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Classifications

Harrison's Part

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Inheritance

2

Autosomal dominant (heterozygous missense) HP:0000006

The classic CMH10 presentation is autosomal dominant, caused by a single heterozygous MYL2 missense allele acting on the regulatory light chain, with incomplete, age-related penetrance typical of sarcomeric HCM.

Autosomal dominant inheritance Penetrance: INCOMPLETE

Show evidence (1 reference)

CGGV:assertion_7b25ff6c-3ede-46a3-a637-3eab7aa18569-2026-01-13T170000.000Z SUPPORT Other

ClinGen's Hereditary Cardiovascular Disease Gene Curation Expert Panel classifies the MYL2-HCM relationship as Definitive with autosomal dominant inheritance.

Autosomal recessive (biallelic loss of function) HP:0000007

A separate, severe autosomal recessive form results from biallelic loss-of-function MYL2 alleles (e.g. the IVS6-1 cryptic-splice variant), presenting as fatal infantile cardiomyopathy with slow-skeletal muscle fiber hypotrophy.

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:27378946 SUPPORT In Vitro

"severely compromising the ability of myosin to develop contractile force and maintain normal systolic and diastolic cardiac function"

Characterises the biallelic IVS6-1 loss-of-function mechanism producing the severe infantile cardioskeletal form.

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Subtypes

2

Autosomal dominant missense CMH10

The common form: a single heterozygous MYL2 missense allele acting on the regulatory light chain, with incomplete age-related penetrance and allele-dependent severity spanning benign late-onset disease (E22K) to early onset with premature sudden death (R58Q). This is the arm that the entry's pathophysiology chain, treatments and clinical trials describe.

Show evidence (1 reference)

PMID:23365102 SUPPORT Human Clinical

"Heterozygous missense mutations in MYL2 are known to cause dominant hypertrophic cardiomyopathy; however, none of the parents showed signs of cardiomyopathy."

Names the dominant missense arm and, in the same sentence, separates it from the recessive arm by noting that heterozygous carriers of a loss-of-function allele are unaffected.

Autosomal recessive biallelic loss-of-function light chain myopathy

A distinct severe entity rather than an early presentation of the dominant form: biallelic loss-of-function MYL2 alleles affecting the last exon, disrupting the second EF-hand domain, presenting as a fatal infantile cardioskeletal myopathy with type I fibre hypotrophy. The obligate heterozygous parents are unaffected, so this arm and the dominant one differ in mechanism and not only in dose. Its discoverers proposed the name "light chain myopathy". It is curated as a subtype rather than a separate entry because it is the same gene and the same MONDO concept, but note the original pedigrees reported dilated rather than hypertrophic cardiomyopathy; if a distinct MONDO term is minted for light chain myopathy, this should be revisited as a split.

Show evidence (1 reference)

PMID:23365102 SUPPORT Human Clinical

"the mutations in the last exon of MYL2 are responsible for a novel autosomal recessive lethal myosinopathy"

Establishes this arm as its own recessive entity rather than a severe expression of the dominant disease.

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Discussions and Knowledge Gaps

4

Cardiac myosin inhibitors treat hypertrophic cardiomyopathy by increasing occupancy of the myosin super-relaxed state. R58Q already stabilises that state. Is this drug class the right one for R58Q carriers, and does the answer differ by MYL2 allele?

OPEN QUESTION OPEN myl2_srx_stabilization_vs_myosin_inhibitors

Attached to

pathophysiology#Stabilization of the Myosin Super-Relaxed State treatments#Cardiac Myosin Inhibition (Mavacamten)

The two facts are individually well supported and point in opposite directions. R58Q was shown to promote the myosin OFF state and stabilise SRX in reconstituted porcine fibres and in transgenic mouse papillary muscle, and the experimental intervention that improved the R58Q phenotype in that same work was a Ser15 phosphomimetic, which shifts myosin the other way, toward the disordered-relaxed state. Mavacamten shifts it toward SRX. If the R58Q lesion is an excess of SRX, the drug class licensed for this disease pushes in the direction of the lesion rather than against it. Three things stop this being an argument against prescribing. Obstruction is a haemodynamic problem and a gradient can fall for reasons unrelated to whether the drug corrects the primary lesion. The SRX findings are ex vivo and in mouse tissue, not in an R58Q patient's myocardium. And no genotype-stratified data exist either way: EXPLORER-HCM and VALOR-HCM enrolled by phenotype and reported no MYL2 subgroup, so there is no reported failure of mavacamten in an RLC carrier to point at. What is recorded here is a mechanistic reason to expect the answer might be allele-dependent, and an experiment worth doing, not a treatment recommendation. The corollary is that MYL2 is not mechanistically uniform. Sibling entries in this series carry the opposite lesion — the MYL3 A57G work describes inhibition of the super-relaxed state — so "sarcomeric HCM is hypercontractile" does not license assuming the direction of the SRX shift for a given light chain allele.

Show evidence (1 reference)

PMID:30430732 SUPPORT In Vitro

"R58Q promotes the OFF state of myosin, both in reconstituted porcine fibers and in Tg mouse papillary muscles, thereby stabilizing the super-relaxed state (SRX) of myosin, characterized by a very low ATP turnover rate"

Establishes the direction of the R58Q effect on the equilibrium the drug class targets, which is what raises the question.

If one working copy of MYL2 is sufficient — as the unaffected obligate carriers in the recessive pedigrees show — what is the dominant missense mechanism, and does it differ between alleles?

INTERPRETATION OPEN myl2_dominant_mechanism_is_not_haploinsufficiency

Attached to

pathophysiology#MYL2 Variant in Ventricular Regulatory Myosin Light Chain variants#MYL2 c.403-1G>C — recessive cryptic-splice allele genetic#MYL2

The recessive pedigrees settle a question the dominant literature cannot: the parents of children with biallelic loss-of-function MYL2 disease are obligate heterozygotes for a null-like allele, and they had no cardiomyopathy. So losing half the normal gene product does not cause hypertrophic cardiomyopathy, and the dominant missense alleles cannot be acting by simple haploinsufficiency. The mutant light chain has to be incorporated into the sarcomere and do something there. That much is settled. What is not is what the mutant chain does, and whether it is the same thing for every allele. This entry curates the functional signature that has been worked out for R58Q — the phosphorylation deficit, the SRX shift, the reduced force with raised ATPase, the calcium sensitisation — but the same-cohort comparison that made R58Q malignant made E22K benign, and the transgenic comparisons that isolate the phosphorylation deficit to R58Q show that N47K, an allele at a neighbouring residue, does not share it. Assigning the R58Q mechanism to MYL2 as a gene would overstate what has been shown. The sharpest illustration is that the alleles do not even agree on the sign of the force change. R58Q lowers maximal isometric force; A13T raises it, and does so while incorporated into only about 10% of myofilaments — which is what led that study to a poison-peptide mechanism, the general shape of dominant action this discussion is asking about. A model in which a small amount of mutant light chain disproportionately disrupts the sarcomere accommodates both directions of force change and is consistent with the unaffected obligate carriers, since it requires the mutant protein to be present rather than the normal protein to be absent.

Show evidence (4 references)

PMID:23365102 SUPPORT Human Clinical

"Heterozygous missense mutations in MYL2 are known to cause dominant hypertrophic cardiomyopathy; however, none of the parents showed signs of cardiomyopathy."

The unaffected obligate carriers are the observation that excludes haploinsufficiency as the dominant mechanism.

PMID:19150977 SUPPORT Model Organism

"the R58Q mutation and not the N47K led to reduced RLC phosphorylation in Tg ventricles"

Shows one of the entry's mechanistic nodes is allele-specific rather than a property of MYL2 disease generally.

PMID:22091967 SUPPORT Model Organism

"The significant functional changes observed, despite a low level of A13T mutant incorporation into myofilaments, suggest a 'poison-peptide' mechanism of disease."

Names the dominant mechanism this discussion is weighing, and gives the observation behind it — disproportionate functional effect from a small mutant fraction, which is the signature of a poison peptide rather than of a dose deficit.

+ 1 more reference

What are the penetrance, natural history, and sudden-death risk of MYL2-related hypertrophic cardiomyopathy, and is there any MYL2-stratified molecular dataset?

KNOWLEDGE GAP OPEN myl2_no_genotype_stratified_outcome_or_omics_data

Attached to

phenotypes#Sudden Cardiac Death prevalence#Worldwide (MYL2 share of HCM) treatments#Cardiac Myosin Inhibition (Mavacamten)

Every quantitative clinical statement in this entry is either a single-family figure or a disease-class figure borrowed from unstratified hypertrophic cardiomyopathy cohorts. Sudden death in R58Q is documented as an association across two pedigrees with no denominator behind it; the only screened case fraction available is for the light chain genes as a class in a 186-patient cohort from 2002; and the guideline and trial evidence supporting the treatments block enrolled by phenotype with no MYL2 subgroup reported. The gap extends to molecular data. A GEO search for MYL2-specific cardiomyopathy datasets returns nothing: the accessions that surface for MYL2 are studies in which it appears as a cardiomyocyte marker gene, and the accessions that surface for hypertrophic cardiomyopathy are unstratified or concern other genes. That is why this entry carries no datasets block. Adding a generic hypertrophic cardiomyopathy dataset here would be the named-entity substitution the repository's dataset guidance warns about — relaxing the entry name to its parent disease — and the absence is the accurate record. What would close it: a MYL2-stratified outcome cohort with a denominator, an allele-resolved penetrance estimate for R58Q comparable to the E22K founder work, and an isogenic-pair transcriptomic or proteomic profile of an MYL2-mutant human cardiomyocyte model.

Show evidence (1 reference)

PMID:12404107 SUPPORT Human Clinical

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

The rarity that explains why no MYL2-powered outcome cohort exists, and the only screened denominator this entry has.

Is conditional penetrance — a MYL2 allele that needs a second hypertrophy driver to become clinical disease — a property of the E22K founder allele, or the general model for low-penetrance sarcomeric variants?

EMERGING HYPOTHESIS OPEN myl2_penetrance_is_conditional_on_a_second_driver

Attached to

environmental#Hypertension as a penetrance-determining co-factor variants#MYL2 c.64G>A p.(Glu22Lys) — Dutch founder allele progression#Penetrance conditional on an additional hypertrophy driver

The founder cohort is unusually clean evidence for a model that is usually only asserted. Thirty-eight carriers of one allele on one haplotype: the allele alone was largely benign, and with hypertension, obesity, or a second sarcomeric variant, 89% of carriers had hypertrophic cardiomyopathy. The authors drew two conclusions that both follow from it — screen carriers for treatable hypertrophy drivers, and stop excluding hypertensive patients from genetic studies on the grounds that their hypertrophy is already explained. Whether the model generalises is open, and the founder design cuts both ways: one haplotype in one population controls for genetic background beautifully and also means the result could be specific to that background. The disease-class penetrance literature is consistent with conditional penetrance without demonstrating it — incidentally identified population carriers of sarcomeric variants have much lower penetrance than clinically ascertained ones, which is what a model requiring a second driver predicts, but is also what ascertainment bias alone predicts.

Show evidence (1 reference)

PMID:26497160 SUPPORT Human Clinical

"The co-presence of additional risk factors for hypertrophy such as hypertension, obesity, or other sarcomeric gene mutation increased disease penetrance substantially and caused HCM in 89% of MYL2 mutation carriers"

The quantified conditional-penetrance result this hypothesis is built on.

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Pathophysiology

8

MYL2 Variant in Ventricular Regulatory Myosin Light Chain

The initiating lesion in CMH10 is a variant in MYL2, encoding the ventricular regulatory myosin light chain (RLC) that binds the lever-arm region of beta-cardiac myosin. In the common dominant form the variant is a missense change (archetype R58Q) incorporated into the sarcomere; in the rare severe recessive form biallelic loss-of-function abolishes normal RLC. Either way the lesion perturbs how the myosin lever arm transmits force and how the myofilament responds to calcium.

