04349072
    reference_title: "A Randomized, Double-blind, Placebo-controlled Study to Evaluate Mavacamten in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy Who Are Eligible for Septal Reduction Therapy"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      will evaluate the effect of mavacamten treatment on reducing the number of
      septal reduction therapy (SRT) procedures performed in subjects with
      symptomatic obstructive hypertrophic cardiomyopathy
    explanation: >-
      Establishes the trial's septal-reduction-avoidance endpoint, which is the
      link between the pharmacotherapy and surgical arms of this entry.
  notes: >-
    Not MYL3-stratified. Note also that eligibility was defined by guideline
    criteria written around subaortic obstruction, so the trial population is
    not the mid-cavity anatomy that characterises MYL3 disease.
- name: NCT05186818
  phase: PHASE_III
  status: COMPLETED
  description: >-
    SEQUOIA-HCM. Randomised, double-blind, placebo-controlled trial of aficamten,
    a second-generation selective cardiac myosin inhibitor, in symptomatic
    obstructive hypertrophic cardiomyopathy. Provides independent confirmation
    of the drug class with a second agent.
  target_phenotypes:
  - preferred_term: Left ventricular outflow tract obstruction
    term:
      id: HP:0032092
      label: Left ventricular outflow tract obstruction
  evidence:
  - reference: clinicaltrials:NCT05186818
    reference_title: "A Phase 3, Multi-Center, Randomized, Double-blind, Placebo-controlled Trial to Evaluate the Efficacy and Safety of CK-3773274 in Adults With Symptomatic Hypertrophic Cardiomyopathy and Left Ventricular Outflow Tract Obstruction"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The purpose of this study is to evaluate the efficacy and safety of
      aficamten (CK-3773274) versus placebo in adults with symptomatic
      hypertrophic cardiomyopathy (HCM) and left ventricular outflow tract
      obstruction.
    explanation: >-
      Confirms the design and population of the aficamten trial cited in the
      cardiac myosin inhibition treatment entry.
  notes: >-
    Not MYL3-stratified, and enrolment required left ventricular outflow tract
    obstruction — the pattern MYL3 patients characteristically do not have. The
    extrapolation to MYL3 mid-cavity disease is mechanistic, not empirical.
histopathology:
- name: Sarcomeric ultrastructural disruption with interstitial and replacement fibrosis
  diagnostic: false
  description: >-
    Myocardial fibrosis progressing with age, together with sarcomeric
    ultrastructural defects, is the tissue-level correlate of MYL3 disease. The
    direct observations are from transgenic mouse models of the MYL3 A57G and
    E143K essential light chain mutations; in humans, histopathology contributed
    to the diagnosis in the infantile MYL3 case, but no published MYL3 series
    describes the human histological pattern in detail.
  finding_term:
    preferred_term: interstitial and replacement myocardial fibrosis
    term:
      id: NCIT:C3044
      label: Fibrosis
  evidence:
  - reference: PMID:28371863
    reference_title: "Hypercontractile mutant of ventricular myosin essential light chain leads to disruption of sarcomeric structure and function and results in restrictive cardiomyopathy in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The hearts of mutant-mice demonstrated ultrastructural defects and
      fibrosis that progressively worsened in senescent animals
    explanation: >-
      Direct histological and ultrastructural observation in a MYL3 essential
      light chain mutant model.
  - reference: PMID:23594557
    reference_title: "Infantile hypertrophic cardiomyopathy associated with a novel MYL3 mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report on genetic and histopathological findings in a 3-month-old
      infant presenting with severe progressive HCM arising from a mutation in
      the gene encoding the essential light chain of myosin (MYL3).
    explanation: >-
      Establishes that human MYL3 histopathology has been examined and
      contributed to a diagnosis. PARTIAL because the abstract states that
      histopathological findings were obtained without describing them, so it
      cannot support any specific tissue finding.
  notes: >-
    Myofiber disarray (HP:0031318) is the classic hypertrophic cardiomyopathy
    histological finding and is very likely present in MYL3 disease, but it is
    deliberately NOT curated here: no cached MYL3 source describes it, and
    asserting it would mean either an unsourced claim or a snippet quoted from a
    non-MYL3 paper. This absence is a gap in the MYL3 literature, not an
    oversight in this entry.
discussions:
- discussion_id: myl3_natural_history_gap
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    What is the natural history, penetrance, and sudden-death risk of
    MYL3-related hypertrophic cardiomyopathy, and does MYL3 genotype modify
    outcome relative to other sarcomeric genes?
  attaches_to:
  - pathophysiology#MYL3 Essential Light Chain Variant — Altered Lever-Arm and Actin Contact
  - phenotypes#Sudden Cardiac Death
  rationale: >-
    MYL3 is a definitive hypertrophic cardiomyopathy gene, but published human
    data are limited to single families and case reports. Penetrance is the one
    dimension where this has partly improved: a meta-analysis of
    cascade-screened nonproband relatives places MYL3 at roughly 32%, the lowest
    of the definitive sarcomere genes, and allele-specific pedigree estimates
    run from 40% (p.V79I) to 88% (p.R94H) — so penetrance is now bounded, but
    only as a pooled cross-study figure plus two single-pedigree values, with no
    prospective MYL3 cohort behind any of them and a spread wide enough that no
    single number can be quoted to a family. The rest of the natural history
    remains genuinely unmeasured: sudden death is asserted as an association
    without a denominator, no MYL3-stratified outcome cohort exists, and no
    MYL3-specific survival curve, arrhythmia rate, atrial fibrillation
    incidence, or stroke rate has been published. Consequently every management
    recommendation in this entry is extrapolated from hypertrophic
    cardiomyopathy generally rather than from MYL3 evidence.
- discussion_id: myl3_loss_of_function_vs_hypercontractility
  kind: CONTROVERSY
  status: OPEN
  prompt: >-
    Does MYL3 Glu143Lys act through loss of function, as originally proposed
    from the human recessive pedigree, or through myosin hypercontractility, as
    characterised in transgenic mice?
  attaches_to:
  - pathophysiology#Thick Filament Interface Disruption and Loss of Super-Relaxed State
  - genetic#MYL3 Glu143Lys (Recessive Allele)
  rationale: >-
    The human recessive pedigree inferred a loss-of-function mechanism from the
    requirement for two mutant alleles and the normal phenotype of
    heterozygotes, and a later study of three consanguineous families found
    biallelic nonsense and splice-acceptor MYL3 alleles with failure of
    zebrafish rescue — strong independent support for genuine loss of function
    in the recessive form. Transgenic E143K mice, by contrast, show increased
    duty ratio, increased actin affinity, increased actin-activated ATPase and
    stabilisation of the super-relaxed state — a hypercontractile, not
    hypomorphic, molecular phenotype. The most likely reconciliation is that
    MYL3 disease is mechanistically split (dominant missense alleles acting by
    altered cross-bridge mechanics; recessive null alleles acting by ELC
    insufficiency), but this has not been shown directly, and it matters
    because myosin-inhibitor therapy is rational only under the
    hypercontractility model and could be harmful under the deficiency model.
  evidence:
  - reference: PMID:33288880
    reference_title: "Autosomal recessive cardiomyopathy and sudden cardiac death associated with variants in MYL3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There are, however, no reports of DCM associated with MYL3 variants or
      cardiomyopathy associated with likely ELC deficiency due to nonsense or
      essential splice acceptor variants in MYL3.
    explanation: >-
      Frames ELC deficiency from null alleles as a mechanism distinct from the
      previously described missense disease, motivating the two-mechanism
      reading.
- discussion_id: myl3_mouse_to_human_fidelity
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Do the transgenic MYL3 mouse models faithfully reproduce human MYL3
    hypertrophic cardiomyopathy, given that Tg-A57G mice develop eccentric
    hypertrophy with enhanced left ventricular cavity dimension rather than the
    concentric hypertrophy that defines the human disease?
  attaches_to:
  - pathophysiology#Cardiomyocyte Hypertrophy, Myocardial Stiffness and Fibrosis
  - phenotypes#Myocardial Fibrosis
  rationale: >-
    Most of the mechanistic content in this entry — super-relaxed state
    inhibition, calcium sensitisation, fibrosis, progressive remodeling — comes
    from transgenic mice expressing human MYL3 A57G or E143K. Echocardiography
    in Tg-A57G mice showed a phenotype of eccentric hypertrophy with enhanced
    left ventricular cavity dimension and no change in wall thickness, which is
    not the human hypertrophic cardiomyopathy morphology; and E143K, a recessive
    allele in humans, is modeled as a dominantly expressed transgene producing
    restrictive cardiomyopathy. The translational validity of these models for
    human CMH8 therefore remains an open question rather than an absence of
    evidence.
  evidence:
  - reference: PMID:23748425
    reference_title: "Discrete effects of A57G-myosin essential light chain mutation associated with familial hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Echocardiography examination showed a phenotype of eccentric hypertrophy
      in Tg-A57G mice, enhanced left ventricular (LV) cavity dimension without
      changes in LV posterior/anterior wall thickness.
    explanation: >-
      Documents the eccentric, cavity-dilating murine morphology that differs
      from the concentric hypertrophy of human hypertrophic cardiomyopathy.
- discussion_id: myl3_skeletal_muscle_gap
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Is skeletal myopathy a genuine and generalisable component of MYL3-related
    disease, or was it specific to the original 1996 kindreds?
  attaches_to:
  - pathophysiology#Skeletal Muscle Involvement
  - phenotypes#Skeletal Myopathy
  rationale: >-
    The founding report described abnormal skeletal muscle alongside cardiac
    hypertrophy for essential and regulatory light chain mutations together,
    but later MYL3 case reports and cohort screens are cardiac-only and do not
    report systematic skeletal muscle evaluation. Whether skeletal involvement
    is under-ascertained or genuinely absent from most MYL3 genotypes is
    unknown, and no MYL3 series reports muscle biopsy or CK data.
classifications:
  harrisons_chapter:
  - classification_value: CARDIOVASCULAR
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
datasets:

📚

References & Deep Research

References

1

PMID:20301725

Nonsyndromic Hypertrophic Cardiomyopathy Overview

No top-level findings curated for this source.

Deep Research

1

Claude Code ▸

1. Disease Information

claude-haiku-4-5-20251001, claude-opus-5[1m] 16 citations 2026-08-01T21:25:36.807453

1. Disease Information

1.1 Overview

Hypertrophic cardiomyopathy 8 (CMH8) is the form of familial hypertrophic cardiomyopathy caused by variants in MYL3, the gene encoding the ventricular/slow-skeletal myosin essential light chain (ELC, also "alkali light chain", MLC-1v/MLC1SB, CMLC1). It is one of the eight sarcomere genes with a Definitive ClinGen gene–disease relationship to HCM, but is quantitatively a minor HCM gene (well under 5% of genotype-positive HCM; myosin light chain genes together ≈1% of HCM).

Two features distinguish CMH8 from the "generic" HCM entry and justify a separate knowledge-base entity:

A characteristic morphological subtype — hypertrophy that is maximal in the mid-ventricular segments and papillary muscles, producing mid-cavity (intracavitary) obstruction rather than classical subaortic LVOT obstruction, sometimes with restrictive physiology and (in one report) an LV apical aneurysm. This is reflected in the OMIM alternative title "Cardiomyopathy, hypertrophic, mid-left ventricular chamber type, 1."
A genuine dual inheritance architecture — classic autosomal dominant missense disease and well-documented autosomal recessive disease from biallelic loss-of-function (LOF) MYL3 variants, which is unusual among sarcomeric cardiomyopathies and has direct counseling consequences.