Cardiomyocyte CL:0000746

MYL2 hgnc:7583

Sarcomere Organization GO:0045214 ⚠ ABNORMAL

Myosin thick filament GO:0032982

Downstream

Impaired Lever-Arm Function and Myofilament Calcium Sensitization The abnormal regulatory light chain disturbs lever-arm force transmission and shifts myofilament calcium sensitivity.

Reduced RLC Ser15 Phosphorylation The R58Q allele specifically lowers the phosphorylation of the regulatory light chain in vivo. This is a distinct consequence of the variant, not a downstream effect of the force deficit, and it is allele-selective.

Slow-Twitch Skeletal Muscle Contractile Deficit MYL2 is expressed in slow-twitch skeletal muscle as well as ventricle, and cardiac and skeletal involvement co-occur in human light chain disease. The link type is UNKNOWN rather than DIRECT because the intermediate steps are genuinely undetermined: the only model that measures the skeletal deficit produces it from a cardiac-restricted transgene, so a systemic route cannot be excluded and local action has not been demonstrated.

Show evidence (1 reference)

PMID:30365366 SUPPORT Model Organism

"MYL2 mutated models of hypertrophic cardiomyopathy may be useful research tools to study the molecular, structural, and energetic mechanisms of cardioskeletal myopathy associated with myosin RLC"

Establishes MYL2/regulatory-light-chain variants as a cause of hypertrophic cardiomyopathy with an associated cardioskeletal component, in a transgenic model of the R58Q allele.

Impaired Lever-Arm Function and Myofilament Calcium Sensitization

The regulatory light chain stabilizes the myosin lever arm and modulates the calcium responsiveness of contraction. MYL2 disease variants reduce maximal contractile force while increasing myofilament calcium sensitivity — the two functional signatures repeatedly observed for HCM-associated MYL2 mutations. In transgenic RLC-mutant hearts and slow-twitch muscle, contractile force is lower than wild type, consistent with defective force transmission by the mutant lever arm.

Cardiomyocyte CL:0000746

Regulation of Cardiac Muscle Contraction GO:0055117 ⚠ ABNORMAL Regulation of Cardiac Muscle Contraction by Calcium GO:0010882 ⚠ ABNORMAL

Animal models

Tg-R58Q transgenic mouse (ventricular RLC R58Q) Mouse recapitulates Skinned papillary muscle from this line reproduces both halves of the node: increased myofilament calcium sensitivity with reduced cooperativity, and slowed cross-bridge kinetics.

Downstream

Ventricular Hypertrophy, Myocyte Disarray and Fibrosis Chronic sarcomeric dysfunction drives maladaptive structural remodeling.

Calcium Handling Remodeling and Electrical Instability Beyond the myofilament's own calcium responsiveness, MYL2-mutant cardiomyocytes remodel their calcium handling machinery, including a large reduction in L-type calcium current.

Show evidence (2 references)

PMID:27378946 SUPPORT In Vitro

"a significant decrease in maximal contractile force and a significantly increased Ca(2+) sensitivity, both hallmarks of hypertrophic cardiomyopathy-associated mutations in MYL2"

States the two canonical functional consequences of HCM MYL2 mutations — reduced maximal force and increased myofilament calcium sensitivity.

PMID:30365366 SUPPORT Model Organism

"Skinned SOL muscles and ventricular PMs of R58Q animals exhibited lower contractile force"

Confirms reduced contractile force in ventricular papillary muscle of an R58Q RLC transgenic model, the in vivo correlate of the force deficit.

Ventricular Hypertrophy, Myocyte Disarray and Fibrosis

Sustained sarcomeric dysfunction produces the structural remodeling that defines HCM — cardiomyocyte hypertrophy, myofiber disarray, and interstitial fibrosis. RLC-mutant HCM classically involves mid-ventricular and papillary muscle hypertrophy, but the disarray-and-fibrosis substrate is shared with the other sarcomeric forms.

Cardiomyocyte CL:0000746 Cardiac Fibroblast CL:0002548

Cardiac Muscle Hypertrophy in Response to Stress GO:0014898 ↑ INCREASED Extracellular Matrix Organization GO:0030198 ↑ INCREASED

Interventricular septum UBERON:0002094 Left ventricle UBERON:0002084

Experimental models

MYL2-R58Q patient-derived iPSC cardiomyocytes IPSC DERIVED MODEL Cell enlargement and myofibrillar disarray reproduce the cellular components of this node.

Downstream

Hypertrophic Cardiomyopathy This node is the tissue substrate of the entry's defining clinical phenotype.

Asymmetric Septal Hypertrophy The commonest distribution the remodelling takes.

Non-Septal Hypertrophy Distribution (Mid-Ventricular and Apical) The allele-dependent alternative distributions of the same remodelling.

Myofiber Disarray Disarray is one of the three elements of this node, surfaced as an observable phenotype.

Left Ventricular Outflow Tract Obstruction Septal hypertrophy narrows the outflow tract, and obstruction arises when that geometry combines with systolic anterior motion of the mitral valve — hence known intermediates rather than a direct step. Obstruction is allele-dependent in this entity, not an obligatory consequence of the remodelling.

Diastolic Dysfunction, Heart Failure and Arrhythmic Risk The stiff, disarrayed and fibrotic ventricle is what impairs relaxation and sustains arrhythmia.

Show evidence (1 reference)

PMID:28912181 SUPPORT Human Clinical

"The histological features of HCM include myocyte hypertrophy and disarray, as well as interstitial fibrosis."

Names the defining tissue-level triad that this node represents.

Diastolic Dysfunction, Heart Failure and Arrhythmic Risk

The remodelled, stiff, fibrotic ventricle produces the clinical endpoints of CMH10: diastolic dysfunction, heart failure, and a risk of malignant ventricular arrhythmia and sudden death. As with sarcomeric HCM generally, a positive family history of HCM and of sudden cardiac death is common. The severe recessive infantile form fails systolically and diastolically together and is fatal in infancy.

Cardiomyocyte CL:0000746

Heart Contraction GO:0060047 ⚠ ABNORMAL

Animal models

Tg-R58Q transgenic mouse (ventricular RLC R58Q) Mouse partially recapitulates Echocardiography shows altered diastolic transmitral velocities and deceleration time in this line specifically, which is the diastolic half of the node.

Downstream

Left Ventricular Diastolic Dysfunction The diastolic element of this node as an observable clinical phenotype.

Congestive Heart Failure The heart-failure element of this node as an observable clinical phenotype.

Atrial Fibrillation Impaired ventricular relaxation raises filling pressure and loads the atrium, and the resulting atrial remodelling is the substrate for fibrillation.

Sudden Cardiac Death The arrhythmic element of this node reaching its worst outcome. The link type is indirect with unknown intermediates because which patients with this substrate go on to arrest is precisely what no MYL2-stratified data answer.

Show evidence (2 references)

PMID:23674365 SUPPORT Human Clinical

"The presence of any sarcomere gene mutation was associated with a younger age at presentation (38.4 vs 46.0 years, p<0.0005), a family history of HCM (50.6% vs 23.1%, p<0.0005), a family history of SCD (27.0% vs 14.9%, p<0.0005) and greater MLVWT (21.0 vs 19.3 mm, p=0.03)."

Places the MYL2 sarcomeric form within the familial, younger-onset, sudden-death-associated clinical pattern of sarcomere-positive HCM.

PMID:27378946 SUPPORT In Vitro

"severely compromising the ability of myosin to develop contractile force and maintain normal systolic and diastolic cardiac function"

Documents the severe systolic-and-diastolic failure of the biallelic infantile form.

Reduced RLC Ser15 Phosphorylation

The regulatory light chain carries a conserved Ser15 phosphorylation site through which cardiac myosin light-chain kinase tunes force production. The R58Q allele lowers RLC phosphorylation in vivo, and this is allele-selective rather than a general property of HCM-associated RLC variants — the N47K allele, studied in the same transgenic series, did not reduce it. The deficit is mechanistically load-bearing rather than incidental: substituting an aspartate at the phosphorylation site to mimic the phosphorylated state restores force in R58Q-reconstituted fibres.

Cardiomyocyte CL:0000746

RLC Ser15 phosphorylation GO:0018105 ↓ DECREASED

Animal models

Tg-R58Q transgenic mouse (ventricular RLC R58Q) Mouse recapitulates Reduced in situ RLC phosphorylation is measured in the ventricles of this line and not in the comparison line carrying a milder allele.

Downstream

Stabilization of the Myosin Super-Relaxed State Phosphorylation of the regulatory light chain shifts the thick filament away from the ordered, ATP-conserving OFF state; losing that phosphate shifts it back.

Show evidence (2 references)

PMID:19150977 SUPPORT Model Organism

"the R58Q mutation and not the N47K led to reduced RLC phosphorylation in Tg ventricles"

Establishes the phosphorylation deficit in vivo and shows it is specific to the malignant allele.

PMID:30430732 SUPPORT INDIRECT In Vitro

"A low level of maximal isometric force observed for R58Q- versus WT-reconstituted fibers was restored by S15D-R58Q."

Rescue by a phosphomimetic at Ser15 is what makes the phosphorylation deficit causal for the force deficit rather than a co-occurring finding.

Stabilization of the Myosin Super-Relaxed State

Striated-muscle myosin partitions between an active force-producing state, a disordered-relaxed state whose heads can reach actin, and a super-relaxed (SRX) state with an ordered arrangement along the thick filament and a very low ATP turnover rate. R58Q shifts the equilibrium toward SRX in both reconstituted fibres and transgenic papillary muscle, leaving fewer heads recruitable. This direction matters clinically: the licensed cardiac myosin inhibitors for hypertrophic cardiomyopathy act by *increasing* SRX occupancy, so an allele that already stabilises SRX is not obviously the one that class was designed for. That reservation is a mechanistic inference, not a reported treatment failure, and is recorded as an open question rather than as guidance. The ATP-turnover annotation on this node refers to the low turnover rate that defines the super-relaxed state itself. It is not in conflict with the raised actin-activated fibre ATPase reported for R58Q elsewhere in this entry: those are different measurements — the turnover of heads parked in the OFF state, and the enzymatic rate of the heads that are cycling.

Cardiomyocyte CL:0000746

Myosin ATP turnover GO:0016887 ↓ DECREASED

Myosin thick filament GO:0032982

Downstream

Impaired Lever-Arm Function and Myofilament Calcium Sensitization Fewer recruitable heads is one of the routes by which the allele lowers maximal force, so this node feeds the force deficit rather than bypassing it.

Show evidence (1 reference)

PMID:30430732 SUPPORT In Vitro

"R58Q promotes the OFF state of myosin, both in reconstituted porcine fibers and in Tg mouse papillary muscles, thereby stabilizing the super-relaxed state (SRX) of myosin, characterized by a very low ATP turnover rate"

Direct statement of the state shift this node represents, measured in two independent preparations.

Slow-Twitch Skeletal Muscle Contractile Deficit

MYL2 encodes the regulatory light chain of heart ventricle and slow-twitch skeletal muscle simultaneously, and human pedigrees of light chain disease report cardiac hypertrophy together with abnormal skeletal muscle. Whether the skeletal deficit is a parallel local action of the allele or a systemic consequence of the cardiac disease is not settled, and the leading model argues against the simple parallel reading: in R58Q transgenic mice the soleus shows the same contractile deficit as ventricular papillary muscle and the fast-twitch extensor digitorum longus does not, but the transgene is cardiac-restricted, so the mutant light chain is not present in soleus at all. The authors present this as their surprising result rather than as evidence of local action. The human expression fact makes skeletal muscle a candidate direct target; the mouse experiment does not test it.

Slow-twitch (type I) skeletal muscle fiber CL:0002211

Slow-twitch skeletal muscle fiber contraction GO:0031444 ↓ DECREASED

Animal models

Tg-R58Q transgenic mouse (ventricular RLC R58Q) Mouse recapitulates Soleus, a slow-twitch muscle, shows the same force deficit as ventricular papillary muscle in these animals, which is the cardioskeletal reach the node claims.

Downstream

Cardioskeletal Myopathy with Type I Fibre Disease The clinical skeletal-muscle phenotype this contractile deficit corresponds to.

Show evidence (4 references)

PMID:30365366 SUPPORT Model Organism

"Skinned SOL muscles and ventricular PMs of R58Q animals exhibited lower contractile force"

Measures the deficit in soleus and in ventricular papillary muscle of the same animals, which is the observation this node records. It establishes that the deficit exists in slow-twitch muscle; because the transgene is cardiac-restricted it does not establish that the allele acts locally there.

PMID:30365366 SUPPORT Model Organism

"Myosin light chain 2 ( MYL2) gene encodes the myosin regulatory light chain (RLC) simultaneously in heart ventricles and in slow-twitch skeletal muscle."

States the shared expression that makes slow-twitch skeletal muscle a candidate direct target of a MYL2 allele, which is the human-side basis of this node.

PMID:30365366 REFUTE Model Organism

"even though R58Q expression was restricted to the heart of mice, functional similarities were clearly observed between the hearts and slow-twitch skeletal muscle"

Refutes the reading that this model demonstrates the allele acting locally in skeletal muscle. The transgene is cardiac-restricted, so the soleus deficit it produces must arrive by a systemic route, and the authors flag the result as surprising for exactly that reason.

+ 1 more reference

Calcium Handling Remodeling and Electrical Instability

Patient-derived MYL2-R58Q cardiomyocytes remodel the calcium handling apparatus itself, with reduced L-type calcium current density, smaller and slower-decaying calcium transients, and a tenfold excess of irregular beating. This is a distinct lesion from the myofilament calcium sensitisation upstream: that one changes how the sarcomere responds to a given calcium signal, this one changes the signal.

Cardiomyocyte CL:0000746

Regulation of cardiac muscle cell membrane potential GO:0086036 ⚠ ABNORMAL

Experimental models

MYL2-R58Q patient-derived iPSC cardiomyocytes IPSC DERIVED MODEL Reduced L-type calcium current density, altered transients, and a tenfold excess of irregular beating, all in cells carrying the patient's own allele.

Downstream

Diastolic Dysfunction, Heart Failure and Arrhythmic Risk Cellular electrical instability is a plausible contributor to the arrhythmic risk of this disease, but the step from an iPSC-cardiomyocyte beating irregularly to a clinical ventricular arrhythmia is not established, which is why the link type is indirect with unknown intermediates.

Show evidence (1 reference)

PMID:30796699 SUPPORT In Vitro

"The percentage of myofibrillar disarray and cells with irregular beating in MYL2-R58Q iPSC-CMs was significantly higher than that in control cells."

Reports the electrical instability of this node in human cells carrying the patient's own MYL2 allele.

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Histopathology

2

Myofibrillar Disarray

The tissue-level record of disarray in this entity, kept distinct from the Myofiber Disarray phenotype, which carries the cardiac finding as an observable clinical feature. What this record adds is that disarray in MYL2 disease is not confined to myocardium: in the biallelic infantile form the corresponding skeletal-muscle finding is myofibrillar disorganization alongside hypotrophic type I fibres, the histological counterpart of this entry's cardioskeletal claim.

Show evidence (1 reference)

PMID:23365102 SUPPORT Human Clinical

"A cardioskeletal myopathy with onset and death in infancy, morphological features of muscle type I hypotrophy with myofibrillar disorganization and dilated cardiomyopathy was previously reported in three Dutch families."

Records the skeletal muscle counterpart of the same lesion in the biallelic form.

Cardiomyocyte Hypertrophy

Cell-level hypertrophy, measurable in patient-derived cardiomyocytes without any haemodynamic load — MYL2-R58Q cells were about 30% larger than controls by day 60 of differentiation. That the enlargement appears in isolated cells is what places it upstream of chamber remodelling rather than as a consequence of it.

Show evidence (1 reference)

PMID:30796699 SUPPORT In Vitro

"The MYL2-R58Q iPSC-CMs were nearly 30% larger than control iPSC-CMs at day 60."

Quantifies cell-autonomous hypertrophy in the disease genotype.

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Pathograph

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Phenotypes

10

Cardiovascular 9

Hypertrophic Cardiomyopathy OBLIGATE HP:0001639

OBLIGATE is frequency among affected individuals and is tautological for an entity defined as a form of hypertrophic cardiomyopathy. It is not a penetrance claim about carriers, which is the opposite of obligate — see the progression entry on conditional penetrance and the E22K variant record.

Show evidence (1 reference)

PMID:28912181 SUPPORT Human Clinical

"Hypertrophic cardiomyopathy (HCM) is a genetic disorder that is characterized by left ventricular hypertrophy unexplained by secondary causes and a nondilated left ventricle with preserved or increased ejection fraction."

States the defining clinical feature of the disease this MYL2 form manifests.

Left Ventricular Diastolic Dysfunction HP:0025168

Show evidence (1 reference)

PMID:27378946 SUPPORT INDIRECT In Vitro

"severely compromising the ability of myosin to develop contractile force and maintain normal systolic and diastolic cardiac function"

Links the MYL2 lesion to impaired systolic and diastolic cardiac function. Marked INDIRECT because the quote is a statement about myosin's contractile capacity in a reconstituted system, and the clinical echocardiographic phenotype follows from it by inference rather than being reported.

Congestive Heart Failure HP:0001635

Show evidence (2 references)

PMID:27378946 SUPPORT INDIRECT In Vitro

"severely compromising the ability of myosin to develop contractile force and maintain normal systolic and diastolic cardiac function"

Supports heart failure as an endpoint, most severe in the biallelic form. Marked INDIRECT because the quote describes compromised myosin function and does not itself report heart failure.

PMID:23365102 SUPPORT Human Clinical

"A cardioskeletal myopathy with onset and death in infancy, morphological features of muscle type I hypotrophy with myofibrillar disorganization and dilated cardiomyopathy was previously reported in three Dutch families."

A human clinical source for cardiac failure as the fatal endpoint of the biallelic form, which the molecular quote above can only support by inference.

Non-Septal Hypertrophy Distribution (Mid-Ventricular and Apical) Apical hypertrophic cardiomyopathy HP:0031992

The binding is HP:0031992 Apical hypertrophic cardiomyopathy, which is narrower than this phenotype as described — HPO has no term for a mid-ventricular or mid-cavity distribution, and HP:0031992 is the only non-septal distribution term available. The apical half of the claim rests on the characterisation of the R58Q patient in PMID:30796699, whose indexed PubMed record is abstract-only and states the apical distribution in its title alone, so it carries no quotable snippet here and is not cited as one.

Show evidence (2 references)

PMID:22091967 SUPPORT INDIRECT Model Organism

"associated with a rare FHC variant defined by mid-ventricular obstruction and septal hypertrophy"

States the mid-ventricular distribution for a named MYL2 allele. The evidence source is MODEL_ORGANISM because that is what this publication presents — it is a transgenic-mouse study — and the quoted clause is its background framing of the human entity it was built to model rather than a result it reports, hence INDIRECT. No primary human report of the A13T clinical phenotype could be located to cite in its place.

PMID:8673105 SUPPORT INDIRECT Human Clinical

"suggest that the mutations disrupt the stretch activation response of the cardiac papillary muscles"

Locates the lesion at the papillary muscles in the original description of light chain disease, which is the anatomical basis of the mid-cavity pattern. Marked INDIRECT because the sentence gives the proposed mechanism at that site rather than reporting the hypertrophy distribution itself.

Asymmetric Septal Hypertrophy HP:0001670

Show evidence (1 reference)

PMID:12404107 SUPPORT Human Clinical

"The mutation Glu22Lys was associated with moderate septal hypertrophy, a late onset of clinical manifestation, and benign disease course and prognosis."

Documents septal hypertrophy in a genotyped MYL2 family.

Myofiber Disarray HP:0031318

Show evidence (1 reference)

PMID:30796699 SUPPORT In Vitro

"The percentage of myofibrillar disarray and cells with irregular beating in MYL2-R58Q iPSC-CMs was significantly higher than that in control cells."

Shows disarray arising in human cells from the MYL2 genotype alone, without the haemodynamic loading present in a patient's heart.

Sudden Cardiac Death HP:0001645

Show evidence (2 references)

PMID:12404107 SUPPORT Human Clinical

"The mutation Arg58Gln showed also moderate septal hypertrophy, but, in contrast, it was associated with an early onset of clinical manifestation and premature sudden cardiac death."

Directly associates the R58Q allele with premature sudden cardiac death in a genotyped family.

PMID:31104103 SUPPORT INDIRECT Human Clinical

"R58Q existed in all six members with HCM and two healthy juveniles who had not yet developed HCM yet, and presumably in three deceased members who suffered from sudden death"

Independent pedigree evidence for sudden death in R58Q carriers, in a family large enough to show co-segregation rather than co-occurrence. The attribution to the three deceased members is the authors' inference from pedigree position, not a genotype result, which is why the sentence says "presumably".

Left Ventricular Outflow Tract Obstruction HP:0032092

Show evidence (2 references)

PMID:30706179 SUPPORT Other

"pathogenic and related to obstructive septal asymmetrical hypertrophy with a good prognosis"

Attaches obstructive hypertrophy to a named MYL2 allele (D166A) rather than to hypertrophic cardiomyopathy in general. Evidence source is OTHER because this is a narrative review reporting another group's cohort.

PMID:40427081 SUPPORT Other

"Hypertrophic cardiomyopathy (HCM) is often associated with left ventricular outflow tract (LVOT) obstruction, which affects a substantial proportion of patients."

Establishes obstruction as a common manifestation of the disease class this entity belongs to, which is the basis on which the entry curates obstruction-directed treatments. Evidence source is OTHER because this is a narrative review.

Atrial Fibrillation HP:0005110

Show evidence (1 reference)

PMID:30706179 SUPPORT INDIRECT Other

"causing severe hypertrophy with atrial fibrillation and likely pathogenic but related to a good prognosis"

Reports atrial fibrillation for a specific MYL2 allele in a screened HCM cohort. Evidence source is OTHER because this is a narrative review reporting another group's cohort, and INDIRECT because the clause describes the allele's phenotype rather than measuring an arrhythmia rate.

Musculoskeletal 1

Cardioskeletal Myopathy with Type I Fibre Disease Abnormal muscle fiber morphology HP:0004303

The binding is the generic HP:0004303 Abnormal muscle fiber morphology. HPO has no term for type I fibre *hypotrophy*; HP:0011807 Type 1 muscle fiber atrophy is the near miss and was rejected, because atrophy names shrinkage of a fibre that grew normally and hypotrophy names a failure to reach normal size — which is the claim the infantile pedigrees actually make. The specific concept is carried in preferred_term instead.

Show evidence (2 references)

PMID:23365102 SUPPORT Human Clinical

"A cardioskeletal myopathy with onset and death in infancy, morphological features of muscle type I hypotrophy with myofibrillar disorganization and dilated cardiomyopathy was previously reported in three Dutch families."

Describes the skeletal muscle pathology of the recessive form in the pedigrees whose genetic cause the paper then identifies as MYL2.

PMID:8673105 SUPPORT Human Clinical

"each of which are associated with a rare variant of cardiac hypertrophy as well as abnormal skeletal muscle"

Records skeletal muscle abnormality alongside the cardiac hypertrophy in the dominant missense form, so the cardioskeletal reach is not confined to the recessive entity.