Olson et al. framed the dominant/recessive duality explicitly: "Distinct mutations affecting the same sarcomeric protein can cause either dominant or recessive cardiomyopathy." (PMID:12021217)

1.2 Key identifiers

Resource	Identifier	Notes
OMIM (phenotype)	#608751 — CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 8; CMH8	Phenotype–gene relationship: MYL3, 3p21.31
OMIM (gene)	*160790 — MYOSIN, LIGHT CHAIN 3, ALKALI, VENTRICULAR, SKELETAL, SLOW; MYL3
MONDO	MONDO:0012111 — hypertrophic cardiomyopathy 8	Verified with OAK (`ols:mondo`)
MedGen	CUI C1837471 (UID 324806)	Gene: MYL3, 3p21.31; xref Monarch MONDO:0012111
HGNC (gene)	hgnc:7584 — MYL3	Lowercase prefix per repo convention; already used in `kb/disorders/Hypertrophic_Cardiomyopathy.yaml`
UniProt	P08590 (MYL3_HUMAN), 195 aa, ~21.9 kDa	3 EF-hand regions (49–86, 128–163, 163–195); N-terminal disordered extension ~1–37
Ensembl	ENSG00000160808
ClinVar	517 records for MYL3[gene]; 14 pathogenic/likely-pathogenic (queried 2026-08-01 via E-utilities)
ICD-10	I42.1 (obstructive hypertrophic cardiomyopathy) / I42.2 (other hypertrophic cardiomyopathy)	No CMH8-specific code
ICD-11	BC43.0 Hypertrophic cardiomyopathy (BC43.00 obstructive)	No CMH8-specific code
MeSH	D024741 Cardiomyopathy, Hypertrophic, Familial (verified via MeSH E-utilities UID 68024741); broader D002312 Cardiomyopathy, Hypertrophic
Orphanet	No CMH8-specific ORPHA code; subsumed under familial isolated hypertrophic cardiomyopathy	The local `references_cache/` contains no ORPHA record for this entity and orpha.net is bot-gated — not verified
ClinGen	MYL3–Hypertrophic cardiomyopathy (MONDO:0005045): Definitive, HCM GCEP, 2021-06-07, AD	Also MYL3–DCM: Disputed (DCM GCEP, 2025-05-30); MYL3–ARVC: Limited (2019-09-13); dosage: haploinsufficiency score 0, triplosensitivity 0 (2015-11-18)

1.3 Synonyms and alternative names

Cardiomyopathy, familial hypertrophic, 8; CMH8; HCM8
Cardiomyopathy, hypertrophic, mid-left ventricular chamber type, 1 (OMIM alternative title; MedGen synonym)
MYL3-related familial hypertrophic cardiomyopathy (MedGen synonym)
Myosin essential light chain–associated HCM; ELC-associated HCM
Mid-cavitary / mid-ventricular obstructive hypertrophic cardiomyopathy (phenotype-level descriptor, not a formal synonym)

1.4 Nature of the underlying evidence

Knowledge of CMH8 is derived almost entirely from aggregated disease-level resources and small family/case series, not from EHR or patient-level registries: - Landmark family-based linkage/candidate-gene studies (PMID:8673105; PMID:12021217) - Consanguineous-family exome studies (PMID:33288880) - Cohort screening studies of sarcomere genes (PMID:12404107; PMID:20031618; PMID:25611685; PMID:26443374; PMID:37431535) - Curated variant/gene resources (ClinVar, ClinGen HCM GCEP, gnomAD) - Single case reports for the rarest phenotypes (PMID:35288424; PMID:23594557) - Mechanistic transgenic-mouse, iPSC-CM, zebrafish and biophysics literature

There is no CMH8-specific patient registry; MYL3 carriers are pooled into general HCM registries (e.g., SHaRe, PMID:30297972) and meta-analyses (PMID:37929589).

2. Etiology

2.1 Primary causal factor

CMH8 is a monogenic sarcomeropathy: heterozygous (dominant) or homozygous/biallelic (recessive) variants in MYL3 (hgnc:7584), encoding the ventricular myosin essential light chain that stabilizes the myosin lever arm/neck region and, through its cardiac-specific N-terminal extension, contacts actin.

Poetter et al. established causality in the founding report: "We report here the identification of distinct missense mutations in a skeletal/ventricular ELC and RLC, each of which are associated with a rare variant of cardiac hypertrophy as well as abnormal skeletal muscle. We show that myosin containing the mutant ELC has abnormal function…" (PMID:8673105, Nat Genet 1996; HUMAN_CLINICAL + IN_VITRO)

2.2 Genetic risk factors

Causal variants (autosomal dominant, missense): M149V, R154H (PMID:8673105); R94H (PMID:26443374); V79I (PMID:22957257); E152K/c.454G>A (PMID:35288424); E56G, E177G (UniProt P08590 variant annotations; biophysically characterized in PMID:36509720); c.530A>G exon 5 (infantile, PMID:23594557).

Causal variants (autosomal recessive): homozygous E143K (PMID:12021217); homozygous A57D (c.170C>A), homozygous nonsense E36* (c.106G>T), and homozygous essential splice-acceptor c.482-1G>A (PMID:33288880).

Susceptibility/penetrance context: MYL3 has the lowest measured penetrance among the definitive sarcomere genes — "Penetrance varied from ≈32% for MYL3 (myosin light chain 3) to ≈55% for MYBPC3 …, ≈60% for TNNT2 … and TNNI3 …, and ≈65% for MYH7" (PMID:37929589, Circulation 2024). This makes MYL3 heterozygosity better modeled as a strongly-penetrant-but-incomplete risk allele than as a deterministic one.

Consanguinity as a population-level genetic risk factor: In a prospective Egyptian HCM cohort (n=514) vs. European comparison (n=684), "A higher prevalence of homozygous variants was observed in Egyptian patients (4.1% vs. 0.1%, P = 2 × 10-7), with variants in the minor HCM genes MYL2, MYL3, and CSRP3 more likely to present in homozygosity than the major genes, suggesting these variants are less penetrant in heterozygosity." (PMID:37431535, Eur Heart J 2023)

Modifier genes: No CMH8-specific modifier locus is established. Generic HCM modifiers (polygenic background, common-variant scores, second sarcomere variants) apply; note that digenic/compound sarcomere genotypes are documented in HCM cohorts generally (e.g., 5/42 mutation-positive pediatric patients carried two mutations, PMID:20031618). One report explicitly invoked genetic background to explain a null iPSC-CM result: "this may also reflect the genetic background of the heterozygote and the presence of gene modifiers in this individual" (PMID:33288880).

2.3 Environmental risk factors

No MYL3-specific environmental cause is established. Recognized general modifiers of HCM expression/outcome (extrapolated, not MYL3-specific): - Age — dominant determinant of penetrance; mean age at HCM diagnosis in P/LP carriers 38 years (95% CI 36–40) (PMID:37929589) - Sex — detection rates in clinical testing were "higher in females compared with males" (PMID:25611685); sex differences in HCM expression are well described - Family history / first-degree relationship to a proband — the operational risk factor driving cascade screening - Intense competitive exercise, afterload (hypertension), obesity — general HCM/LVH modifiers; no MYL3-stratified data - Catabolic/hemodynamic stressors (pregnancy, atrial fibrillation onset) precipitate decompensation but are not causal

2.4 Protective factors

Genetic: No validated protective allele. Notably, N-terminal ELC truncation is protective in mice for the HCM allele — "In A57G×Δ43 mice, Δ43 expression improved heart function and reduced hypertrophy and fibrosis" (PMID:39211545, iScience 2024, MODEL_ORGANISM) — a therapeutic hypothesis, not a human protective variant.
Heterozygosity for recessive LOF alleles is effectively "protected": "Family members with one Glu143Lys allele had normal echocardiograms and ECGs, even in late adulthood" (PMID:12021217), attributed to "compensatory mechanisms that preserve cardiac structure and function."
Environmental: No MYL3-specific protective exposure. Guideline-endorsed general measures (avoidance of dehydration/vasodilator excess in obstructive disease, treatment of hypertension, moderate exercise) are supportive, not disease-preventing (PMID:38718139).

2.5 Gene–environment interaction

No formal GxE study exists for MYL3. The mechanistically plausible interactions are (a) allele × age (dominant, quantified: penetrance ≈32%, late onset — PMID:22957257 reported mean age 47 in penetrant vs. 15 in non-penetrant carriers of p.V79I); (b) allele × consanguinity/ancestry (PMID:37431535); (c) allele × hemodynamic load — transgenic A57G mice show "a significant increase in passive tension in response to stretch … indicating a mutation-induced myocardial stiffness" (PMID:23748425), i.e., a load-dependent amplification loop.

3. Phenotypes

3.1 Cardiac structural phenotypes

Phenotype	HPO term (OAK-verified)	Onset	Severity	Course	Frequency	Evidence
Hypertrophic cardiomyopathy	HP:0001639 Hypertrophic cardiomyopathy	Infancy→late adult	Mild→severe	Progressive	Defining feature	PMID:8673105; 12021217; 33288880
Left ventricular hypertrophy	HP:0001712 Left ventricular hypertrophy	variable	max WT 18–21 mm reported	Progressive	Very frequent	PMID:22957257 (max WT 21 mm); PMID:26443374 (18±3 mm)
Asymmetric septal hypertrophy	HP:0001670 Asymmetric septal hypertrophy (also HP:0005144 Ventricular septal hypertrophy)	Adult	Substantial	Progressive	Frequent (R94H, A57G-family phenotype)	PMID:26443374; A57G described in "familial asymmetric septal hypertrophy" families per PMID:33288880
Mid-ventricular / mid-cavitary hypertrophy with mid-cavity obstruction	No exact HPO term (nearest: HP:0001712 + HP:0025445 Abnormal papillary muscle morphology) — ontology gap worth flagging	Childhood→adult	Gradients 16→41 mm Hg documented	Progressive/dynamic	The signature CMH8 morphology; 6/13 affected in the original M149V family had mid-LV chamber thickening	PMID:8673105; PMID:12021217; PMID:35288424
Papillary muscle hypertrophy	HP:0025445 Abnormal papillary muscle morphology (no dedicated hypertrophy term)	—	—	—	Reported	PMID:8673105 (papillary muscle involvement); PMID:35288424 (discussion of Poetter phenotype)
Left ventricular apical aneurysm	HP:6000144 Left ventricular aneurysm	Adult	High-risk feature	Progressive	Single case (first report in MYL3)	PMID:35288424: "To our knowledge, the presence of a left ventricular apical aneurysm has not been previously reported in literature concerning the MYL3 gene mutation."
Restrictive cardiomyopathy / restrictive physiology	HP:0001723 Restrictive cardiomyopathy	Childhood (recessive E143K)	Severe	Progressive	Homozygous E143K siblings	PMID:12021217
Dilated cardiomyopathy	HP:0001644 Dilated cardiomyopathy	Age 6 (transplanted)	Severe	Progressive	Rare; recessive LOF only; ClinGen calls MYL3–DCM Disputed	PMID:33288880
Left atrial enlargement	HP:0031295 Left atrial enlargement	Adult	54 mm reported	Progressive	Frequent	PMID:22957257
Myofiber disarray	HP:0031318 Myofiber disarray	—	—	—	Histopathologic hallmark of HCM (assumed for CMH8; MYL3-specific histopathology reported in PMID:23594557)	PMID:23594557
Myocardial fibrosis / late gadolinium enhancement	HP:0001685 Myocardial fibrosis	Adult	Diffuse LGE	Progressive	Reported	PMID:35288424 ("diffuse delayed gadolinium enhancement")
Cardiomegaly	HP:0001640 Cardiomegaly	—	—	—	Secondary	General HCM

3.2 Functional / hemodynamic and arrhythmic phenotypes

Phenotype	HPO term	Notes / evidence
Left ventricular diastolic dysfunction	HP:0025168	Grade II diastolic dysfunction reported (PMID:35288424)
Left ventricular systolic dysfunction	HP:0025169	EF 49–50%, mild-to-moderate LVSD (PMID:35288424)
Congestive heart failure	HP:0001635	NYHA class III CHF; BNP 4394 pg/mL (PMID:35288424)
Increased circulating brain natriuretic peptide	HP:0033534	Same case
Ventricular tachycardia (non-sustained)	HP:0004756	Holter NSVT (PMID:35288424)
Atrial fibrillation	HP:0005110	Refractory AF/atrial flutter (PMID:35288424)
Sudden cardiac death	HP:0001645	Recurring theme: "Mutations in MYL3 … are rare and have been associated with sudden death" (PMID:22957257); 4 SCD events in family A and 3 in family C (PMID:33288880)
Cardiac arrest	HP:0001695	Component of SCD
Syncope	HP:0001279	Notably absent in the mid-cavity/aneurysm case (PMID:35288424)
Dyspnea / exertional dyspnea	HP:0002094	Presenting symptom at age 26 (PMID:33288880); orthopnea (PMID:35288424)
Heart murmur	HP:0030148 (systolic: HP:0031664)	Index presentation of a 38-year-old asymptomatic male "referred because of a murmur" (PMID:22957257)
Palpitations	HP:0001962	MedGen HPO annotation for CMH8
Abnormal T-wave	HP:0005135; Abnormal EKG HP:0003115	MedGen HPO annotations
Exercise intolerance	HP:0003546	General HCM
Chest pain	HP:0100749	General HCM
Stroke (cardioembolic)	HP:0001297	Recurrent CVAs incl. retinal artery occlusion and gangliocapsular/corona radiata infarcts in the apical-aneurysm case (PMID:35288424)

3.3 Extracardiac phenotypes

Skeletal muscle involvement: The founding paper described the ELC/RLC phenotype as "a rare myopathy in human heart and skeletal muscle" with "abnormal skeletal muscle" (PMID:8673105) — HPO HP:0003198 Myopathy. This is not reproduced in most later cohorts: in the three recessive families, "Affected individuals from the three families showed no evidence of muscle weakness by neurological examination or by history." (PMID:33288880). Curation guidance: model skeletal myopathy as a rare/variable, historically-reported feature attached specifically to the Poetter alleles, not as a general CMH8 feature.
Horseshoe kidney in one homozygous E36* proband (PMID:33288880) — almost certainly coincidental in a consanguineous pedigree; do not curate as a CMH8 phenotype.