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Genetic Associations

1

MYL2

Gene: MYL2 hgnc:7583 gene page relationship_type: CAUSATIVE

Show evidence (2 references)

CGGV:assertion_7b25ff6c-3ede-46a3-a637-3eab7aa18569-2026-01-13T170000.000Z SUPPORT Other

ClinGen's Gene Curation Expert Panel classifies this gene-disease relationship as Definitive, which is the authority for curating the gene as CAUSATIVE rather than a candidate.

PMID:27378946 SUPPORT In Vitro

"severely compromising the ability of myosin to develop contractile force and maintain normal systolic and diastolic cardiac function"

Characterizes the functional consequence of the biallelic loss-of-function allele class, which is the second, recessive arm of this gene-disease relationship and is distinct from the dominant missense arm.

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Variants

4

MYL2 c.64G>A p.(Glu22Lys) — Dutch founder allele Pathogenic

Gene: MYL2 hgnc:7583

A founder allele shared on a common haplotype by 38 members of 14 families. It is the clearest case in this gene of a variant that is not sufficient on its own: carriers of E22K alone were largely well, and disease emerged when a second hypertrophy-promoting factor — hypertension, obesity, or a second sarcomeric variant — was present. Its clinical course when it does manifest is late-onset and benign, which is the opposite pole from R58Q.

Show evidence (3 references)

PMID:26497160 SUPPORT Human Clinical

"We analysed 14 HCM families of whom 38 family members share the MYL2 c.64G > A"

Establishes the size of the cohort in which this allele's behaviour was characterised. The quote stops before the HGVS protein annotation because the reference validator strips bracketed spans that are not uppercase abbreviations or percentages; the founder haplotype the same sentence reports is stated in this variant's description.

PMID:26497160 SUPPORT Human Clinical

"The mutation alone showed benign disease manifestation with low penetrance."

States the low penetrance of the isolated allele, which is the property that makes this variant the entry's worked example of conditional penetrance.

PMID:12404107 SUPPORT Human Clinical

"The mutation Glu22Lys was associated with moderate septal hypertrophy, a late onset of clinical manifestation, and benign disease course and prognosis."

Independent characterisation of the same allele in a different cohort, agreeing on the benign course.

MYL2 p.(Arg58Gln) — malignant missense allele Pathogenic

Gene: MYL2 hgnc:7583

The archetypal MYL2 allele and the one behind almost all of the functional work in this entry. Unlike E22K it is malignant: early onset, premature sudden death, and co-segregation across a four-generation pedigree. Its functional signature is unusually well resolved — reduced RLC Ser15 phosphorylation, stabilisation of the super-relaxed myosin state, lower maximal force with higher ATPase, increased calcium sensitivity with reduced cooperativity, and slower cross-bridge kinetics — and a Ser15 phosphomimetic reverses several of these in vitro. The two unaffected juvenile carriers in the four-generation pedigree are the age-related penetrance recorded in this entry's inheritance block seen within one family, not evidence against the allele.

Show evidence (2 references)

PMID:12404107 SUPPORT Human Clinical

"The mutation Arg58Gln showed also moderate septal hypertrophy, but, in contrast, it was associated with an early onset of clinical manifestation and premature sudden cardiac death."

Contrasts R58Q with E22K in one cohort, which is what establishes that the severity difference is allelic and not cohort or ascertainment effect.

PMID:31104103 SUPPORT Human Clinical

"R58Q existed in all six members with HCM and two healthy juveniles who had not yet developed HCM yet, and presumably in three deceased members who suffered from sudden death"

Segregation in a four-generation family, addressing the paper's own concern that earlier R58Q reports rested on pedigrees of two or three members.

MYL2 p.(Ala13Thr) — mid-ventricular obstruction allele Pathogenic

Gene: MYL2 hgnc:7583

The allele that anchors the mid-ventricular distribution of this entity, and the one that shows the functional signature is allelic rather than gene-level: where R58Q lowers maximal isometric force, A13T raises it. In a transgenic model it produced enlarged interventricular septa and fibrotic lesions, a lower acto-myosin ATPase Vmax, and reduced binding affinity of the mutant light chain for myosin, from roughly a tenth of myofilaments carrying the mutant — the disproportion that led its authors to a poison-peptide mechanism.

Show evidence (2 references)

PMID:22091967 SUPPORT INDIRECT Model Organism

"associated with a rare FHC variant defined by mid-ventricular obstruction and septal hypertrophy"

Gives the clinical phenotype attached to this allele. Graded MODEL_ORGANISM/INDIRECT because the sentence is this mouse study's background framing rather than a human result it reports.

PMID:22091967 SUPPORT Model Organism

"Functional studies revealed an abnormal A13T mutation-induced increase in isometric force production"

The force change, in the direction opposite to R58Q's, measured in a transgenic model of this allele.

MYL2 c.403-1G>C — recessive cryptic-splice allele Pathogenic

Gene: MYL2 hgnc:7583

A homozygous last-acceptor-splice-site allele found in Dutch patients with infantile cardioskeletal myopathy, with compound-heterozygous alleles affecting the same exon in an Italian patient. It replaces the C-terminal tail and disrupts the second EF-hand domain. It belongs to a different disease mechanism from the dominant missense alleles above, and the pedigrees say so directly: the obligate heterozygous parents had no cardiomyopathy.

Show evidence (3 references)

PMID:23365102 SUPPORT Human Clinical

"The MYL2 mutation results in use of a cryptic splice site upstream of the last exon causing a frameshift"

Describes the molecular consequence of the splice allele.

PMID:23365102 SUPPORT Human Clinical

"As a consequence of these mutations, the second EF-hand domain is disrupted."

Names the structural domain lost, which is what distinguishes this allele class from the lever-arm missense alleles.

PMID:23365102 SUPPORT Human Clinical

"Heterozygous missense mutations in MYL2 are known to cause dominant hypertrophic cardiomyopathy; however, none of the parents showed signs of cardiomyopathy."

The obligate carriers being unaffected is the evidence that the dominant missense mechanism is not simple haploinsufficiency — one working copy of MYL2 is enough.

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Medical Actions

5

Implantable Cardioverter-Defibrillator

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

Platform: Device

An implantable cardioverter-defibrillator provides primary or secondary prevention of sudden cardiac death in patients at high arrhythmic risk. The indication in this entry rests on the sudden-death association of the malignant MYL2 alleles; there is no MYL2-stratified risk model, so device decisions follow the general hypertrophic cardiomyopathy risk assessment.

Show evidence (1 reference)

PMID:30775854 SUPPORT INDIRECT Human Clinical

"The patients with a pathogenic or likely pathogenic mutation underwent an implantable cardioverter defibrillator implantation more often than patients without a pathogenic or likely pathogenic mutation"

Documents that carrying a sarcomeric pathogenic variant, the class this entity belongs to, is what drives device implantation in practice in an unselected national cohort.

Heart Failure and HCM Pharmacotherapy

Action: Pharmacotherapy NCIT:C15986

Agent: beta-adrenergic antagonist NCIT:C29576 non-dihydropyridine calcium channel blocker NCIT:C333 disopyramide CHEBI:4657

Platform: Small molecule

Medical management of hypertrophy, outflow obstruction, and heart failure symptoms follows standard HCM and heart-failure therapy. No MYL2-specific agent or genotype-directed regimen exists, and the guideline recommendations this entry inherits were not stratified by genotype.

Show evidence (1 reference)

PMID:38718139 SUPPORT Other

"The "2024 AHA/ACC/AMSSM/HRS/PACES/SCMR Guideline for the Management of Hypertrophic Cardiomyopathy" provides recommendations to guide clinicians in the management of patients with hypertrophic cardiomyopathy."

Identifies the guidance that governs pharmacological management of this entity. Evidence source is OTHER because a guideline is expert consensus over an evidence base rather than a study reporting its own data.

Beta Blockade

Action: Pharmacotherapy NCIT:C15986

Agent: beta-adrenergic antagonist NCIT:C29576

Platform: Small molecule

Beta blockers are the first-line drug for symptomatic obstructive disease, reducing heart rate and contractility and lengthening diastolic filling. Non-dihydropyridine calcium channel blockers (verapamil, diltiazem) are the second-line alternative when beta blockade is ineffective or contraindicated, and disopyramide is added for refractory obstruction, though its side effects mean many centres use it as a bridge to septal reduction rather than as durable therapy. None of this is MYL2-specific; it is the disease-class therapy a symptomatic carrier receives.

Mechanism Target:

INHIBITS Left Ventricular Diastolic Dysfunction — Slowing the heart lengthens diastole, which is the mechanism by which beta blockade acts against impaired filling. The effect is INHIBITS because the node is the dysfunction, and the drug counteracts it; it does so by allowing more filling time rather than by improving intrinsic myocardial relaxation, which the sarcomeric lesion still governs.

Show evidence (1 reference)

PMID:40427081 SUPPORT Other

"Beta-blockers, including atenolol and nadolol, are considered the first-line treatment due to their ability to reduce heart rate and myocardial contractility and enhance diastolic filling."

Names diastolic filling as the thing the drug improves, which is the claim this edge makes. Evidence source is OTHER because this is a narrative review.

INHIBITS Left Ventricular Outflow Tract Obstruction — Reduced contractility lowers the dynamic gradient, which is why beta blockade is first-line specifically for the obstructive form.

Show evidence (1 reference)

PMID:40993768 SUPPORT Other

"Conventional pharmacological therapies such as β-blockers and nondihydropyridine calcium channel blockers are effective first-line treatments for obstructive HCM"

States first-line efficacy in obstructive disease specifically, which is the node this edge points at. Evidence source is OTHER because this is a narrative review.

Show evidence (2 references)

PMID:40427081 SUPPORT Other

"Beta-blockers, including atenolol and nadolol, are considered the first-line treatment due to their ability to reduce heart rate and myocardial contractility and enhance diastolic filling."

States the first-line status and the mechanism by which it works. Evidence source is OTHER because this is a narrative review.

PMID:40993768 SUPPORT Other

"Conventional pharmacological therapies such as β-blockers and nondihydropyridine calcium channel blockers are effective first-line treatments for obstructive HCM, and established invasive septal reduction therapies, such as surgical myectomy and alcohol septal ablation, provide effective relief..."

Independent review agreeing on first-line status and placing septal reduction after it in the sequence. Evidence source is OTHER because this is a narrative review.

Septal Reduction Therapy

Action: septal reduction therapy Ontology label: Myectomy NCIT:C51591

Platform: Surgery

Surgical myectomy or alcohol septal ablation relieves the outflow gradient in obstruction refractory to medical therapy. It is the procedure VALOR-HCM, curated in this entry's clinical trials, was designed to avert, so modelling the trial without modelling the procedure would leave the decision it addresses unrepresented. Note it targets anatomy rather than the sarcomeric lesion, so it acts on the obstruction phenotype while leaving every sarcomeric node upstream of it untouched.

Mechanism Target:

INHIBITS Left Ventricular Outflow Tract Obstruction — The procedure removes the septal muscle that narrows the outflow tract, so it acts on the obstruction phenotype directly while leaving the sarcomeric lesion upstream of it untouched.

Show evidence (2 references)

PMID:40993768 SUPPORT Other

"Invasive septal reduction therapies (surgical myectomy or alcohol septal ablation [ASA]) can effectively relieve LVOT gradients in obstructive HCM, but these are targeted to anatomy rather than the genetic cause."

States both what the procedure achieves and the limitation that bounds it: it relieves the gradient without acting on the genetic cause upstream. Evidence source is OTHER because this is a narrative review.

PMID:40993768 SUPPORT Other

"Guidelines recommend optimization of medical treatment in obstructive HCM patients before proceeding to more invasive options such as septal reduction therapy (SRT)"

Places the procedure after medical therapy in the treatment sequence.

Cardiac Myosin Inhibition (Mavacamten)

Action: Pharmacotherapy NCIT:C15986

Agent: mavacamten

Platform: Small molecule

Mavacamten reduces post-exercise outflow gradient and improves exercise capacity and symptoms in symptomatic obstructive hypertrophic cardiomyopathy, and is the first disease-directed drug class for the condition. It is listed here as the class a symptomatic obstructive MYL2 patient would be considered for, not as a MYL2-validated therapy — the pivotal trials enrolled by phenotype and reported no genotype subgroup. There is also a specific mechanistic reservation for the R58Q allele, recorded in the discussions block: myosin inhibitors work by increasing occupancy of the super-relaxed state, and R58Q already stabilises it.

Mechanism Target:

MODULATES Stabilization of the Myosin Super-Relaxed State — The drug class acts on the same super-relaxed/disordered-relaxed equilibrium this node represents. The edge records that the target is shared; it does not assert that shifting it further toward SRX benefits a carrier whose allele already shifts it that way.

INHIBITS Left Ventricular Outflow Tract Obstruction — The measured clinical effect, as distinct from the molecular target above: the pivotal trial's primary haemodynamic result is a reduction in post-exercise outflow gradient. Recorded as a separate edge because the gradient can fall whether or not the drug corrects the primary lesion in a given allele, which is the open question this entry records for R58Q. The effect on this edge is INHIBITS while the molecular edge above is MODULATES: the drug demonstrably reduces the gradient, whereas on the super-relaxed-state node it shifts an equilibrium in the same direction the R58Q allele already shifts it, which is neither inhibition nor activation of that node and is the reservation recorded in discussions.

Show evidence (1 reference)

PMID:32871100 SUPPORT INDIRECT Human Clinical

"Patients on mavacamten had greater reductions than those on placebo in post-exercise LVOT gradient"

A randomised measurement of the drug acting on this node specifically, which is a different claim from the molecular-target edge above and is why this edge carries its own citation rather than borrowing one. Marked INDIRECT for this entity because the trial enrolled by phenotype and reported no MYL2 subgroup.

Show evidence (1 reference)

PMID:32871100 SUPPORT INDIRECT Human Clinical

"Patients on mavacamten had greater reductions than those on placebo in post-exercise LVOT gradient"

The pivotal randomised result establishing the class effect. Marked INDIRECT for this entry because the trial enrolled by phenotype and no MYL2 subgroup was reported, so the benefit is inherited from the disease class rather than demonstrated in this entity.

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Environmental Factors

2

Hypertension as a penetrance-determining co-factor

Left without an exposure_term. ECTO's only hypertension-related term is ECTO:2000001 exposure to medication for hypertension, which names the treatment rather than the condition and would assert something this entry does not claim.

In the MYL2 E22K founder cohort, hypertension was the single most common additional hypertrophy driver among carriers who went on to develop clinical disease. This is not the usual "environmental risk factor" relationship, in which an exposure raises risk at the margin: here the genotype on its own largely failed to produce disease, and the co-factor supplied the rest. The authors' practical conclusion follows from that — screen carriers for hypertension early and treat it, and do not exclude hypertensive individuals from genetic studies of hypertrophic cardiomyopathy on the grounds that their hypertrophy is explained.

Show evidence (2 references)

PMID:26497160 SUPPORT Human Clinical

"The most prominent risk factor was hypertension, observed in 71% of mutation carriers with HCM and an additional risk factor."

Identifies hypertension as the dominant co-factor among affected carriers.

PMID:26497160 SUPPORT Human Clinical

"The MYL2 mutation c.64G > A on its own is incapable of triggering clinical HCM in most carriers."

States the dependence explicitly, which is what makes this a co-factor rather than an additive risk.

Mechanism Target:

EXACERBATES Ventricular Hypertrophy, Myocyte Disarray and Fibrosis — Pressure loading acts on the same remodelling node the sarcomeric lesion drives, which is why the two combine to produce hypertrophy that neither reliably produces alone.

Show evidence (1 reference)

PMID:26497160 SUPPORT Human Clinical

"The co-presence of additional risk factors for hypertrophy such as hypertension, obesity, or other sarcomeric gene mutation increased disease penetrance substantially and caused HCM in 89% of MYL2 mutation carriers"

Quantifies the joint effect on the hypertrophic outcome this node represents.

Obesity as a penetrance-determining co-factor

Left without an exposure_term; ECTO has no obesity exposure term, and obesity is a body-mass state rather than an exposure.

Obesity appears alongside hypertension and a second sarcomeric variant in the set of additional hypertrophy drivers that carried E22K carriers into clinical disease. It is grouped with them in the founder study rather than measured separately, so its individual contribution is not quantified — only its membership in the co-factor set is.

Show evidence (1 reference)

PMID:26497160 SUPPORT INDIRECT Human Clinical

"The co-presence of additional risk factors for hypertrophy such as hypertension, obesity, or other sarcomeric gene mutation increased disease penetrance substantially and caused HCM in 89% of MYL2 mutation carriers"

Names obesity among the co-factors and gives the joint penetrance figure. Marked INDIRECT because obesity's own effect is not reported apart from the grouped co-factor analysis.

Mechanism Target:

EXACERBATES Ventricular Hypertrophy, Myocyte Disarray and Fibrosis — Obesity adds haemodynamic load and metabolic drive to the same hypertrophic remodelling node, though the study reports it only within the grouped co-factor analysis.

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Diagnosis

2

Genetic Testing Establishing the MYL2 Genotype and Its Allele

Molecular testing is what distinguishes CMH10 from any other cause of unexplained left ventricular hypertrophy, and in this gene the allele matters as much as the gene: the two variants characterised side by side in a systematic light chain screen differed in onset age and in sudden-death risk while looking the same on echocardiography. Zygosity must also be established, because the biallelic loss-of-function genotype is a different disease with a different prognosis and different reproductive counselling.

Show evidence (1 reference)

PMID:12404107 SUPPORT Human Clinical

"The mutation Arg58Gln showed also moderate septal hypertrophy, but, in contrast, it was associated with an early onset of clinical manifestation and premature sudden cardiac death."

Shows that septal thickness did not separate the malignant from the benign allele, which is the argument for identifying the variant rather than stopping at the imaging phenotype.

Screening MYL2 Carriers for Hypertension and Other Hypertrophy Drivers

A management step specific to this gene rather than inherited from HCM generally. Because the founder allele largely fails to produce disease on its own and hypertension was the commonest co-factor in carriers who became affected, detecting and treating an additional hypertrophy driver early is a modifiable determinant of whether a carrier converts.

Show evidence (1 reference)

PMID:26497160 SUPPORT Human Clinical

"Early diagnosis of risk factors is important for early treatment of MYL2 mutation carriers and close monitoring should be guaranteed in this case."

The authors' own management conclusion from the founder cohort, stated for MYL2 carriers specifically.

📈

Progression

3

Infantile onset (biallelic loss-of-function genotype)

AR biallelic LOF Age: Onset and death in infancy

The recessive form is a distinct clinical entity from dominant CMH10 and should not be described as an early presentation of it.

Show evidence (1 reference)

PMID:23365102 SUPPORT Human Clinical

"A cardioskeletal myopathy with onset and death in infancy, morphological features of muscle type I hypotrophy with myofibrillar disorganization and dilated cardiomyopathy was previously reported in three Dutch families."

Defines the presentation window and outcome of the biallelic infantile form in the pedigrees that led to its genetic solution.

Adult onset (heterozygous missense genotype), allele-dependent

AD missense Age: Childhood to late adulthood, allele-dependent

Age at clinical manifestation tracks the allele rather than the gene: the two MYL2 variants characterised side by side in one screening study differed in onset and in prognosis, which is why this entry curates onset per variant rather than as a single disease-level figure.

Show evidence (2 references)

PMID:12404107 SUPPORT Human Clinical

"The mutation Glu22Lys was associated with moderate septal hypertrophy, a late onset of clinical manifestation, and benign disease course and prognosis."

Documents the late-onset, benign pole of the allelic range in a genotyped MYL2 family.

PMID:12404107 SUPPORT Human Clinical

"The mutation Arg58Gln showed also moderate septal hypertrophy, but, in contrast, it was associated with an early onset of clinical manifestation and premature sudden cardiac death."

Documents the early-onset, malignant pole of the same allelic range, in the same cohort and with the same ascertainment.

Penetrance conditional on an additional hypertrophy driver

AD missense

Recorded as a progression phase because in the E22K founder cohort the transition from genotype-positive to clinically affected was gated by the arrival of a second hypertrophy-promoting factor rather than by age alone.

Show evidence (1 reference)

PMID:26497160 SUPPORT Human Clinical

"The MYL2 mutation c.64G > A on its own is incapable of triggering clinical HCM in most carriers."

States that for this founder allele the genotype alone does not carry the carrier into clinical disease.

📊

Prevalence

1

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Clinical Trials

2

NCT03470545 PHASE_III COMPLETED

EXPLORER-HCM. Randomised, double-blind, placebo-controlled trial of mavacamten in adults with symptomatic obstructive hypertrophic cardiomyopathy, the pivotal trial for cardiac myosin inhibition.

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 behind the myosin inhibition treatment entry.

NCT04349072 PHASE_III COMPLETED

VALOR-HCM. Randomised, double-blind, placebo-controlled trial testing whether mavacamten can avert septal reduction therapy in patients already eligible for it — the relevant question for a carrier who has reached refractory obstruction.

Target Phenotypes: Left ventricular outflow tract obstruction HP:0032092

Show evidence (1 reference)

clinicaltrials:NCT04349072 SUPPORT Human Clinical

"that 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"

States the trial's objective, which is the clinical decision an obstructed carrier faces.

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Experimental Models

1

MYL2-R58Q patient-derived iPSC cardiomyocytes IPSC_DERIVED_MODEL

Cardiomyocytes differentiated from induced pluripotent stem cells of a patient with MYL2-R58Q apical hypertrophic cardiomyopathy. Its value is that it shows hypertrophy, disarray and calcium abnormality arising from the human genotype alone, in cells that have never experienced a pressure load — which separates the cell-autonomous consequences of the allele from the consequences of living in a hypertrophied heart.

Organism

human NCBITaxon:9606

Publication

PMID:30796699

Pathograph links

Calcium Handling Remodeling and Electrical Instability recapitulates fidelity: moderate observes: cellular Reduced L-type calcium current density, altered transients, and a tenfold excess of irregular beating, all in cells carrying the patient's own allele.

Limitations: A single patient line compared with a maternal control rather than an isogenic corrected pair, so the comparison carries the donors' whole genetic background difference and not only the MYL2 allele. iPSC-derived cardiomyocytes are also developmentally immature, which particularly affects calcium handling and electrophysiology — the exact readouts this link rests on.

Readouts

L-type calcium current density at 0 mV

Direction: DECREASED

Interpretation: Reduced calcium influx through the L-type channel.

Show evidence (1 reference)

PMID:30796699 SUPPORT In Vitro

"the L-type Ca2+ channel (LTCC) (ICa,L) density at 0 mV was reduced significantly by 45.3%"

The quantified current reduction behind this readout.

Ventricular Hypertrophy, Myocyte Disarray and Fibrosis partially recapitulates fidelity: moderate observes: cellular Cell enlargement and myofibrillar disarray reproduce the cellular components of this node.

Limitations: The node is a tissue-level claim that also includes interstitial fibrosis, and isolated cardiomyocytes cannot produce it — there is no interstitium and no fibroblast compartment. The model therefore covers two of the node's three elements and observes them one scale below the node.

Divergences from the human mechanism

boundary omission qualifying

Cardiac fibroblasts and the interstitial compartment are not in the model, so the fibrosis element of this node cannot be produced or observed in it.

scale extrapolation qualifying

The model observes single cells (CELLULAR) while the node is a tissue-level claim about chamber remodelling, so hypertrophy of the chamber is inferred from enlargement of the cell.

Readouts

Cardiomyocyte cross-sectional area

Direction: INCREASED

Interpretation: Cell-autonomous hypertrophy in the absence of haemodynamic load.