3.4 Laboratory abnormalities

Elevated BNP/NT-proBNP (LOINC 30934-4 / 33762-6; HP:0033534) — nonspecific heart-failure marker.
Troponin elevation is variable and not diagnostic. No CMH8-specific biomarker exists.

3.5 Quality-of-life impact

No MYL3-specific PRO data. From the HCM literature that CMH8 patients are enrolled in: - KCCQ-CSS and HCMSQ-SoB are the validated instruments; obstructive HCM produces clinically meaningful KCCQ deficits reversible with myosin inhibition (KCCQ-CSS +9.1 points vs. placebo, PMID:32871100). - Peak VO₂ impairment is the objective functional correlate (mean baseline peak VO₂ deficits; +1.7 mL/kg/min treatment effect with aficamten, PMID:38739079). - The dominant QoL burdens in this genotype specifically are (a) exertional dyspnea from mid-cavity gradient and diastolic dysfunction; (b) anxiety/activity restriction from SCD risk and ICD carriage; (c) stroke-related disability where apical aneurysm/AF coexist (PMID:35288424); (d) for families, the psychological burden of cascade screening in a low-penetrance gene where VUS are common.

4. Genetic / Molecular Information

4.1 Gene and protein

MYL3, 3p21.31, ~6 kb, 7 exons; transcript NM_000258 (variant nomenclature in the literature uses NM_000258.2/.3).
Protein P08590, 195 aa, ventricular/slow-skeletal myosin essential (alkali) light chain; contains a cardiac-specific N-terminal extension (~residues 1–43, disordered) that binds actin, plus three EF-hand-like regions (49–86, 128–163, 163–195) that are structural (the cardiac ELC does not bind Ca²⁺ productively; the "EF-hand Ca²⁺-binding motif" language used in the clinical literature refers to the motif architecture).
Expression: ventricular myocardium and slow-twitch skeletal muscle (long ELC isoform only in heart): "Cardiac musculature has been shown to only exhibit the long isoform, and studies have postulated the role of ELC as a modulator of crossbridge kinetics and optimum force production." (PMID:35288424)
Suggested GO annotations: GO:0032036 myosin heavy chain binding; GO:0003779 actin binding; GO:0003774 cytoskeletal motor activity; GO:0005509 calcium ion binding (motif-level); components GO:0030017 sarcomere, GO:0032982 myosin filament, GO:0016460 myosin II complex, GO:0005859 muscle myosin complex, GO:0031672 A band.

4.2 Reported pathogenic and candidate variants

Variant (protein)	cDNA	Type	Inheritance	Domain/position	Phenotype	Evidence
M149V	—	missense	AD (3-generation family)	conserved residue; lever-arm interface	HCM incl. mid-LV chamber thickening (6/13 affected)	PMID:8673105; biophysics PMID:36509720
R154H	—	missense	AD (de novo/family)	—	Young boy with massive mid-cavity chamber obstruction	PMID:8673105
E143K	—	missense (charge reversal)	AR (homozygous)	EF-hand region 2	Childhood-onset mid-cavitary hypertrophy + restrictive physiology in 3 siblings	PMID:12021217; mouse PMID:28371863
A57D	c.170C>A (rs139794067)	missense	AR (homozygous; VUS by ACMG)	EF-hand Ca²⁺-binding motif	Recessive HCM + SCD family history (family A)	PMID:33288880; contradicted functionally by PMID:29914921
E36*	c.106G>T	nonsense (LOF)	AR (homozygous)	truncates 159 C-terminal aa	Infantile DCM, transplant at age 6; sibling SCD age 2	PMID:33288880
c.482-1G>A	—	essential splice acceptor (LOF)	AR (presumed homozygous)	exon 5 skipping → p.(Gly161_Glu186del); disrupts EF-hands 2 and 3	Unclassified cardiomyopathy age 2.5, SCD age 8	PMID:33288880
R94H	c.281G>A	missense	AD	—	Asymmetric septal hypertrophy, max WT 18±3 mm, penetrance 88%, no obstruction	PMID:26443374
V79I	—	missense	AD	ELC–myosin lever-arm contact region	Late-onset, low-expressivity HCM; penetrance 40%	PMID:22957257
E152K	c.454G>A (exon 4)	missense	AD (heterozygous)	EF-hand region	Mid-cavity obstruction + LV apical aneurysm + NSVT + recurrent stroke	PMID:35288424
—	c.530A>G (exon 5)	missense	AD, paternally inherited (father asymptomatic)	—	Severe progressive infantile HCM at 3 months, fatal	PMID:23594557
E56G, E177G	—	missense	AD (reported)	E56G near EF-hand 1; E177G EF-hand 3	HCM (clinical detail sparse for E56G)	UniProt P08590; function PMID:36509720; PMID:33288880 notes "No clinical information is available for the p.(Glu56Gly) variant"
A57G	—	missense	AD	EF-hand Ca²⁺ motif	Reported in two Korean families and one Japanese patient with "dominant familial asymmetric septal hypertrophy and a high incidence of SCD" (as summarized in PMID:33288880); the canonical mouse HCM allele	PMID:33288880; PMID:23748425; PMID:32034976

4.3 Variant classification, allele frequency, and interpretive caveats

ClinVar (2026-08-01): 517 MYL3 records; only 14 pathogenic/likely pathogenic — i.e., the great majority are VUS/benign. This ratio is the practical clinical problem for this gene.
ClinGen Cardiomyopathy VCEP: 5 MYL3 variant assertions, predominantly Uncertain Significance.
gnomAD: c.170C>A (A57D) present on one allele, "frequency 0.01588%"; c.106G>T and c.482-1G>A absent from gnomAD and the Greater Middle East Variome; none homozygous in any database (PMID:33288880). The E152K variant was "not been detected in the ExAC … 1000 Genomes … and gnomAD database" (PMID:35288424).
Somatic vs germline: exclusively germline. No somatic MYL3 disease mechanism is described.
A cautionary, curation-relevant contradiction: the same A57D allele that ClinVar labeled "likely pathogenic" behaved benignly in an isogenic iPSC-CM panel — "The heterozygous VUS MYL3(170C>A)-iPSC-CMs did not show an HCM phenotype at the gene expression, morphology, or functional levels. Furthermore, genome-edited homozygous VUS MYL3(170C>A)- and frameshift mutation MYL3(170C>A/fs)-iPSC-CMs lines were also asymptomatic, supporting a benign assessment for this particular MYL3 variant." (PMID:29914921, Circulation 2018, IN_VITRO). PMID:33288880 (zebrafish rescue failure) reaches the opposite conclusion. This is an ideal discussions entry with kind: KNOWLEDGE_GAP or a hypothesis-group split (model-system discordance for A57D), and arguably HUMAN_MODEL_MISMATCH given the iPSC-vs-zebrafish-vs-human-family divergence.
Dosage: ClinGen haploinsufficiency score 0 (no evidence, 2015) — yet PMID:33288880 demonstrates that biallelic LOF causes disease. The reconciliation is that MYL3 LOF is recessive, not haploinsufficient; the ClinGen score is consistent with, not contradictory to, the recessive LOF data.

4.4 Functional consequences (allelic mechanism classes)

Three mechanistically distinct classes should be modeled separately:

Dominant missense — gain of function / hypercontractility. A57G destabilizes the SRX state and increases available heads: "The hypercontractile activity of A57G-ELC cross-bridges was manifested by the inhibition of the SRX state, increased number of myosin heads available for interaction with actin, and higher ATPase activity." (PMID:32034976)
Dominant missense — restrictive/hypercontractile with SRX stabilization. E143K: "E143K-myosin had increased duty ratio and binding affinity to actin compared with WT-myosin, increased actin-activated ATPase activity and slower rates of ATP-dependent dissociation of the acto-myosin complex, indicating an E143K-induced myosin hypercontractility." (PMID:28371863). Paradoxically, at the SRX level the two alleles diverge: "The HCM-A57G and RCM-E143K mutations had antagonistic effects on the ATP-dependent myosin energetic states, with HCM-A57G cross-bridges fostering the disordered relaxed (DRX) state and the RCM-E143K model favoring the energy-conserving SRX state." (PMID:34014247)
Recessive loss of function. "Our data demonstrate that homozygous MYL3 loss-of-function variants can cause of recessive cardiomyopathy and occurrence of sudden cardiac death, most likely due to impaired or loss of myosin essential light chain function." (PMID:33288880); and for E143K homozygosity, "These findings, coupled with previous studies of myosin light chain structure and function in the heart, suggest a loss-of-function disease mechanism." (PMID:12021217)

Allele-specific biophysics is heterogeneous even among HCM alleles: "Only the M149V mutation upregulated the actin-activated ATPase activity of S1. All mutations significantly increased the Ca2+-sensitivity of the sliding velocity of thin filaments … while mutations E56G and M149V (but not E177G) reduced the sliding velocity of regulated thin filaments and F-actin filaments almost twice. Therefore, despite the fact that all studied mutations in ELCv are involved in the development of hypertrophic cardiomyopathy, the mechanisms of their influence on the actin–myosin interaction are different." (PMID:36509720, IN_VITRO)

4.5 Structural interface hypothesis (2026)

A cryo-EM-based thick-filament interactome mapping study included 5 MYL3 variants among 233: "We identified HCM variants residing in 30 molecular interfaces of the complex thick filament interactome, including the two main interfaces of the myosin interacting-heads motif (IHM), and interfaces involving the MHC, essential and regulatory light chains, and cMyBP-C. None of the 21 variants classified as benign were within interfaces. We demonstrated earlier disease onset and adverse outcomes in HCM patients with pathogenic variants within vs. outside of molecular interfaces." (PMID:42372158, PNAS 2026). This provides a structure-based risk-stratification hypothesis directly applicable to MYL3 variant curation.

4.6 Epigenetics and chromosomal abnormalities

Epigenetics: No MYL3-specific methylation/histone data. Generic HCM epigenetic remodeling (and one 2025 report of altered myocardial lactylation in obstructive HCM, PMID:40281739 — not MYL3-specific) exists. Not applicable at the CMH8 level; record as a knowledge gap.
Chromosomal abnormalities: None. MYL3 CNVs are not an established mechanism (ClinGen dosage score 0). Copy-number screening of "minor" HCM genes has low yield (PMID:28771489). Not applicable.

5. Environmental Information

Environmental toxicants/radiation/occupational exposure: No established contribution. CTD contains no curated MYL3–chemical–disease axis relevant to CMH8. Not applicable.
Lifestyle: No MYL3-specific data. General HCM guidance (individualized exercise prescription rather than blanket restriction; treat hypertension/obesity; moderate alcohol) is from the 2024 AHA/ACC guideline (PMID:38718139).
Infectious agents: Not applicable — CMH8 is not infection-triggered. (Myocarditis is a differential diagnosis, not an etiologic cofactor.)

6. Mechanism / Pathophysiology

6.1 Causal chain (upstream → downstream), suitable for a dismech pathograph

Node 1 (MOLECULAR, trigger). MYL3 variant alters the myosin essential light chain — either a missense substitution in the N-terminal actin-binding extension / EF-hand regions / lever-arm contact surface, or a LOF allele (nonsense, splice) reducing/abolishing functional ELC. - GO: GO:0032036 myosin heavy chain binding; GO:0003779 actin binding - Evidence: PMID:8673105; PMID:33288880

Node 2 (MOLECULAR). Impaired ELC N-terminal tension-sensor function and disrupted N-ELC–actin interaction. "HCM-mutant pathology involved an impaired N-ELC tension sensor, disrupted N-ELC-actin interactions, an altered force-pCa relationship, and a destabilized myosin's super-relaxed state." (PMID:39211545). Mechanistic basis: "These results support an important role for the N-terminal ELC extension in prepositioning the cross-bridge for optimal force production." (PMID:21885653)

Node 3 (MOLECULAR). Shift of the myosin SRX↔DRX equilibrium and altered cross-bridge kinetics. A57G-type alleles inhibit SRX → more heads available → higher ATPase (PMID:32034976); E143K stabilizes SRX yet raises duty ratio and actin affinity (PMID:28371863; PMID:34014247). Also altered RLC phosphorylation (≈40% higher in HCM-A57G; ≈2-fold lower in RCM-E143K) (PMID:34014247). - GO: GO:0016887 ATP hydrolysis activity; GO:0030049 muscle filament sliding

Node 4 (CELLULAR). Increased myofilament Ca²⁺ sensitivity with altered maximal force. "Compared with the Tg-WT, there was a significant increase in the Ca²⁺ sensitivity of force (ΔpCa₅₀ ≅ 0.1) and an ~1.3-fold decrease in maximal force per cross section of muscle observed in the mutant preparations." (PMID:23748425). Confirmed for E56G/M149V/E177G in vitro (PMID:36509720). - GO: GO:0060048 cardiac muscle contraction; GO:0006936 muscle contraction

Node 5 (CELLULAR/TISSUE). Cardiomyocyte hypercontractility, increased passive tension and myocardial stiffness, impaired relaxation. "a significant increase in passive tension in response to stretch was monitored in Tg-A57G vs. Tg-WT strips indicating a mutation-induced myocardial stiffness" (PMID:23748425); "augmented active and passive tension measured in skinned papillary muscle fibres" for E143K (PMID:28371863). Force-transient duration diverges by allele: "shorter (HCM-A57G) or longer (RCM-E143K) transients measured in electrically stimulated papillary muscles" (PMID:34014247). - CL: CL:0002131 regular ventricular cardiac myocyte / CL:2000046 ventricular cardiac muscle cell

Node 6 (MOLECULAR/CELLULAR, parallel). Increased energetic demand and metabolic adaptation. "proteomic analysis evidenced RCM-dependent metabolic adaptations and higher energy demands" (PMID:28371863); Δ43 hearts (SRX-stabilized) show "significantly decreased ATP utilization and low actin-activated myosin ATPase" (PMID:32034976). This node is the mechanistic bridge to the classic HCM "energy-depletion" hypothesis.