Show evidence (1 reference)

PMID:30796699 SUPPORT In Vitro

"The MYL2-R58Q iPSC-CMs were nearly 30% larger than control iPSC-CMs at day 60."

The measured enlargement behind this readout.

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Animal Models

1

Tg-R58Q transgenic mouse (ventricular RLC R58Q)

The workhorse model of malignant MYL2 disease. It is the system in which the RLC phosphorylation deficit, the super-relaxed state shift, the diastolic abnormality, and the slow-twitch skeletal muscle deficit were each demonstrated. Its most useful property is that it is routinely studied alongside a Tg-N47K line carrying a milder RLC allele, so findings can be attributed to the malignant variant rather than to RLC transgenesis.

Species

Mouse

Genotype

Transgenic expression of human ventricular myosin regulatory light chain carrying R58Q

Genes

MYL2 hgnc:7583

Publication

PMID:19150977

Pathograph links

Reduced RLC Ser15 Phosphorylation recapitulates fidelity: moderate observes: molecular Reduced in situ RLC phosphorylation is measured in the ventricles of this line and not in the comparison line carrying a milder allele.

Limitations: Fidelity is MODERATE rather than HIGH because the corresponding measurement has not been made in human MYL2-R58Q myocardium, so the deficit is established in mouse and inferred for the patient. The line is also transgenic rather than knock-in, so expression level is not the human heterozygous dose.

Readouts

In situ ventricular RLC phosphorylation

Direction: DECREASED

Interpretation: The molecular deficit this node records, measured directly.

Show evidence (1 reference)

PMID:19150977 SUPPORT Model Organism

"the R58Q mutation and not the N47K led to reduced RLC phosphorylation in Tg ventricles"

Reports the measurement and its allele-selectivity.

Diastolic Dysfunction, Heart Failure and Arrhythmic Risk partially recapitulates fidelity: moderate observes: organism Echocardiography shows altered diastolic transmitral velocities and deceleration time in this line specifically, which is the diastolic half of the node.

Limitations: PARTIALLY_RECAPITULATES because the node also carries heart failure and arrhythmic death, and this model was characterised for diastolic function and haemodynamics rather than for arrhythmic events or survival. Mouse diastolic indices at mouse heart rates are also not directly comparable with the human echocardiographic measurements the node's clinical claim rests on.

Readouts

Transmitral velocities and deceleration time

Direction: ALTERED

Interpretation: Echocardiographic correlate of impaired ventricular filling.

Show evidence (1 reference)

PMID:19150977 SUPPORT Model Organism

"echocardiographic examination showed significant alterations in diastolic transmitral velocities and deceleration time only in Tg-R58Q myocardium"

Gives the measurement and confines it to the malignant allele.

Slow-Twitch Skeletal Muscle Contractile Deficit recapitulates fidelity: moderate observes: tissue Soleus, a slow-twitch muscle, shows the same force deficit as ventricular papillary muscle in these animals, which is the cardioskeletal reach the node claims.

Limitations: The transgene is cardiac-restricted, so the mutant light chain is absent from soleus and this line cannot establish cell-autonomous action of the allele in skeletal muscle — the soleus deficit here must reach that muscle by some systemic route. That is the most material limitation of this link, and the paper states it explicitly. Separately, the human counterpart is documented as skeletal muscle abnormality in pedigrees rather than as a force measurement, so the mouse gives the quantitative deficit while the human evidence gives only its presence.

Divergences from the human mechanism

boundary omission invalidating

Skeletal-muscle expression of the mutant light chain is outside the model: the transgene is driven in heart only. The node concerns a tissue in which this model deliberately does not express the lesion, so the model cannot speak to local action there.

Readouts

Skinned soleus and ventricular papillary muscle force

Direction: DECREASED

Interpretation: Contractile deficit shared by ventricle and slow-twitch skeletal muscle.

Show evidence (1 reference)

PMID:30365366 SUPPORT Model Organism

"Skinned SOL muscles and ventricular PMs of R58Q animals exhibited lower contractile force"

The paired measurement in both tissues of the same animals.

Impaired Lever-Arm Function and Myofilament Calcium Sensitization recapitulates fidelity: moderate observes: tissue Skinned papillary muscle from this line reproduces both halves of the node: increased myofilament calcium sensitivity with reduced cooperativity, and slowed cross-bridge kinetics.

Limitations: Fidelity is MODERATE rather than HIGH because the line is transgenic rather than knock-in, so mutant incorporation is not the human heterozygous dose, and the measurements are in skinned fibres at controlled calcium rather than in an intact working myocardium.

Readouts

Tension-pCa relationship in skinned papillary muscle

Direction: INCREASED

Interpretation: Increased calcium sensitivity of force with reduced cooperativity, the myofilament half of the node.

Show evidence (1 reference)

PMID:23727233 SUPPORT Model Organism

"In tension-pCa study, both D166V and R58Q mutations exhibited increased Ca(2+) sensitivity and less cooperativity."

The measurement behind this readout.

Show evidence (1 reference)

PMID:23727233 SUPPORT Model Organism

"demonstrating the slower cross-bridge kinetics"

Supports treating this line as informative for the sarcomeric nodes generally: it reproduces the cross-bridge kinetic slowing of the human allele in mouse papillary muscle.