Node 7 (TISSUE). Maladaptive hypertrophic remodeling with interstitial fibrosis and ultrastructural/sarcomeric disarray. "the hearts of Tg-A57G mice demonstrated a high level of fibrosis and hypertrophy manifested by increased heart weight-to-body weight ratios" (PMID:23748425); "The hearts of mutant-mice demonstrated ultrastructural defects and fibrosis that progressively worsened in senescent animals" with "upregulation of stress-response and collagen genes" (PMID:28371863). - GO: GO:0003300 cardiac muscle hypertrophy; GO:0014898 cardiac muscle hypertrophy in response to stress; CL: CL:0002548 fibroblast of cardiac tissue; HP:0001685; HP:0031318

Node 8 (ORGAN). Regionally patterned hypertrophy: mid-ventricular segments and papillary muscles → mid-cavity obstruction ± apical aneurysm; or asymmetric septal hypertrophy. Poetter et al. proposed the mechanistic explanation that the mutations "disrupt the stretch activation response of the cardiac papillary muscles" (PMID:8673105) — a still-unresolved but testable hypothesis for why ELC disease is topographically distinctive. Clinically: "left ventricular hypertrophy at mid-ventricular segments resulting in a mid-cavitary obstruction and a left ventricular apical aneurysm" (PMID:35288424). - UBERON: UBERON:0002084 heart left ventricle; UBERON:0002494 papillary muscle of heart / UBERON:0004524 papillary muscle of left ventricle; UBERON:0002094 interventricular septum

Node 9 (ORGANISM). Diastolic dysfunction ± restrictive physiology, intracavitary gradient, heart failure; arrhythmogenic substrate (fibrosis + aneurysm + hypertrophy) → NSVT/VT → sudden cardiac death; atrial remodeling → AF → cardioembolic stroke. - HP:0025168, HP:0001723, HP:0001635, HP:0004756, HP:0001645, HP:0005110, HP:0001297

6.2 Mechanism annotations by requested subheading

Molecular pathways: Actomyosin cross-bridge cycling and thick-filament autoinhibition (IHM/SRX) — the primary axis. Downstream: stress-response/hypertrophic signaling with collagen gene upregulation (PMID:28371863). No canonical Wnt/MAPK/mTOR pathway is established as MYL3-specific; treat generic hypertrophic signaling as inferred, not evidenced.
Cellular processes: cardiomyocyte hypertrophy, increased myofilament Ca²⁺ sensitivity, impaired relaxation, myofibrillar disarray, cardiac fibroblast activation/fibrosis, senescence-associated worsening (PMID:28371863 notes progression "in senescent animals").
Protein dysfunction: Neither misfolding nor aggregation. The dominant class is a functional/allosteric defect at protein–protein interfaces (ELC–MHC lever arm, N-ELC–actin, thick-filament interfaces: PMID:42372158); the recessive class is quantitative loss of protein/domain (truncation; EF-hand 2/3 deletion: PMID:33288880).
Metabolic changes: increased ATP utilization/energy demand in hypercontractile alleles (PMID:32034976; PMID:28371863). Reported proteomic/metabolic adaptation in RCM-E143K hearts. CHEBI:15422 ATP is the relevant chemical entity.
Immune involvement: No autoimmune or immunodeficiency component. Sterile inflammation accompanying fibrosis is plausible but unstudied for MYL3. Not applicable / knowledge gap.
Tissue damage mechanisms: myocyte stress/death with replacement fibrosis; ischemia at the level of microvascular supply–demand mismatch in hypertrophied mid-ventricular myocardium (mechanistically expected; not MYL3-specifically demonstrated); apical wall stress from mid-cavity obstruction → aneurysm formation (PMID:35288424).
Biochemical abnormalities: altered actin-activated myosin ATPase, altered myosin duty ratio/actin affinity, altered RLC phosphorylation stoichiometry (PMID:28371863; PMID:34014247; PMID:36509720). No enzyme deficiency, receptor defect, or ion-channel defect.
Epigenetic changes: none characterized (gap).
Molecular profiling: Transcriptomics — "Gene expression profiles of E143K-hearts supported the histopathology results and showed an upregulation of stress-response and collagen genes" (PMID:28371863). Proteomics — mutant-specific proteome/metabolic signatures (PMID:28371863; PMID:26668058 proteomic comparison of physiological vs. pathological ELC-mutant remodeling). Structural genomics — cryo-EM thick-filament interactome mapping (PMID:42372158). Metabolomics/lipidomics — no MYL3-specific data. Single-cell/spatial transcriptomics — no MYL3-specific data. CRISPR/RNAi functional screens — no MYL3 screen; but targeted CRISPR isogenic editing has been applied (PMID:29914921) and a MYL3 knockout hESC line now exists (PMID:40311326).

7. Anatomical Structures Affected

Organ level - Primary: heart (UBERON:0000948), specifically left ventricle (UBERON:0002084) with predilection for mid-ventricular segments and papillary muscles (UBERON:0002494; left-sided UBERON:0004524); interventricular septum (UBERON:0002094) in septal-hypertrophy alleles (R94H, A57G). - Secondary: left atrium (UBERON:0002079) — dilation/AF; brain (via cardioembolic stroke: retinal artery, gangliocapsular, corona radiata territories — PMID:35288424); lungs (pulmonary congestion); systemic venous congestion. - Body systems: cardiovascular (primary), central nervous (secondary/embolic), respiratory (secondary), musculoskeletal (rare, historical: slow-twitch skeletal muscle).

Tissue and cell level - Cardiac muscle tissue (UBERON:0001133); cardiac muscle tissue of papillary muscle (UBERON:0004494) — the tissue in which the ELC "stretch activation" defect was hypothesized. - Cells: CL:0002131 regular ventricular cardiac myocyte; CL:2000046 ventricular cardiac muscle cell; CL:0000746 cardiac muscle cell (parent); CL:0002548 fibroblast of cardiac tissue (fibrotic remodeling). - Skeletal muscle tissue (UBERON:0001134), slow-twitch fibers — rare/historical (PMID:8673105); explicitly absent in the recessive families (PMID:33288880).

Subcellular level - GO:0030017 sarcomere; GO:0032982 myosin filament; GO:0016460 myosin II complex; GO:0005859 muscle myosin complex; GO:0031672 A band. Mitochondria are implicated only indirectly via energetic demand (GO:0005739 mitochondrion — inferred).

Localization / lateralization - Left-sided and, within the LV, regional/segmental (mid-cavity, papillary, or septal) rather than uniform — a distinguishing feature. Right ventricular involvement is not a described feature of CMH8. Apical aneurysm is a focal apical lesion (HP:6000144).

8. Temporal Development

Onset - Extremely broad: 3 months (fatal infantile HCM, c.530A>G — PMID:23594557); age 2–2.5 years (recessive unclassified cardiomyopathy — PMID:33288880); age 6 (recessive DCM, transplanted — PMID:33288880); childhood (homozygous E143K siblings — PMID:12021217); 26 years (recessive A57D HCM — PMID:33288880); 38 years (asymptomatic murmur, V79I — PMID:22957257); late adult. - HPO onset terms: Congenital/Infantile onset HP:0003593, Childhood onset HP:0011463, Adult onset HP:0003581 — model as variable onset, with a genotype rule of thumb: biallelic LOF → infantile/childhood onset and severe course; heterozygous missense → adolescent-to-adult onset, often late. - Onset pattern: insidious/chronic, frequently detected on family screening or incidentally (murmur) before symptoms. Presentation may be abrupt if the first event is SCD or arrhythmia.

Progression - Course: chronic, progressive, lifelong; punctuated by episodic arrhythmic events. - Documented dynamic progression of the mid-cavity gradient: in the Olson family, "a dynamic progression in peak intracavitary LV gradient from 16 to 41 mm Hg across a span of 2 years" (reviewed in PMID:35288424) — "This reported feature demonstrates the potential for dynamic progression of the condition and may well indicate consideration of serial morphological measurements of the structures." - Stages (adapted from general HCM staging): (i) genotype-positive/phenotype-negative (subclinical); (ii) classic hypertrophic phase ± obstruction; (iii) adverse remodeling with fibrosis, AF, LGE burden; (iv) end-stage/burnt-out HCM with systolic dysfunction or restrictive physiology → transplant. - Recessive LOF course is fast and malignant: "Homozygosity for LOF variants … appear to cause a more severe phenotype resulting in early SCD and fatality" (PMID:33288880). - Phenotypic conversion rate (all sarcomere genes, longitudinal family studies): "the pooled phenotypic conversion across all genes was 15% over an average of ≈8 years of follow-up" (PMID:37929589).

Patterns - Remission: No spontaneous remission. Treatment-induced phenotypic improvement (gradient reduction, symptom class, favorable remodeling) is achievable with myosin inhibitors or septal reduction (PMID:32871100; PMID:37639243), but this is disease modification, not remission. - Critical periods: (a) infancy/early childhood for biallelic LOF genotypes — the window for transplant referral; (b) adolescence through the 5th decade — the window of highest arrhythmic risk and the interval in which cascade-screening surveillance must be repeated (mean diagnosis age 38 years, PMID:37929589); (c) periods of hemodynamic stress (pregnancy, new-onset AF).

9. Inheritance and Population

9.1 Epidemiology

HCM overall: classically ~1 in 500 (0.2%; 200/100,000); Semsarian et al. argue for a higher true figure once genotype-positive/phenotype-negative individuals and modern imaging are counted — "For the past 20 years, most data have supported the occurrence of HCM at about 1 in 500 … They suggest that HCM is more common than previously estimated" (PMID:25814232). The commonly quoted revised figure is ~1 in 200 including subclinical carriers.
CMH8 specifically: no direct prevalence estimate exists. Derivable bounds:
Myosin light chain genes (MYL2 + MYL3) account for "about 1% of cases" of HCM — "In conclusion, myosin light chain mutations are a very rare cause of HCM responsible for about 1% of cases." (PMID:12404107; in that series of 186 HCM patients, no MYL3 mutation was found at all).
Pediatric HCM: "mutations in TNNT2, ACTC, MYL3, and TNNI3 accounted for <5% of cases each" (PMID:20031618; 79 children ≤13 years).
Sarcomere detection rate in unselected HCM probands ≈32% (PMID:25611685); ≈34% prevalence of sarcomere variants in clinically diagnosed HCM (PMID:37929589).
Order-of-magnitude estimate for a dismech Prevalence record: if HCM point prevalence ≈200/100,000 and MYL3 explains ≈0.5–1% of HCM, CMH8 point prevalence ≈1–2 per 100,000 → prevalence_class: BAND_1_9_PER_100000, measure_type: POINT_PREVALENCE, with notes making the derivation explicit. This is a derived estimate, not a published figure — label it as such.
Incidence: no published incidence for CMH8. Not available.

9.2 Inheritance

Autosomal dominant (HP:0000006) — the ClinGen-curated MOI for MYL3–HCM (Definitive, 2021). Classic families: M149V (3 generations), R94H, V79I, E152K.
Autosomal recessive (HP:0000007) — independently established twice: homozygous E143K (PMID:12021217) and homozygous LOF alleles in three consanguineous Iranian families (PMID:33288880). "we identify homozygous variants in MYL3 in three unrelated families with cardiomyopathies and occurrence of SCD, but no skeletal myopathy. The recessive inheritance of the likely LOF MYL3 variants are associated with a particularly severe phenotype resulting in early SCD and lethality."
Curation guidance: model both Inheritance blocks with bound HPO terms (HP:0000006 and HP:0000007), and consider a subtype split (has_subtypes: e.g., AD missense / AR LOF) since onset, severity, morphology and counseling all differ. CMH8 is a legitimate member of a "dominant-and-recessive same-gene" pattern; it is not digenic (do not use HP:0010984).
Penetrance: incomplete and age-dependent; the lowest of the definitive sarcomere genes at ≈32% (PMID:37929589). Allele-specific values span the range: 40% for V79I ("The penetrance, if we consider this borderline HCM the phenotype of the p.V79I mutation, was 40%, but the mean age of the nonpenetrant mutation carriers is 15, while the mean age of the penetrant mutation carriers is 47" — PMID:22957257) to 88% for R94H ("disease-penetrance of 88%" — PMID:26443374). Heterozygotes for recessive alleles show 0% penetrance into late adulthood (PMID:12021217).
Expressivity: highly variable, intra- and interfamilial — "this case highlights the marked phenotypic heterogeneity associated with sarcomeric protein mutations both within and between families" (PMID:23594557); "a rare cause of HCM with inter- and intrafamilial variability ranging from benign to malignant forms with cardiac failure and SCD" (PMID:33288880).
Genetic anticipation: none (not a repeat-expansion disorder). Not applicable.
Germline mosaicism: not reported for MYL3. Not available.
Founder effects: none established. A57G has been reported in two Korean families and a Japanese patient (per PMID:33288880), which is suggestive of recurrence rather than a proven founder allele.
Consanguinity: central to the recessive form — all three recessive families were consanguineous (first or second cousins) (PMID:33288880); and at population scale, homozygous minor-gene variants are ~40× more frequent in the consanguineous Egyptian cohort (PMID:37431535).
Carrier frequency: no published carrier frequency for MYL3 LOF alleles. gnomAD allele counts for the specific LOF variants are 0–1, i.e. ultra-rare. Not available.

9.3 Population demographics

Affected populations: reported worldwide — USA/Europe (PMID:8673105; PMID:12021217; PMID:22957257 Danish/South African context), Japan (PMID:26443374, Kanazawa registry; R94H found in 5 affected relatives + 2 additional registry carriers out of 600), Korea/Japan (A57G, via PMID:33288880), Iran (recessive, PMID:33288880), India/UK (PMID:35288424), Egypt/North Africa (homozygous minor-gene variants, PMID:37431535).
Geographic distribution of variants: recessive LOF alleles cluster where consanguinity is common (Middle East, North Africa); no other geographic signature is established.
Sex ratio: No CMH8-specific ratio. General HCM cohorts are male-predominant in ascertainment (SHaRe: "37% of patients were female", PMID:30297972) while genetic testing yield is "higher in females compared with males" (PMID:25611685). Model as no established sex bias for CMH8; report the ascertainment asymmetry as a caveat.
Age distribution: bimodal by genotype class — infantile/childhood (biallelic LOF, rare severe missense) and adult (heterozygous missense, mean HCM diagnosis ~38 years for sarcomere carriers generally).

10. Diagnostics

10.1 Imaging (the diagnostic core)

Transthoracic echocardiography (NCIT:C16525 Echocardiography Test; LOINC 34552-0 class): unexplained LV wall thickness ≥15 mm (≥13 mm with family history), with particular attention to mid-ventricular segments and papillary muscles, resting/provoked mid-cavity gradient, absence of LVOT obstruction/SAM, diastolic function grading, left atrial size. In the index mid-cavity case: "TTE identified biatrial dilation, LV hypertrophy predominantly in the mid-ventricular segments, mid-cavitary rest gradient of 33 mm Hg, mild-to-moderate LV systolic dysfunction, grade II diastolic dysfunction and no evidence of LVOTO or SAM of the mitral valve at rest." (PMID:35288424)
Cardiac MRI with late gadolinium enhancement (essential in this genotype, because apical aneurysm and mid-cavity obliteration are frequently missed on echo): "Subsequent cardiac magnetic resonance … detected an EF of 49% with positive morphologies of mid-cavitary HCM, obliterated in systole with flow acceleration in the LV apical aneurysm and diffuse delayed gadolinium enhancement" (PMID:35288424).
Provocation (Valsalva, exercise echo) to unmask dynamic gradients; serial imaging is specifically warranted given documented gradient progression (16→41 mm Hg over 2 years).

10.2 Electrophysiology and functional testing

12-lead ECG (HP:0003115; abnormal T-waves HP:0005135) — abnormal in most affected and in some borderline carriers: "Cascade screening revealed a further nine heterozygote mutation carriers, three of whom had ECG and/or echocardiographic abnormalities but did not fulfil diagnostic criteria for HCM." (PMID:22957257)
Ambulatory (Holter) monitoring — NSVT detection is decisive for ICD decisions: "Holter analysis revealed sinus rhythm with runs of non-sustained ventricular tachycardia" (PMID:35288424).
Cardiopulmonary exercise testing (peak VO₂) — functional staging and trial endpoint (PMID:32871100; PMID:38739079).
Invasive hemodynamics/catheterization when intracavitary vs. valvular/outflow gradients must be separated; coronary angiography to exclude CAD as a cause of apical aneurysm (normal epicardial coronaries documented, PMID:35288424).

10.3 Laboratory tests and biomarkers

BNP / NT-proBNP (HP:0033534) for heart-failure staging (BNP 4394 pg/mL in decompensated case, PMID:35288424).
High-sensitivity troponin — prognostic in HCM generally, not CMH8-specific.
No CMH8-specific biochemical biomarker exists. Biomarker testing is chiefly used to exclude phenocopies: NT-proBNP/troponin, serum/plasma free light chains and immunofixation (AL amyloidosis), alpha-galactosidase A activity and lyso-Gb3 (Fabry disease), CK (metabolic/mitochondrial myopathy), glucose/HbA1c and creatinine (PRKAG2/Danon considerations).
FDA/BEST biomarker context: no qualified biomarker for HCM subtype assignment.

10.4 Biopsy / pathology

Endomyocardial biopsy is not required for diagnosis; when tissue is available (explant, autopsy, or the infantile case), findings are the HCM canon: myocyte hypertrophy, myofiber disarray (HP:0031318), interstitial and replacement fibrosis (HP:0001685), and (per MedGen's HPO annotation set for CMH8) endomyocardial fibrosis. Histopathology was specifically reported in the infantile MYL3 case (PMID:23594557: "We report on genetic and histopathological findings in a 3-month-old infant presenting with severe progressive HCM").

10.5 Genetic testing

Recommended approach: multigene HCM panel (NCIT:C15709 Genetic Testing) covering at minimum the 8 definitive sarcomere genes (MYBPC3, MYH7, TNNT2, TNNI3, TPM1, ACTC1, MYL2, MYL3) plus phenocopy genes; MYL3 is on essentially all commercial HCM panels and on the Genomics England HCM PanelApp green list.
Yield: "The detection rate is ~32% among unselected probands, with inconclusive results in an additional 15%", and "An expanded gene panel encompassing more than 50 genes identified only a very small number of additional pathogenic variants beyond those identifiable in our original panels" (PMID:25611685) — i.e., do not order oversized panels; the ClinGen curation exists precisely because "Of 4191 HCM variants in ClinVar, 31% were in genes with limited or no evidence of disease association" (PMID:30681346).
WES/WGS: useful in atypical, syndromic, pediatric, or consanguineous presentations. WES identified MYL3 R94H as the sole surviving candidate in a large family (PMID:26443374: "WES combined with CADD score and HHE gene data may be useful even in HCM"), and identified all three recessive MYL3 genotypes (PMID:33288880).
Single-gene MYL3 testing: appropriate only for targeted familial variant testing (cascade/site-specific).
Homozygosity mapping / segregation analysis in consanguineous families is essential — recessive MYL3 disease will be misinterpreted as non-informative heterozygosity otherwise (PMID:12021217; PMID:33288880).
CMA, karyotype, FISH, mtDNA, repeat-expansion testing: not indicated for CMH8 (no CNV or repeat mechanism; ClinGen dosage score 0). CMA/mtDNA testing belongs to the differential-diagnosis workup of syndromic or mitochondrial LVH, not to MYL3 diagnosis.
Functional adjuncts for VUS resolution (research-grade, increasingly clinical): isogenic CRISPR-edited iPSC-CM panels (PMID:29914921), zebrafish cmlc1 rescue assays and minigene splicing assays (PMID:33288880), and structural interface mapping (PMID:42372158).

10.6 Omics-based diagnostics

RNA sequencing: no clinical role for MYL3; relevant only for splice-variant interpretation (the c.482-1G>A minigene assay is the functional analogue: "skipping of exon 5 … thereby disrupting the EF-hand Ca2+ binding motifs 2 and 3", PMID:33288880).
Proteomics / metabolomics / epigenomics / liquid biopsy: no validated diagnostic application. Not applicable.

10.7 Clinical criteria and differential diagnosis

Diagnostic criteria: 2024 AHA/ACC/AMSSM/HRS/PACES/SCMR HCM guideline (PMID:38718139, Circulation 2024;149:e1239–e1311) and 2023 ESC Guidelines for the management of cardiomyopathies (PMID:37622657) — unexplained LV wall thickness ≥15 mm (adults; ≥13 mm with family history/positive genotype), or z-score-based criteria in children, in the absence of another cause.
Differential diagnosis (with the discriminating feature):
Other sarcomeric HCM (MYH7, MYBPC3, TNNT2, TNNI3, TPM1, ACTC1, MYL2) — genotype; MYL3 favored by mid-cavity/papillary morphology
Apical HCM and other causes of apical aneurysm (LAD stenosis/prior MI) — coronary imaging (excluded in PMID:35288424)
Cardiac amyloidosis (ATTR/AL) — LGE pattern, free light chains, bone scintigraphy
Fabry disease, Danon disease, PRKAG2 glycogen storage cardiomyopathy — enzyme/gene testing, conduction disease/WPW
Noonan/RASopathy LVH, mitochondrial cardiomyopathy — syndromic features
Athlete's heart, hypertensive LVH, aortic stenosis — loading conditions
Idiopathic restrictive cardiomyopathy — relevant because homozygous E143K produces restrictive physiology (PMID:12021217)

10.8 Screening

Cascade family screening is the highest-yield intervention: "the finding that one sixth of patients with sarcomeric disease were diagnosed in infancy suggests that current views on pathogenesis and natural history of familial HCM may have to be revised … all first-degree relatives of any child diagnosed with HCM should be offered screening" (PMID:20031618). Cascade genotyping "eliminated the need for longitudinal cardiac evaluations in 691 individuals" with substantial cost savings (PMID:25611685).
CMH8-specific caveat: with ≈32% penetrance, genotype-positive/phenotype-negative status is the modal outcome of cascade testing in MYL3 families — surveillance intervals (typically 1–3 years in children/adolescents, 3–5 years in adults per guideline) must be explained accordingly.
No newborn screening or population carrier screening for MYL3 exists or is recommended.

11. Outcome / Prognosis

11.1 Survival and mortality

No CMH8-specific survival curve is published. Genotype-class stratification is the usable signal:
Biallelic LOF: malignant — SCD at ages 2, 5–9 years; transplant at age 6 (PMID:33288880). "Homozygosity for LOF variants, p.(Glu36Ter) in family B, and likely homozygosity of the splice acceptor variant, c.482-1G>A in family C, appear to cause a more severe phenotype resulting in early SCD and fatality."
Homozygous E143K: "those with two mutant alleles developed severe cardiomyopathy in childhood"; "homozygous carriers of a sarcomeric protein defect may have a malignant course" (PMID:12021217).
Severe pediatric missense: fatal infantile HCM (PMID:23594557, "Fatal Outcome" MeSH tag).
Heterozygous missense in adults: ranges from lifelong asymptomatic (nonpenetrant carriers) to SCD; MYL3 variants are noted as "associated with sudden death" (PMID:22957257) and "The majority of reported variants are, however, associated with SCD at a young age" (PMID:33288880).
General sarcomere-positive HCM benchmark (applicable by extension): "Patients with pathogenic/likely pathogenic sarcomere mutations had two-fold greater risk for adverse outcomes compared to patients without mutations"; "Young HCM patients (20-29 years) had 4-fold higher mortality than the general United States population at a similar age"; and "Ventricular arrhythmias occurred in 32% [23%, 40%] of patients <40 years at diagnosis, but in 1% [1%, 2%] >60 years" (PMID:30297972, SHaRe, n=4591).
Mortality/DALY figures specific to CMH8 are not available (GBD/CDC report HCM at most, not gene-level).