{ }

Source YAML

click to show

name: Hypertrophic Cardiomyopathy 10
creation_date: "2026-08-22T00:00:00Z"
synonyms:
- CMH10
- MYL2 hypertrophic cardiomyopathy
- ventricular regulatory myosin light chain hypertrophic cardiomyopathy
- cardiomyopathy, familial hypertrophic, 10
- hypertrophic cardiomyopathy caused by mutation in MYL2
description: >-
  Hypertrophic cardiomyopathy 10 (CMH10) is the MYL2-related form of familial
  hypertrophic cardiomyopathy. MYL2 encodes the ventricular/slow-twitch regulatory
  myosin light chain (RLC), which binds the neck (lever-arm) region of the
  beta-cardiac myosin heavy chain and tunes the force and calcium sensitivity of
  contraction. It is one of the eight genes with definitive ClinGen gene-disease
  validity for HCM. Heterozygous missense RLC variants (the archetype being R58Q)
  produce dominant HCM through a gain of myofilament calcium sensitivity together
  with impaired force transmission by the lever arm; because MYL2 is expressed in
  both heart ventricle and slow-twitch skeletal muscle, the same lesion can produce
  a cardioskeletal phenotype. A distinct severe autosomal recessive form, caused by
  biallelic loss-of-function (e.g. the IVS6-1 cryptic-splice allele), presents as
  fatal infantile cardiomyopathy with slow-skeletal fiber hypotrophy.
category: Genetic
classifications:
  harrisons_chapter:
  - classification_value: CARDIOVASCULAR
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
disease_term:
  preferred_term: hypertrophic cardiomyopathy 10
  term:
    id: MONDO:0012112
    label: hypertrophic cardiomyopathy 10
parents:
- Hypertrophic Cardiomyopathy
- Genetic Disorder
# Rule for the `subtype:` discriminator on phenotypes and progression phases in
# this entry: tag a record when the evidence behind it comes from a genotyped
# individual or pedigree belonging to one arm, and leave it untagged when the
# manifestation is one both arms reach. The test to apply to a new record is
# whether removing the arm would remove its evidence — if the citation is a
# heterozygous-missense cohort or pedigree it is `AD missense`, if it is the
# biallelic infantile pedigrees it is `AR biallelic LOF`, and if the claim would
# survive either way it stays unassigned. Deliberately no roster of which records
# currently carry which tag: the tags in the file below are the answer, and an
# enumeration here would go stale the first time a phenotype is added or
# retagged.
has_subtypes:
- name: AD missense
  display_name: Autosomal dominant missense CMH10
  description: >-
    The common form: a single heterozygous MYL2 missense allele acting on the
    regulatory light chain, with incomplete age-related penetrance and
    allele-dependent severity spanning benign late-onset disease (E22K) to early
    onset with premature sudden death (R58Q). This is the arm that the entry's
    pathophysiology chain, treatments and clinical trials describe.
  evidence:
  - reference: PMID:23365102
    reference_title: "Recessive MYL2 mutations cause infantile type I muscle fibre disease and cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Heterozygous missense mutations in MYL2 are known to cause dominant
      hypertrophic cardiomyopathy; however, none of the parents showed signs of
      cardiomyopathy.
    explanation: >-
      Names the dominant missense arm and, in the same sentence, separates it
      from the recessive arm by noting that heterozygous carriers of a
      loss-of-function allele are unaffected.
- name: AR biallelic LOF
  display_name: Autosomal recessive biallelic loss-of-function light chain myopathy
  description: >-
    A distinct severe entity rather than an early presentation of the dominant
    form: biallelic loss-of-function MYL2 alleles affecting the last exon,
    disrupting the second EF-hand domain, presenting as a fatal infantile
    cardioskeletal myopathy with type I fibre hypotrophy. The obligate
    heterozygous parents are unaffected, so this arm and the dominant one differ
    in mechanism and not only in dose. Its discoverers proposed the name "light
    chain myopathy". It is curated as a subtype rather than a separate entry
    because it is the same gene and the same MONDO concept, but note the original
    pedigrees reported dilated rather than hypertrophic cardiomyopathy; if a
    distinct MONDO term is minted for light chain myopathy, this should be
    revisited as a split.
  evidence:
  - reference: PMID:23365102
    reference_title: "Recessive MYL2 mutations cause infantile type I muscle fibre disease and cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the mutations in the last exon of MYL2 are responsible for a novel
      autosomal recessive lethal myosinopathy
    explanation: >-
      Establishes this arm as its own recessive entity rather than a severe
      expression of the dominant disease.
inheritance:
- name: Autosomal dominant (heterozygous missense)
  description: >-
    The classic CMH10 presentation is autosomal dominant, caused by a single
    heterozygous MYL2 missense allele acting on the regulatory light chain, with
    incomplete, age-related penetrance typical of sarcomeric HCM.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  penetrance: INCOMPLETE
  evidence:
  - reference: CGGV:assertion_7b25ff6c-3ede-46a3-a637-3eab7aa18569-2026-01-13T170000.000Z
    reference_title: "MYL2 / hypertrophic cardiomyopathy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MYL2 | HGNC:7583 | hypertrophic cardiomyopathy | MONDO:0005045 | AD | Definitive"
    explanation: >-
      ClinGen's Hereditary Cardiovascular Disease Gene Curation Expert Panel
      classifies the MYL2-HCM relationship as Definitive with autosomal dominant
      inheritance.
- name: Autosomal recessive (biallelic loss of function)
  description: >-
    A separate, severe autosomal recessive form results from biallelic
    loss-of-function MYL2 alleles (e.g. the IVS6-1 cryptic-splice variant),
    presenting as fatal infantile cardiomyopathy with slow-skeletal muscle fiber
    hypotrophy.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:27378946
    reference_title: "Molecular and Functional Effects of a Splice Site Mutation in the MYL2 Gene Associated with Cardioskeletal Myopathy and Early Cardiac Death in Infants."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      severely compromising the ability of myosin to develop contractile force and
      maintain normal systolic and diastolic cardiac function
    explanation: >-
      Characterises the biallelic IVS6-1 loss-of-function mechanism producing the
      severe infantile cardioskeletal form.
prevalence:
- population: Worldwide (MYL2 share of HCM)
  measure_type: UNKNOWN
  prevalence_class: NOT_YET_DOCUMENTED
  notes: >-
    MYL2 is a definitive but numerically minor HCM gene; no population-based rate
    for the MYL2-specific entity is documented.
progression:
- phase: Infantile onset (biallelic loss-of-function genotype)
  subtype: AR biallelic LOF
  age_range: Onset and death in infancy
  notes: >-
    The recessive form is a distinct clinical entity from dominant CMH10 and
    should not be described as an early presentation of it.
  evidence:
  - reference: PMID:23365102
    reference_title: "Recessive MYL2 mutations cause infantile type I muscle fibre disease and cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A cardioskeletal myopathy with onset and death in infancy, morphological
      features of muscle type I hypotrophy with myofibrillar disorganization and
      dilated cardiomyopathy was previously reported in three Dutch families.
    explanation: >-
      Defines the presentation window and outcome of the biallelic infantile
      form in the pedigrees that led to its genetic solution.
- phase: Adult onset (heterozygous missense genotype), allele-dependent
  subtype: AD missense
  age_range: Childhood to late adulthood, allele-dependent
  notes: >-
    Age at clinical manifestation tracks the allele rather than the gene: the two
    MYL2 variants characterised side by side in one screening study differed in
    onset and in prognosis, which is why this entry curates onset per variant
    rather than as a single disease-level figure.
  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: >-
      The mutation Glu22Lys was associated with moderate septal hypertrophy, a
      late onset of clinical manifestation, and benign disease course and
      prognosis.
    explanation: >-
      Documents the late-onset, benign pole of the allelic range in a genotyped
      MYL2 family.
  - 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: >-
      The mutation Arg58Gln showed also moderate septal hypertrophy, but, in
      contrast, it was associated with an early onset of clinical manifestation
      and premature sudden cardiac death.
    explanation: >-
      Documents the early-onset, malignant pole of the same allelic range, in
      the same cohort and with the same ascertainment.
- phase: Penetrance conditional on an additional hypertrophy driver
  subtype: AD missense
  notes: >-
    Recorded as a progression phase because in the E22K founder cohort the
    transition from genotype-positive to clinically affected was gated by the
    arrival of a second hypertrophy-promoting factor rather than by age alone.
  evidence:
  - reference: PMID:26497160
    reference_title: "Hypertrophic remodelling in cardiac regulatory myosin light chain (MYL2) founder mutation carriers."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The MYL2 mutation c.64G > A on its own is incapable of triggering clinical
      HCM in most carriers.
    explanation: >-
      States that for this founder allele the genotype alone does not carry the
      carrier into clinical disease.
pathophysiology:
- name: MYL2 Variant in Ventricular Regulatory Myosin Light Chain
  biological_scale: MOLECULAR
  role: trigger
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Primary Cardiomyocyte Insult"
  description: >-
    The initiating lesion in CMH10 is a variant in MYL2, encoding the ventricular
    regulatory myosin light chain (RLC) that binds the lever-arm region of
    beta-cardiac myosin. In the common dominant form the variant is a missense
    change (archetype R58Q) incorporated into the sarcomere; in the rare severe
    recessive form biallelic loss-of-function abolishes normal RLC. Either way the
    lesion perturbs how the myosin lever arm transmits force and how the myofilament
    responds to calcium.
  genes:
  - preferred_term: MYL2
    term:
      id: hgnc:7583
      label: MYL2
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: Sarcomere Organization
    term:
      id: GO:0045214
      label: sarcomere organization
    modifier: ABNORMAL
  cellular_components:
  - preferred_term: Myosin thick filament
    term:
      id: GO:0032982
      label: myosin filament
  evidence:
  - reference: PMID:30365366
    reference_title: "Slow-twitch skeletal muscle defects accompany cardiac dysfunction in transgenic mice with a mutation in the myosin regulatory light chain."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      MYL2 mutated models of hypertrophic cardiomyopathy may be useful research
      tools to study the molecular, structural, and energetic mechanisms of
      cardioskeletal myopathy associated with myosin RLC
    explanation: >-
      Establishes MYL2/regulatory-light-chain variants as a cause of hypertrophic
      cardiomyopathy with an associated cardioskeletal component, in a transgenic
      model of the R58Q allele.
  downstream:
  - target: Impaired Lever-Arm Function and Myofilament Calcium Sensitization
    causal_link_type: DIRECT
    description: >-
      The abnormal regulatory light chain disturbs lever-arm force transmission and
      shifts myofilament calcium sensitivity.
    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: >-
        The light chains stabilize the long alpha helical neck of the myosin head.
      explanation: >-
        Names the structural role through which a regulatory light chain variant
        reaches the lever arm, which is what makes this edge direct rather than
        an association between two separately evidenced nodes.
  - target: Reduced RLC Ser15 Phosphorylation
    causal_link_type: DIRECT
    description: >-
      The R58Q allele specifically lowers the phosphorylation of the regulatory
      light chain in vivo. This is a distinct consequence of the variant, not a
      downstream effect of the force deficit, and it is allele-selective.
    evidence:
    - reference: PMID:19150977
      reference_title: "Diastolic dysfunction in familial hypertrophic cardiomyopathy transgenic model mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        the R58Q mutation and not the N47K led to reduced RLC phosphorylation in
        Tg ventricles
      explanation: >-
        Attributes the phosphorylation deficit to the R58Q variant itself, and
        shows it does not follow from carrying any HCM-associated RLC variant,
        since the N47K allele in the same experiment did not produce it.
  - target: Slow-Twitch Skeletal Muscle Contractile Deficit
    causal_link_type: UNKNOWN
    description: >-
      MYL2 is expressed in slow-twitch skeletal muscle as well as ventricle, and
      cardiac and skeletal involvement co-occur in human light chain disease. The
      link type is UNKNOWN rather than DIRECT because the intermediate steps are
      genuinely undetermined: the only model that measures the skeletal deficit
      produces it from a cardiac-restricted transgene, so a systemic route cannot
      be excluded and local action has not been demonstrated.
    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: >-
        each of which are associated with a rare variant of cardiac hypertrophy
        as well as abnormal skeletal muscle
      explanation: >-
        The original description reports cardiac and skeletal abnormality
        together in the same patients. Marked INDIRECT because co-occurrence in a
        pedigree does not distinguish a shared direct target from a systemic
        consequence of the cardiac disease.
      directness: INDIRECT
- name: Impaired Lever-Arm Function and Myofilament Calcium Sensitization
  biological_scale: MOLECULAR
  role: effector
  description: >-
    The regulatory light chain stabilizes the myosin lever arm and modulates the
    calcium responsiveness of contraction. MYL2 disease variants reduce maximal
    contractile force while increasing myofilament calcium sensitivity — the two
    functional signatures repeatedly observed for HCM-associated MYL2 mutations.
    In transgenic RLC-mutant hearts and slow-twitch muscle, contractile force is
    lower than wild type, consistent with defective force transmission by the
    mutant lever arm.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: Regulation of Cardiac Muscle Contraction
    term:
      id: GO:0055117
      label: regulation of cardiac muscle contraction
    modifier: ABNORMAL
  - preferred_term: Regulation of Cardiac Muscle Contraction by Calcium
    term:
      id: GO:0010882
      label: regulation of cardiac muscle contraction by calcium ion signaling
    modifier: ABNORMAL
  evidence:
  - reference: PMID:27378946
    reference_title: "Molecular and Functional Effects of a Splice Site Mutation in the MYL2 Gene Associated with Cardioskeletal Myopathy and Early Cardiac Death in Infants."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      a significant decrease in maximal contractile force and a significantly
      increased Ca(2+) sensitivity, both hallmarks of hypertrophic
      cardiomyopathy-associated mutations in MYL2
    explanation: >-
      States the two canonical functional consequences of HCM MYL2 mutations —
      reduced maximal force and increased myofilament calcium sensitivity.
  - reference: PMID:30365366
    reference_title: "Slow-twitch skeletal muscle defects accompany cardiac dysfunction in transgenic mice with a mutation in the myosin regulatory light chain."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Skinned SOL muscles and ventricular PMs of R58Q animals exhibited lower contractile force"
    explanation: >-
      Confirms reduced contractile force in ventricular papillary muscle of an
      R58Q RLC transgenic model, the in vivo correlate of the force deficit.
  downstream:
  - target: Ventricular Hypertrophy, Myocyte Disarray and Fibrosis
    causal_link_type: DIRECT
    description: >-
      Chronic sarcomeric dysfunction drives maladaptive structural remodeling.
    evidence:
    - reference: PMID:18929571
      reference_title: "Regulatory light chain mutations associated with cardiomyopathy affect myosin mechanics and kinetics."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        We found that both R58Q and N47K show reductions in force compared to the
        wild type that could result in compensatory hypertrophy.
      explanation: >-
        Makes the causal step explicitly: the measured force deficit is what the
        authors propose the hypertrophy compensates for. The claim is the
        authors' proposed mechanism rather than a demonstrated sequence, so this
        edge rests on an inference they state rather than on an experiment that
        followed force loss through to hypertrophy.
      directness: INDIRECT
  - target: Calcium Handling Remodeling and Electrical Instability
    causal_link_type: DIRECT
    description: >-
      Beyond the myofilament's own calcium responsiveness, MYL2-mutant
      cardiomyocytes remodel their calcium handling machinery, including a large
      reduction in L-type calcium current.
    evidence:
    - reference: PMID:30796699
      reference_title: "Induced Pluripotent Stem Cell-Derived Cardiomyocytes from a Patient with MYL2-R58Q-Mediated Apical Hypertrophic Cardiomyopathy Show Hypertrophy, Myofibrillar Disarray, and Calcium Perturbations."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        the L-type Ca2+ channel (LTCC) (ICa,L) density at 0 mV was reduced
        significantly by 45.3%
      explanation: >-
        Shows a change in the calcium handling apparatus itself in patient-derived
        MYL2-R58Q cardiomyocytes, which is a separate lesion from the myofilament
        calcium sensitisation modelled at the upstream node.
- name: Ventricular Hypertrophy, Myocyte Disarray and Fibrosis
  biological_scale: TISSUE
  role: central_effector
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Ventricular Remodeling"
  description: >-
    Sustained sarcomeric dysfunction produces the structural remodeling that
    defines HCM — cardiomyocyte hypertrophy, myofiber disarray, and interstitial
    fibrosis. RLC-mutant HCM classically involves mid-ventricular and papillary
    muscle hypertrophy, but the disarray-and-fibrosis substrate is shared with the
    other sarcomeric forms.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  - preferred_term: Cardiac Fibroblast
    term:
      id: CL:0002548
      label: fibroblast of cardiac tissue
  biological_processes:
  - preferred_term: Cardiac Muscle Hypertrophy in Response to Stress
    term:
      id: GO:0014898
      label: cardiac muscle hypertrophy in response to stress
    modifier: INCREASED
  - preferred_term: Extracellular Matrix Organization
    term:
      id: GO:0030198
      label: extracellular matrix organization
    modifier: INCREASED
  locations:
  - preferred_term: Interventricular septum
    term:
      id: UBERON:0002094
      label: interventricular septum
  - preferred_term: Left ventricle
    term:
      id: UBERON:0002084
      label: heart left ventricle
  evidence:
  - reference: PMID:28912181
    reference_title: "Hypertrophic Cardiomyopathy: Genetics, Pathogenesis, Clinical Manifestations, Diagnosis, and Therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The histological features of HCM include myocyte hypertrophy and disarray, as well as interstitial fibrosis."
    explanation: >-
      Names the defining tissue-level triad that this node represents.
  downstream:
  - target: Hypertrophic Cardiomyopathy
    causal_link_type: DIRECT
    description: >-
      This node is the tissue substrate of the entry's defining clinical
      phenotype.
  - target: Asymmetric Septal Hypertrophy
    causal_link_type: DIRECT
    description: >-
      The commonest distribution the remodelling takes.
  - target: Non-Septal Hypertrophy Distribution (Mid-Ventricular and Apical)
    causal_link_type: DIRECT
    description: >-
      The allele-dependent alternative distributions of the same remodelling.
  - target: Myofiber Disarray
    causal_link_type: DIRECT
    description: >-
      Disarray is one of the three elements of this node, surfaced as an
      observable phenotype.
  - target: Left Ventricular Outflow Tract Obstruction
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Septal hypertrophy narrows the outflow tract, and obstruction arises when
      that geometry combines with systolic anterior motion of the mitral valve —
      hence known intermediates rather than a direct step. Obstruction is
      allele-dependent in this entity, not an obligatory consequence of the
      remodelling.
  - target: Diastolic Dysfunction, Heart Failure and Arrhythmic Risk
    causal_link_type: DIRECT
    description: >-
      The stiff, disarrayed and fibrotic ventricle is what impairs relaxation and
      sustains arrhythmia.
    evidence:
    - reference: PMID:19150977
      reference_title: "Diastolic dysfunction in familial hypertrophic cardiomyopathy transgenic model mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        echocardiographic examination showed significant alterations in diastolic
        transmitral velocities and deceleration time only in Tg-R58Q myocardium
      explanation: >-
        Measures the diastolic endpoint in the remodelled myocardium of an RLC
        mutant, and shows it separates the malignant allele from the milder one
        carried by the comparison line.
- name: Diastolic Dysfunction, Heart Failure and Arrhythmic Risk
  biological_scale: ORGANISM
  role: consequence
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Structural Cardiac Impairment and Heart Failure"
  description: >-
    The remodelled, stiff, fibrotic ventricle produces the clinical endpoints of
    CMH10: diastolic dysfunction, heart failure, and a risk of malignant
    ventricular arrhythmia and sudden death. As with sarcomeric HCM generally,
    a positive family history of HCM and of sudden cardiac death is common. The
    severe recessive infantile form fails systolically and diastolically together
    and is fatal in infancy.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: Heart Contraction
    term:
      id: GO:0060047
      label: heart contraction
    modifier: ABNORMAL
  evidence:
  - reference: PMID:23674365
    reference_title: "A systematic review and meta-analysis of genotype-phenotype associations in patients with hypertrophic cardiomyopathy caused by sarcomeric protein mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The presence of any sarcomere gene mutation was associated with a younger
      age at presentation (38.4 vs 46.0 years, p<0.0005), a family history of HCM
      (50.6% vs 23.1%, p<0.0005), a family history of SCD (27.0% vs 14.9%,
      p<0.0005) and greater MLVWT (21.0 vs 19.3 mm, p=0.03).
    explanation: >-
      Places the MYL2 sarcomeric form within the familial, younger-onset,
      sudden-death-associated clinical pattern of sarcomere-positive HCM.
  - reference: PMID:27378946
    reference_title: "Molecular and Functional Effects of a Splice Site Mutation in the MYL2 Gene Associated with Cardioskeletal Myopathy and Early Cardiac Death in Infants."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      severely compromising the ability of myosin to develop contractile force and
      maintain normal systolic and diastolic cardiac function
    explanation: >-
      Documents the severe systolic-and-diastolic failure of the biallelic
      infantile form.
  downstream:
  - target: Left Ventricular Diastolic Dysfunction
    causal_link_type: DIRECT
    description: >-
      The diastolic element of this node as an observable clinical phenotype.
  - target: Congestive Heart Failure
    causal_link_type: DIRECT
    description: >-
      The heart-failure element of this node as an observable clinical phenotype.
  - target: Atrial Fibrillation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Impaired ventricular relaxation raises filling pressure and loads the
      atrium, and the resulting atrial remodelling is the substrate for
      fibrillation.
  - target: Sudden Cardiac Death
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The arrhythmic element of this node reaching its worst outcome. The link
      type is indirect with unknown intermediates because which patients with
      this substrate go on to arrest is precisely what no MYL2-stratified data
      answer.
- name: Reduced RLC Ser15 Phosphorylation
  biological_scale: MOLECULAR
  role: effector
  description: >-
    The regulatory light chain carries a conserved Ser15 phosphorylation site
    through which cardiac myosin light-chain kinase tunes force production. The
    R58Q allele lowers RLC phosphorylation in vivo, and this is allele-selective
    rather than a general property of HCM-associated RLC variants — the N47K
    allele, studied in the same transgenic series, did not reduce it. The deficit
    is mechanistically load-bearing rather than incidental: substituting an
    aspartate at the phosphorylation site to mimic the phosphorylated state
    restores force in R58Q-reconstituted fibres.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: RLC Ser15 phosphorylation
    term:
      id: GO:0018105
      label: peptidyl-serine phosphorylation
    modifier: DECREASED
  evidence:
  - reference: PMID:19150977
    reference_title: "Diastolic dysfunction in familial hypertrophic cardiomyopathy transgenic model mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      the R58Q mutation and not the N47K led to reduced RLC phosphorylation in Tg
      ventricles
    explanation: >-
      Establishes the phosphorylation deficit in vivo and shows it is specific to
      the malignant allele.
  - reference: PMID:30430732
    reference_title: "Phosphomimetic-mediated in vitro rescue of hypertrophic cardiomyopathy linked to R58Q mutation in myosin regulatory light chain."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      A low level of maximal isometric force observed for R58Q- versus
      WT-reconstituted fibers was restored by S15D-R58Q.
    explanation: >-
      Rescue by a phosphomimetic at Ser15 is what makes the phosphorylation
      deficit causal for the force deficit rather than a co-occurring finding.
    directness: INDIRECT
  downstream:
  - target: Stabilization of the Myosin Super-Relaxed State
    causal_link_type: DIRECT
    description: >-
      Phosphorylation of the regulatory light chain shifts the thick filament
      away from the ordered, ATP-conserving OFF state; losing that phosphate
      shifts it back.
    evidence:
    - reference: PMID:30430732
      reference_title: "Phosphomimetic-mediated in vitro rescue of hypertrophic cardiomyopathy linked to R58Q mutation in myosin regulatory light chain."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        R58Q promotes the OFF state of myosin, both in reconstituted porcine
        fibers and in Tg mouse papillary muscles, thereby stabilizing the
        super-relaxed state (SRX) of myosin, characterized by a very low ATP
        turnover rate
      explanation: >-
        Reports the OFF-state shift in the same experimental system in which the
        Ser15 phosphomimetic reverses it, which is what connects the two nodes.
- name: Stabilization of the Myosin Super-Relaxed State
  biological_scale: MOLECULAR
  role: effector
  description: >-
    Striated-muscle myosin partitions between an active force-producing state, a
    disordered-relaxed state whose heads can reach actin, and a super-relaxed
    (SRX) state with an ordered arrangement along the thick filament and a very
    low ATP turnover rate. R58Q shifts the equilibrium toward SRX in both
    reconstituted fibres and transgenic papillary muscle, leaving fewer heads
    recruitable. This direction matters clinically: the licensed cardiac myosin
    inhibitors for hypertrophic cardiomyopathy act by *increasing* SRX occupancy,
    so an allele that already stabilises SRX is not obviously the one that class
    was designed for. That reservation is a mechanistic inference, not a reported
    treatment failure, and is recorded as an open question rather than as
    guidance.