11.2 Morbidity and function

Dominant morbidities: heart failure symptoms, exercise limitation, atrial fibrillation with cardioembolic stroke and its neurological disability, ICD carriage and its complications, anticoagulation-related hemorrhage (an extra-axial hemorrhage extending into the posterior fossa, "potentially secondary to long-term anticoagulation", occurred in the index apical-aneurysm case — PMID:35288424).
From SHaRe: "Heart failure and atrial fibrillation were the most prevalent adverse events, although typically not emerging for several years after diagnosis." (PMID:30297972)
QoL instruments: KCCQ-CSS, HCMSQ-SoB, SF-36, EQ-5D (no CMH8-specific published scores).

11.3 Complications (to curate as downstream nodes)

Mid-cavity obstruction with progressive gradient → LV apical aneurysm → apical thrombus, ventricular tachyarrhythmia, thromboembolism, and (in immature aneurysms) rupture (PMID:35288424 discussion of the Maron apical-aneurysm series); atrial fibrillation → stroke; progressive fibrosis → systolic dysfunction/end-stage HCM → transplant; restrictive physiology → low-output heart failure; SCD.

11.4 Prognostic factors and biomarkers

Genotype/inheritance class: biallelic LOF ≫ heterozygous missense in severity (PMID:33288880; PMID:12021217). Allele-specific penetrance also differs sharply (88% R94H vs. 40% V79I).
Structural position of the variant: "We demonstrated earlier disease onset and adverse outcomes in HCM patients with pathogenic variants within vs. outside of molecular interfaces, emphasizing their importance in normal thick filament function and improving risk stratification of patients." (PMID:42372158) — an emerging, MYL3-inclusive prognostic principle.
Age at diagnosis: "Patients <40 years old at diagnosis had a 77% … cumulative incidence of the overall composite outcome by age 60, compared to 32% … by age 70 for patients diagnosed >60 years" (PMID:30297972).
Imaging/arrhythmic risk markers driving ICD decisions (documented in the MYL3 case): SCD in first-degree relatives, NSVT, extensive LGE, LV systolic dysfunction, LV apical aneurysm — "Risk stratification for an implantable cardioverter defibrillator (ICD) was conducted due to the presence of an LV apical aneurysm, NSVT, LVSD, late gadolinium enhancement (LGE) on CMR and SCD in first-degree relatives." (PMID:35288424)
Formal tools: HCM Risk-SCD (ESC) and the 2024 AHA/ACC risk-marker approach (PMID:37622657; PMID:38718139). No MYL3-specific calculator.
Recovery potential: hypertrophy/fibrosis are not reversed by current therapy; symptomatic and hemodynamic recovery is achievable (myosin inhibitors, myectomy), and favorable remodeling has been documented with prolonged mavacamten (PMID:37639243 and its long-term follow-up).

12. Treatment

There is no MYL3-genotype-specific therapy. Management follows guideline-directed HCM care (PMID:38718139; PMID:37622657), with two genotype-relevant emphases: (i) mid-cavity obstruction and apical aneurysm require different surgical/anticoagulation reasoning than subaortic obstruction, and (ii) the hypercontractility mechanism established for MYL3 alleles is exactly the target of cardiac myosin inhibitors, making mavacamten/aficamten mechanistically rational here (though neither trial reported MYL3-stratified results).

12.1 Pharmacotherapy

Treatment	Mechanism	NCIT / CHEBI suggestions	Evidence
Beta blockers (metoprolol, bisoprolol, propranolol)	Negative inotropy/chronotropy; reduce dynamic gradient, improve diastolic filling	`treatment_term` NCIT:C15986 Pharmacotherapy; `therapeutic_agent` NCIT:C29576 Beta-Adrenergic Antagonist / CHEBI:6904 metoprolol; `therapeutic_modality: SMALL_MOLECULE`	Guideline first line (PMID:38718139)
Non-dihydropyridine calcium channel blockers (verapamil, diltiazem)	Negative inotropy; improve diastolic function	NCIT:C15986 + CHEBI:9948 verapamil	Guideline (PMID:38718139)
Disopyramide	Class IA antiarrhythmic with potent negative inotropy; gradient reduction	NCIT:C15986 + NCIT:C61730 Disopyramide / CHEBI:4657 disopyramide	Guideline add-on for obstructive disease (PMID:38718139)
Mavacamten	Cardiac myosin ATPase inhibitor — reduces the number of force-generating heads / hypercontractility (directly antagonizes the SRX→DRX shift shown for A57G-type ELC alleles)	NCIT:C15986 + NCIT:C174901 Mavacamten; `therapeutic_modality: SMALL_MOLECULE`; `target_mechanisms: INHIBITS` the hypercontractility node	EXPLORER-HCM: "45 (37%) of 123 patients on mavacamten versus 22 (17%) of 128 on placebo met the primary endpoint (difference +19·4%, 95% CI 8·7 to 30·1; p=0·0005)", with post-exercise LVOT gradient −36 mm Hg and pVO₂ +1.4 mL/kg/min (PMID:32871100, NCT03470545). VALOR-HCM week 56 (PMID:37639243) — sustained avoidance of septal reduction therapy
Aficamten	Next-generation selective cardiac myosin inhibitor	NCIT:C15986 + NCIT:C179072 Aficamten	SEQUOIA-HCM: "the mean change in the peak oxygen uptake was 1.8 ml per kilogram per minute … in the aficamten group and 0.0 … in the placebo group (least-squares mean between-group difference, 1.7 ml per kilogram per minute; 95% CI, 1.0 to 2.4; P<0.001)"; "The results for all 10 secondary end points were significantly improved" (PMID:38739079, NCT05186818)
Oral anticoagulation (DOAC or warfarin)	Stroke prevention in AF and/or apical aneurysm with thrombus risk	NCIT:C15986 + e.g. CHEBI:2907 warfarin (verify preferred agent per case)	AF management per guideline; the MYL3 apical-aneurysm case required long-term anticoagulation after recurrent CVAs — and illustrates the bleeding trade-off (PMID:35288424)
Antiarrhythmics (amiodarone, sotalol) / rate control	AF/VT suppression	NCIT:C15986	Guideline
Heart-failure therapy in the non-obstructive/end-stage phase (ACEi/ARB/ARNI, beta blocker, MRA, SGLT2i, diuretics)	Standard HF GDMT — used explicitly in the MYL3 case: "She was diagnosed with New York Heart Association class III congestive cardiac failure and treated with guideline-directed therapy for heart failure."	NCIT:C15986	PMID:35288424
Avoid: high-dose vasodilators, pure afterload reducers, digoxin, and aggressive diuresis in significant obstruction	Worsen dynamic gradient	—	Guideline (PMID:38718139)

Pharmacogenomics: No MYL3-specific PGx. Relevant general PGx: CYP2D6 metabolizer status for metoprolol (CPIC guideline) and mavacamten (CYP2C19/CYP3A4 metabolism, with genotype-informed dosing and REMS-mandated echo monitoring for LVEF <50%); CYP2C9/VKORC1 for warfarin. These are drug-level, not disease-level, annotations.

12.2 Advanced therapeutics

Gene therapy / gene editing: none clinical for MYL3. Mechanistically, the mouse cross-genotype data provide a striking, curatable therapeutic hypothesis — deleting the malfunctioning N-terminal ELC sensor rescues the HCM allele but not the RCM allele: "Removal of the malfunctioning N-ELC sensor led to functional rescue in HCM-truncated mutant hearts. However, the RCM mutation could not be rescued by N-ELC deletion, likely due to its proximity to the myosin motor domain, affecting lever-arm rigidity and myosin function." (PMID:39211545). NCIT:C15238 Gene Therapy; therapeutic_modality: GENE_THERAPY (preclinical only).
RNA-based therapies (ASO/siRNA): none for MYL3. Note that for a recessive LOF genotype, allele-silencing approaches are conceptually inappropriate; gene replacement would be required. Do not create an antisense_oligonucleotide_therapy conformance for this entry.
Cell therapy / immunotherapy / targeted oncology-style therapy: not applicable.

12.3 Surgical and interventional

Intervention	NCIT	Notes
Septal myectomy / extended myectomy — for mid-cavity obstruction this must be an extended (mid-ventricular) myectomy ± papillary muscle reorientation, not a standard subaortic myectomy	NCIT:C51591 Myectomy (also NCIT:C15329 Surgical Procedure)	Guideline Class 1 at experienced centers for drug-refractory obstruction (PMID:38718139). Anatomically the key genotype-specific point for CMH8
Alcohol septal ablation	NCIT:C80439 Septal Ablation	Alternative to myectomy in selected adults; generally unsuitable for mid-cavity obstruction (target septal perforator anatomy does not supply mid-ventricular hypertrophy)
ICD implantation (primary or secondary prevention)	NCIT:C80435 Implantable Cardioverter-Defibrillator Placement (device: NCIT:C93238); `therapeutic_modality: DEVICE`	The decisive intervention in this genotype given SCD burden: "a decision was made for recommendation of an automatic ICD for the purpose of primary prevention of SCD" (PMID:35288424)
Catheter ablation / AF management	NCIT:C49236 Therapeutic Procedure	AF was "refractory to pharmacological and direct current cardioversion" in the reported case (PMID:35288424)
Apical aneurysm resection / surgical exclusion	NCIT:C15329	Selected cases; also LV thrombus management
Heart transplantation	NCIT:C15246 Heart Transplantation; `therapeutic_modality: SURGERY`	End-stage disease; performed at age 6 for the homozygous E36* DCM proband (PMID:33288880)

12.4 Supportive, rehabilitative, and counseling

Symptom-directed supportive care (NCIT:C15747 Supportive Care); volume/hydration management; sleep-apnea treatment.
Cardiac rehabilitation / individualized exercise prescription (NCIT:C15315 Rehabilitation; NCIT:C15302 Physical Therapy) — the 2024 guideline moved away from blanket exercise restriction toward shared decision-making (PMID:38718139).
Genetic counseling (NCIT:C15240 Genetic Counseling) — essential and genotype-nuanced: recurrence risk is 50% for dominant alleles but 25% for sibs in recessive families, and "Recognizing recessive inheritance in children with cardiomyopathy is essential for appropriate family counseling." (PMID:12021217)

12.5 Experimental treatments and trials

NCT03470545 — EXPLORER-HCM (mavacamten, phase 3, completed) (PMID:32871100)
NCT04349072 — VALOR-HCM (mavacamten in patients referred for septal reduction; week 56 results PMID:37639243) (NCT number from the trial report; verify against ClinicalTrials.gov before curating as clinical_trials)
NCT05186818 — SEQUOIA-HCM (aficamten, phase 3) (PMID:38739079)
No trial has enrolled by MYL3 genotype; no MYL3-directed gene therapy has entered trials. Curate trials as HCM-level context with explicit notes that they are not MYL3-stratified.

12.6 Treatment outcomes, adverse effects, and strategy

Response rates: see EXPLORER-HCM/SEQUOIA-HCM numbers above; both drugs improved symptoms and gradients with adverse-event incidence "similar in the two groups" (PMID:38739079).
Key adverse events to flag: myosin-inhibitor–induced reduction in LVEF (requires echocardiographic surveillance and REMS-type programs), disopyramide anticholinergic effects and QT prolongation, beta-blocker fatigue/bradycardia, anticoagulation hemorrhage (documented, PMID:35288424), ICD lead complications and inappropriate shocks.
Algorithm (obstructive CMH8): beta blocker → verapamil/diltiazem if intolerant → add disopyramide or switch to a myosin inhibitor → septal reduction (extended myectomy for mid-cavity disease) for refractory symptoms; in parallel and independent of symptoms, SCD risk stratification with CMR (LGE, apical aneurysm) and Holter, ICD when indicated; anticoagulation on AF/aneurysm-thrombus grounds; cascade genetic testing of relatives.
Personalized medicine: currently limited to (a) family-specific variant cascade testing, (b) morphology-driven procedure selection, (c) emerging variant-position–based risk stratification (PMID:42372158). MYL3 genotype does not yet alter drug choice.

13. Prevention

Primary prevention (of the disease itself): not possible — the cause is germline. The actionable primary-prevention targets are the consequences: SCD (ICD, activity counseling), stroke (anticoagulation in AF/aneurysm), and heart failure (afterload/AF control). For families, reproductive prevention is available: genetic counseling, carrier/partner testing in consanguineous families where a recessive LOF allele has been identified, preimplantation genetic testing (PGT-M) and prenatal diagnosis. Consanguinity counseling is the single highest-yield population measure for the recessive form (PMID:33288880; PMID:37431535).
Secondary prevention (early detection): cascade genetic and clinical screening of first-degree relatives is the core intervention (PMID:20031618; PMID:25611685); serial ECG/echo ± CMR surveillance of genotype-positive/phenotype-negative relatives, with intervals set by age (more frequent through adolescence and early adulthood). Because MYL3 penetrance is only ≈32% and late (PMID:37929589; PMID:22957257), surveillance cannot be discontinued in adulthood for a genotype-positive relative.
Tertiary prevention (complication prevention in affected individuals): ICD for SCD; anticoagulation for AF/apical aneurysm; myosin inhibition or myectomy to prevent progressive remodeling; endocarditis prophylaxis is not indicated for HCM per se; treat hypertension and sleep apnea; annual reassessment of risk markers.
Immunization: no disease-specific vaccine. Routine influenza/COVID/pneumococcal immunization is advisable in heart failure (general, not CMH8-specific).
Behavioral interventions: individualized exercise prescription (avoid burst/isometric extremes in obstructive disease), avoidance of dehydration and stimulants, weight and blood-pressure management (PMID:38718139).
Public-health/environmental interventions: not applicable, except population-level consanguinity education and improved representation of Middle Eastern/North African populations in reference databases — a documented equity problem for this gene: rare variants in Egyptian patients were "less likely to be classified as (likely) pathogenic compared with Europeans (40.8% vs. 61.6%, P = 1.6 × 10-5) due to the underrepresentation of Middle Eastern populations in current reference" resources (PMID:37431535).
Prophylaxis: no pharmacological prophylaxis prevents phenotype conversion in genotype-positive/phenotype-negative carriers (trials of pre-clinical intervention are ongoing in HCM generally; none MYL3-specific).

14. Other Species / Natural Disease

Taxonomy of species with characterized MYL3/ELC biology:
Homo sapiens — NCBITaxon:9606 (MYL3, hgnc:7584)
Mus musculus — NCBITaxon:10090 (Myl3, MGI:97268, chromosome 9, 110,592,746–110,598,870 bp, + strand; 1:1 stringent ortholog of human MYL3; MGI lists 7 mutations/alleles — 5 endonuclease-mediated, 2 targeted — and 20 IMSR strains; MGI links the human MYL3 association to hypertrophic cardiomyopathy 8, OMIM:608751)
Danio rerio — NCBITaxon:7955 (cmlc1, the MYL3 ortholog: "Cmlc1 shows over 70% homology with human ELC, and is highly expressed in zebrafish ventricle and weakly expressed in the atrium, while cmlc2 is homologous to human myosin regulatory light chain (RLC)" — PMID:33288880)
Sus scrofa — NCBITaxon:9823 (porcine cardiac muscle strips were used for recombinant ELC protein-exchange experiments: PMID:23748425)
Rattus norvegicus — NCBITaxon:10116 (1:1 ortholog per MGI)
Breed (VBO): not applicable — no breed-associated MYL3 variant is known.
Orthologous genes: mouse Myl3 (MGI:97268), rat Myl3, zebrafish cmlc1. (NCBI Gene IDs: human 4634; mouse 17897 — the mouse Gene ID should be re-verified before curation.)
Natural disease in other species: None documented. A direct OMIA query by gene symbol MYL3 returned "No phene records found" (omia.org, queried 2026-08-01). This is a notable contrast to feline HCM, where MYBPC3 variants (Maine Coon A31P, Ragdoll R820W) are established — MYL3 has no veterinary counterpart disease, and this absence is itself worth recording.
Veterinary relevance: none established for MYL3.
Comparative pathology / evolutionary conservation: ELC function is deeply conserved — the zebrafish rescue experiments demonstrate cross-species functional equivalence: "Thus, MYL3 shows conserved function to cmlc1 in the zebrafish and represents a valid system for testing pathogenic function of MYL3 variants." (PMID:33288880). The mutated residues are evolutionarily conserved ("Multiple sequence alignment confirms that the p.(Ala57Asp) substitution affects an evolutionarily conserved residue"; E143K was "a highly conserved amino acid that was absent in 150 controls" — PMID:12021217).
Zoonotic potential / cross-species susceptibility: not applicable (non-transmissible genetic disease).

15. Model Organisms

15.1 Mammalian genetic models (mouse, Mus musculus, NCBITaxon:10090)

The University of Miami (Szczesna-Cordary) transgenic series is the definitive MYL3 model resource; all express human ventricular ELC transgenes:

Model	Type	Phenotype recapitulation	Key evidence
Tg-A57G (HCM allele)	Transgenic, cardiac-specific human ELC	Increased Ca²⁺ sensitivity of force (ΔpCa₅₀ ≈ 0.1), ~1.3-fold reduced maximal force, increased passive tension/myocardial stiffness, fibrosis, hypertrophy (increased heart/body weight ratio), increased end-systolic elastance (contractility); SRX inhibited with more heads available and higher ATPase; increased RLC phosphorylation (~40%); shortened force transients	PMID:23748425; PMID:32034976; PMID:34014247
Tg-E143K (RCM allele)	Transgenic	Diastolic dysfunction with augmented active and passive tension, hypercontractile myosin (increased duty ratio, actin affinity, actin-activated ATPase, slower actomyosin dissociation), reduced RLC phosphorylation, ultrastructural defects and progressive fibrosis worsening with age, upregulated stress-response/collagen genes, reduced cardiac output/stroke work; SRX stabilized; lengthened force transients	PMID:28371863; PMID:34014247
Tg-Δ43 (N-terminally truncated ELC, residues 1–43 removed)	Transgenic "near-physiological remodeling" control	Hypertrophy with time but "do not show any abnormalities in cardiac morphology or function"; SRX stabilized, decreased ATP utilization; shifts cross-bridge mass toward thin filaments (X-ray I₁,₁/I₁,₀ increased 1.3-fold)	PMID:32034976; PMID:21885653
Tg-WT-ELC	Transgenic control expressing non-mutated human ventricular ELC	Baseline comparator for all above	PMID:34014247
A57G × Δ43 and E143K × Δ43 crosses	Cross-genotype rescue models	"In A57G×Δ43 mice, Δ43 expression improved heart function and reduced hypertrophy and fibrosis. No improvements were seen in E143K×Δ43" — allele-class-specific rescue	PMID:39211545
Endonuclease-mediated / targeted Myl3 alleles (7 total in MGI)	Knockout/targeted	MGI records 5 phenotypes across 2 alleles/3 backgrounds (growth/size/body, immune system, skeleton categories; also an osteoarthritis model) — notably, no cardiac phenotype is recorded in MGI for the constitutive alleles; a genuine gap and a caution against assuming a mouse Myl3-null cardiac model exists	MGI:97268

Applications: myofilament mechanics (skinned papillary muscle fibers, force–pCa), small/low-angle X-ray diffraction of filament lattice spacing, SRX/DRX single-nucleotide-turnover assays, in vitro motility, echocardiography and invasive PV-loop hemodynamics, histology/fibrosis quantification, cardiac transcriptomics and proteomics (PMID:26668058), and testing of mechanism-directed rescue.

Limitations to record explicitly: (a) transgenic overexpression on a mouse α-MHC background — mouse ventricle is α-MHC-dominant whereas human is β-MHC, altering baseline cross-bridge kinetics; (b) the models capture hypercontractility, stiffness and fibrosis but do not reproduce the human mid-cavity/papillary hypertrophy morphology or apical aneurysm, so the topographic signature of CMH8 remains unmodeled; (c) Tg-A57G shows "a phenotype of eccentric hypertrophy … enhanced left ventricular (LV) cavity dimension without changes in LV posterior/anterior wall thickness" (PMID:23748425) — i.e., the geometric phenotype diverges from human concentric/segmental HCM; (d) no mouse model of the human recessive LOF genotype exists; (e) no mouse model of arrhythmic SCD in ELC disease. These are strong candidates for discussions with kind: HUMAN_MODEL_MISMATCH.

15.2 Non-mammalian in vivo model (zebrafish, NCBITaxon:7955)

cmlc1 morpholino knockdown with human MYL3 mRNA rescue: "morphants displayed a nonfunctioning heart, characterized by a small ventricle with reduced contractility and a dilated atrium"; wild-type human MYL3 rescued (ventricular shortening fraction 7.3% → 17.7%, P ≤ 0.001), whereas "The nonsense-coding variant c.106G>T … was unable to rescue the cmlc1 morphant phenotype" and c.170C>A gave only partial rescue with no significant improvement in shortening fraction (PMID:33288880). Limitations acknowledged by the authors: transient mRNA expression, mosaic uptake, inability to test splice variants (addressed instead with a minigene assay), and inherent morpholino caveats.

15.3 Cellular / in vitro human models

Patient-derived and isogenic CRISPR-edited iPSC-CM panel for MYL3 c.170C>A (A57D): four isogenic lines (corrected control; homozygous VUS; heterozygous frameshift; known pathogenic c.170C>G) assayed for gene expression, sarcomere structure, cell size, contractility, action potentials and calcium handling (PMID:29914921). Result: benign assessment for A57D, pathogenic assessment for c.170C>G — establishing iPSC-CMs as "a promising VUS risk-assessment tool." Cell types: CL:0002131 regular ventricular cardiac myocyte (iPSC-derived); relevant to the repo's MorPhiC-style category: Cellular phenotype pattern with evidence_source: IN_VITRO.
MYL3 knockout hESC line WAe009-A-1H generated by episomal-vector CRISPR/Cas9 (PMID:40311326) — a new, citable resource for modeling ELC loss of function in human cardiomyocytes (directly relevant to the recessive LOF genotype that has no mouse model).
Recombinant protein / protein-exchange biophysics: porcine cardiac muscle strips exchanged with recombinant A57G or WT ELC (PMID:23748425); recombinant human ELCv E56G/M149V/E177G in myosin S1 ATPase and in vitro motility assays (PMID:36509720).
Structural/computational model: cryo-EM-based atomic model of the human cardiac thick filament used to map 5 MYL3 variants onto molecular interfaces (PMID:42372158; COMPUTATIONAL/structural).

15.4 Model resources

MGI (MGI:97268), IMSR (20 strains for Myl3), IMPC/KOMP (targeted alleles), ZFIN (cmlc1), Alliance of Genome Resources, Cellosaurus (for WAe009-A-1H and iPSC lines), Addgene/investigator-held transgenic lines (University of Miami ELC series).

16. Curation Notes and Recommendations for the dismech Entry

Module conformance. CMH8 conforms well to cardiomyopathy_maladaptive_remodeling (#Ventricular Remodeling node) — cardiomyocyte insult → remodeling → contractile dysfunction → heart failure. It does not primarily conform to cardiac_ion_channel_repolarization (this is a structural, not electrical, channelopathy), though the arrhythmic substrate is downstream. The fibrosis arm can reference fibrotic_response (cardiac fibroblast activation, collagen gene upregulation — PMID:28371863). Consider whether a new thick-filament hypercontractility / SRX-DRX module is warranted; it would be shared by MYH7-, MYL2-, MYL3- and MYBPC3-related HCM and would carry the myosin-inhibitor drug-target pattern (target_mechanisms: INHIBITS on the hypercontractility node for mavacamten/aficamten) — an unusually clean recurrent-mechanism + drug-pattern candidate under the repo's module guidance.
Subtypes. Recommend has_subtypes entries AD missense and AR loss-of-function (short slug-friendly names), since onset, morphology, severity, penetrance and counseling all diverge; then attach phenotypes/genetics/prognosis records via the subtype foreign key.
Inheritance blocks. Two blocks with bound terms: HP:0000006 Autosomal dominant inheritance and HP:0000007 Autosomal recessive inheritance, each with its own PMID-anchored evidence (PMID:8673105 / PMID:12021217 + PMID:33288880). Bind the term: — do not leave preferred_term alone.
Ontology gap to flag. There is no HPO term for mid-cavity (mid-ventricular) obstruction or papillary muscle hypertrophy. Use HP:0001712 + HP:0025445 with a more specific preferred_term (the repo explicitly permits a preferred_term more granular than term.label), and record the gap.
Evidence-source discipline. Most mechanistic claims are MODEL_ORGANISM (transgenic mice) or IN_VITRO (motility assays, iPSC-CMs); only the clinical phenotypes, penetrance and epidemiology are HUMAN_CLINICAL. Do not let mouse hypercontractility data stand as the sole support for a human phenotype node. PMID:42372158's interface mapping is best tagged COMPUTATIONAL (structural modeling on a cryo-EM model) even though it also reports human outcome associations — split into two evidence items if both claims are used.
Model-mismatch discussions worth curating. (a) A57D: ClinVar "likely pathogenic" vs. benign isogenic iPSC-CM result vs. failed zebrafish rescue (PMID:29914921 vs. PMID:33288880); (b) mouse Tg-A57G eccentric hypertrophy vs. human segmental/concentric HCM; (c) MGI records no cardiac phenotype for constitutive Myl3 alleles despite a demonstrated human recessive LOF disease; (d) ClinGen haploinsufficiency score 0 (2015) predating the 2021 recessive LOF evidence — a candidate for a KNOWLEDGE_GAP note that the dosage curation is stale rather than wrong.
Prevalence record. Populate structured Prevalence slots only; the derived 1–2/100,000 figure must sit in notes with its derivation, prevalence_class: BAND_1_9_PER_100000, and evidence pointing to PMID:12404107 (≈1% of HCM from MLC genes) plus PMID:25814232 (HCM background prevalence) — not a fabricated single-source citation.
Do not curate as CMH8 features: horseshoe kidney (incidental, PMID:33288880); MYL3–DCM as an established association (ClinGen: Disputed) except as the specific recessive-LOF observation; MYL3–ARVC (ClinGen: Limited, already handled in kb/disorders/Arrhythmogenic_Right_Ventricular_Cardiomyopathy.yaml).

Master Reference List (all verified against PubMed; cached in `references_cache/`)

PMID	Citation	Evidence type
8673105	Poetter K, et al. Mutations in either the essential or regulatory light chains of myosin are associated with a rare myopathy in human heart and skeletal muscle. Nat Genet 1996;13(1):63-9. doi:10.1038/ng0596-63	HUMAN_CLINICAL + IN_VITRO
12021217	Olson TM, Karst ML, Whitby FG, Driscoll DJ. Myosin light chain mutation causes autosomal recessive cardiomyopathy with mid-cavitary hypertrophy and restrictive physiology. Circulation 2002;105(20):2337-40	HUMAN_CLINICAL
12404107	Kabaeva ZT, et al. Systematic analysis of the regulatory and essential myosin light chain genes: genetic variants and mutations in hypertrophic cardiomyopathy. Eur J Hum Genet 2002;10(11):741-8	HUMAN_CLINICAL
11748309	Andersen PS, et al. Myosin light chain mutations in familial hypertrophic cardiomyopathy: phenotypic presentation and frequency in Danish and South African populations. J Med Genet 2001;38(12):E43 (letter; no abstract available)	HUMAN_CLINICAL
20031618	Kaski JP, et al. Prevalence of sarcomere protein gene mutations in preadolescent children with hypertrophic cardiomyopathy. Circ Cardiovasc Genet 2009	HUMAN_CLINICAL
21885653	Muthu P, et al. Structural and functional aspects of the myosin essential light chain in cardiac muscle contraction. FASEB J 2011;25(12):4394-405	MODEL_ORGANISM/IN_VITRO
22957257	Andersen PS, et al. A novel myosin essential light chain mutation causes hypertrophic cardiomyopathy with late onset and low expressivity. Biochem Res Int 2012;2012:685108	HUMAN_CLINICAL
23594557	Jay A, Chikarmane R, Poulik J, Misra VK. Infantile hypertrophic cardiomyopathy associated with a novel MYL3 mutation. Cardiology 2013;124(4):248-51	HUMAN_CLINICAL
23748425	Kazmierczak K, et al. Discrete effects of A57G-myosin essential light chain mutation associated with familial hypertrophic cardiomyopathy. Am J Physiol Heart Circ Physiol 2013;305(4):H575-89	MODEL_ORGANISM
25295008	Kazmierczak K, Yuan CC, Liang J, et al. Remodeling of the heart in hypertrophy in animal models with myosin essential light chain mutations. Front Physiol 2014	MODEL_ORGANISM (review)
25611685	Alfares AA, et al. Results of clinical genetic testing of 2,912 probands with hypertrophic cardiomyopathy: expanded panels offer limited additional sensitivity. Genet Med 2015	HUMAN_CLINICAL
25814232	Semsarian C, Ingles J, Maron MS, Maron BJ. New perspectives on the prevalence of hypertrophic cardiomyopathy. J Am Coll Cardiol 2015;65(12):1249-54	HUMAN_CLINICAL (review)
26443374	Nomura A, et al. Whole exome sequencing combined with integrated variant annotation prediction identifies a causative myosin essential light chain variant in hypertrophic cardiomyopathy. J Cardiol 2016;67(2):133-9	HUMAN_CLINICAL
26668058	Proteomic analysis of physiological versus pathological cardiac remodeling in animal models expressing mutations in myosin essential light chains. J Muscle Res Cell Motil 2015	MODEL_ORGANISM
27532257	Walsh R, et al. Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. Genet Med 2017;19(2):192-203	HUMAN_CLINICAL
28371863	Yuan CC, et al. Hypercontractile mutant of ventricular myosin essential light chain leads to disruption of sarcomeric structure and function and results in restrictive cardiomyopathy in mice. Cardiovasc Res 2017;113(10):1124-36	MODEL_ORGANISM
29914921	Ma N, et al. Determining the pathogenicity of a genomic variant of uncertain significance using CRISPR/Cas9 and human-induced pluripotent stem cells. Circulation 2018;138(23):2666-81	IN_VITRO
30297972	Ho CY, et al. Genotype and lifetime burden of disease in hypertrophic cardiomyopathy: insights from the Sarcomeric Human Cardiomyopathy Registry (SHaRe). Circulation 2018	HUMAN_CLINICAL
30681346	Ingles J, et al. Evaluating the clinical validity of hypertrophic cardiomyopathy genes. Circ Genom Precis Med 2019;12(2):e002460	HUMAN_CLINICAL (curation)
32034976	Sitbon YH, et al. Ablation of the N terminus of cardiac essential light chain promotes the super-relaxed state of myosin and counteracts hypercontractility in hypertrophic cardiomyopathy mutant mice. FEBS J 2020;287(18):3989-4004	MODEL_ORGANISM
32871100	Olivotto I, et al. Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM). Lancet 2020;396(10253):759-69 (NCT03470545)	HUMAN_CLINICAL (RCT)
33288880	Osborn DPS, et al. Autosomal recessive cardiomyopathy and sudden cardiac death associated with variants in MYL3. Genet Med 2021;23(4):787-92	HUMAN_CLINICAL + MODEL_ORGANISM
34014247	Sitbon YH, et al. Cardiomyopathic mutations in essential light chain reveal mechanisms regulating the super relaxed state of myosin. J Gen Physiol 2021;153(7):e202012801	MODEL_ORGANISM
35288424	Mavilakandy A, Ahamed H. Mutation of the MYL3 gene in a patient with mid-ventricular obstructive hypertrophic cardiomyopathy. BMJ Case Rep 2022;15(3):e244573	HUMAN_CLINICAL (case report)
36509720	Yampolskaya DS, et al. Properties of cardiac myosin with cardiomyopathic mutations in essential light chains. Biochemistry (Mosc) 2022;87(11):1260-7	IN_VITRO
37431535	Allouba M, et al. Ethnicity, consanguinity, and genetic architecture of hypertrophic cardiomyopathy. Eur Heart J 2023;44(48):5146-58	HUMAN_CLINICAL
37622657	Arbelo E, et al. 2023 ESC Guidelines for the management of cardiomyopathies	HUMAN_CLINICAL (guideline)
37639243	Desai MY, et al. Mavacamten in patients with hypertrophic cardiomyopathy referred for septal reduction: week 56 results from the VALOR-HCM randomized clinical trial. JAMA Cardiol 2023	HUMAN_CLINICAL (RCT)
37929589	Topriceanu CC, Pereira AC, Moon JC, Captur G, Ho CY. Meta-analysis of penetrance and systematic review on transition to disease in genetic hypertrophic cardiomyopathy. Circulation 2024;149(2):107-23	HUMAN_CLINICAL (meta-analysis)
38718139	Ommen SR, Ho CY, et al. 2024 AHA/ACC/AMSSM/HRS/PACES/SCMR Guideline for the Management of Hypertrophic Cardiomyopathy. Circulation 2024;149(23):e1239-e1311	HUMAN_CLINICAL (guideline)
38739079	Maron MS, et al. Aficamten for symptomatic obstructive hypertrophic cardiomyopathy (SEQUOIA-HCM). N Engl J Med 2024;390(20):1849-61 (NCT05186818)	HUMAN_CLINICAL (RCT)
39132495	Hespe S, et al. ClinGen Hereditary Cardiovascular Disease GCEP: Reappraisal of genes associated with hypertrophic cardiomyopathy. medRxiv 2024 (published version: JACC 2025)	HUMAN_CLINICAL (curation)
39211545	Sitbon YH, et al. Dual effect of N-terminal deletion of cardiac myosin essential light chain in mitigating cardiomyopathy. iScience 2024;27(8):110591	MODEL_ORGANISM
40311326	Generation of a MYL3 knockout stem cell line (WAe009-A-1H) by episomal vector-based CRISPR/Cas9 system. Stem Cell Res 2025	IN_VITRO
42372158	Dutta D, Kim Y, Ho CY, Seidman JG, Seidman CE, Craig R, Padrón R. Thick filament molecular interfaces play a critical role in the pathogenesis of hypertrophic cardiomyopathy. PNAS 2026;123(27):e2529234123	COMPUTATIONAL/structural + HUMAN_CLINICAL

Non-literature sources consulted: OMIM 608751 / 160790 (via MedGen and secondary indexing — omim.org returns HTTP 403 to automated fetches, so OMIM text was not read directly and OMIM-attributed statements here are corroborated by MedGen or primary papers); MedGen CUI C1837471; ClinVar E-utilities (517 MYL3 records; 14 P/LP, queried 2026-08-01); ClinGen search.clinicalgenome.org/kb/genes/HGNC:7584 (gene–disease validity, dosage, VCEP assertions); UniProt REST P08590; MGI:97268; OMIA gene-symbol query (no phene records for MYL3); OAK-verified ontology terms from local HP/CL/CHEBI builds and OLS GO/UBERON/NCIT/MONDO.

Known gaps in this report: no direct OMIM full-text read (403); no Orphanet prevalence record obtained (bot gate; no cached ORPHA file); no gnomAD constraint metrics (pLI/o-e) for MYL3 retrieved; no MYL3-stratified outcome, QoL, sex-ratio, or trial-response data exists in the literature; no metabolomic, lipidomic, epigenomic, single-cell or spatial data specific to MYL3; NCBI Gene ID for mouse Myl3 stated from memory and should be re-verified before curation.

Sources (web): - OMIM #608751 CMH8 · OMIM *160790 MYL3 - MedGen: hypertrophic cardiomyopathy 8 - ClinGen gene page HGNC:7584 (MYL3) · ClinGen HCM GCEP - ClinVar MYL3 - UniProt P08590 - MGI:97268 Myl3 · OMIA - Genomics England PanelApp: MYL3 (HCM) - GeneReviews: Nonsyndromic Hypertrophic Cardiomyopathy Overview - Olson 2002, Circulation (full text) · Osborn 2021, Genet Med · Mavilakandy 2022, BMJ Case Rep · Sitbon 2021, J Gen Physiol · Sitbon 2020, FEBS J (PMC)

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OpenScientist Report

Classifications

Inheritance

Discussions and Knowledge Gaps

Pathophysiology

Histopathology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Diagnosis

Prevalence

Clinical Trials

Source YAML

References & Deep Research

References

Deep Research

1. Disease Information

1.1 Overview

1.2 Key identifiers

1.3 Synonyms and alternative names

1.4 Nature of the underlying evidence

2. Etiology

2.1 Primary causal factor

2.2 Genetic risk factors

2.3 Environmental risk factors

2.4 Protective factors

2.5 Gene–environment interaction

3. Phenotypes

3.1 Cardiac structural phenotypes

3.2 Functional / hemodynamic and arrhythmic phenotypes

3.3 Extracardiac phenotypes

3.4 Laboratory abnormalities

3.5 Quality-of-life impact

4. Genetic / Molecular Information

4.1 Gene and protein

4.2 Reported pathogenic and candidate variants

4.3 Variant classification, allele frequency, and interpretive caveats

4.4 Functional consequences (allelic mechanism classes)

4.5 Structural interface hypothesis (2026)

4.6 Epigenetics and chromosomal abnormalities

5. Environmental Information

6. Mechanism / Pathophysiology

6.1 Causal chain (upstream → downstream), suitable for a dismech pathograph

6.2 Mechanism annotations by requested subheading

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

9.1 Epidemiology

9.2 Inheritance

9.3 Population demographics

10. Diagnostics

10.1 Imaging (the diagnostic core)

10.2 Electrophysiology and functional testing

10.3 Laboratory tests and biomarkers

10.4 Biopsy / pathology

10.5 Genetic testing

10.6 Omics-based diagnostics

10.7 Clinical criteria and differential diagnosis

10.8 Screening

11. Outcome / Prognosis

11.1 Survival and mortality

11.2 Morbidity and function

11.3 Complications (to curate as downstream nodes)

11.4 Prognostic factors and biomarkers

12. Treatment

12.1 Pharmacotherapy

12.2 Advanced therapeutics

12.3 Surgical and interventional

12.4 Supportive, rehabilitative, and counseling

12.5 Experimental treatments and trials

12.6 Treatment outcomes, adverse effects, and strategy

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

15.1 Mammalian genetic models (mouse, Mus musculus, NCBITaxon:10090)

15.2 Non-mammalian in vivo model (zebrafish, NCBITaxon:7955)

15.3 Cellular / in vitro human models

15.4 Model resources

Master Reference List (all verified against PubMed; cached in `references_cache/`)