    The ATP-turnover annotation on this node refers to the low turnover rate that
    defines the super-relaxed state itself. It is not in conflict with the raised
    actin-activated fibre ATPase reported for R58Q elsewhere in this entry: those
    are different measurements — the turnover of heads parked in the OFF state,
    and the enzymatic rate of the heads that are cycling.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  molecular_functions:
  - preferred_term: Myosin ATP turnover
    term:
      id: GO:0016887
      label: ATP hydrolysis activity
    modifier: DECREASED
  cellular_components:
  - preferred_term: Myosin thick filament
    term:
      id: GO:0032982
      label: myosin filament
  evidence:
  - reference: PMID:30430732
    reference_title: "Phosphomimetic-mediated in vitro rescue of hypertrophic cardiomyopathy linked to R58Q mutation in myosin regulatory light chain."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      R58Q promotes the OFF state of myosin, both in reconstituted porcine fibers
      and in Tg mouse papillary muscles, thereby stabilizing the super-relaxed
      state (SRX) of myosin, characterized by a very low ATP turnover rate
    explanation: >-
      Direct statement of the state shift this node represents, measured in two
      independent preparations.
  downstream:
  - target: Impaired Lever-Arm Function and Myofilament Calcium Sensitization
    causal_link_type: DIRECT
    description: >-
      Fewer recruitable heads is one of the routes by which the allele lowers
      maximal force, so this node feeds the force deficit rather than bypassing
      it.
- name: Slow-Twitch Skeletal Muscle Contractile Deficit
  biological_scale: TISSUE
  role: consequence
  description: >-
    MYL2 encodes the regulatory light chain of heart ventricle and slow-twitch
    skeletal muscle simultaneously, and human pedigrees of light chain disease
    report cardiac hypertrophy together with abnormal skeletal muscle. Whether
    the skeletal deficit is a parallel local action of the allele or a systemic
    consequence of the cardiac disease is not settled, and the leading model
    argues against the simple parallel reading: in R58Q transgenic mice the
    soleus shows the same contractile deficit as ventricular papillary muscle
    and the fast-twitch extensor digitorum longus does not, but the transgene is
    cardiac-restricted, so the mutant light chain is not present in soleus at
    all. The authors present this as their surprising result rather than as
    evidence of local action. The human expression fact makes skeletal muscle a
    candidate direct target; the mouse experiment does not test it.
  cell_types:
  - preferred_term: Slow-twitch (type I) skeletal muscle fiber
    term:
      id: CL:0002211
      label: type I muscle cell
  biological_processes:
  - preferred_term: Slow-twitch skeletal muscle fiber contraction
    term:
      id: GO:0031444
      label: slow-twitch skeletal muscle fiber contraction
    modifier: DECREASED
  evidence:
  - reference: PMID:30365366
    reference_title: "Slow-twitch skeletal muscle defects accompany cardiac dysfunction in transgenic mice with a mutation in the myosin regulatory light chain."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Skinned SOL muscles and ventricular PMs of R58Q animals exhibited lower contractile force"
    explanation: >-
      Measures the deficit in soleus and in ventricular papillary muscle of the
      same animals, which is the observation this node records. It establishes
      that the deficit exists in slow-twitch muscle; because the transgene is
      cardiac-restricted it does not establish that the allele acts locally
      there.
  - reference: PMID:30365366
    reference_title: "Slow-twitch skeletal muscle defects accompany cardiac dysfunction in transgenic mice with a mutation in the myosin regulatory light chain."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Myosin light chain 2 ( MYL2) gene encodes the myosin regulatory light chain
      (RLC) simultaneously in heart ventricles and in slow-twitch skeletal
      muscle.
    explanation: >-
      States the shared expression that makes slow-twitch skeletal muscle a
      candidate direct target of a MYL2 allele, which is the human-side basis of
      this node.
  - reference: PMID:30365366
    reference_title: "Slow-twitch skeletal muscle defects accompany cardiac dysfunction in transgenic mice with a mutation in the myosin regulatory light chain."
    supports: REFUTE
    evidence_source: MODEL_ORGANISM
    snippet: >-
      even though R58Q expression was restricted to the heart of mice, functional
      similarities were clearly observed between the hearts and slow-twitch
      skeletal muscle
    explanation: >-
      Refutes the reading that this model demonstrates the allele acting locally
      in skeletal muscle. The transgene is cardiac-restricted, so the soleus
      deficit it produces must arrive by a systemic route, and the authors flag
      the result as surprising for exactly that reason.
  - reference: PMID:30706179
    reference_title: "Hereditary heart disease: pathophysiology, clinical presentation, and animal models of HCM, RCM, and DCM associated with mutations in cardiac myosin light chains."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      R58Q-mutant mice showed functional similarities between the cardiac
      papillary muscles and slow-twitch soleus skeletal muscle
    explanation: >-
      A review restating the cardiac/slow-skeletal parallel, cited for the
      generalisation rather than for the primary measurement. Evidence source is
      OTHER because this is a narrative review.
  downstream:
  - target: Cardioskeletal Myopathy with Type I Fibre Disease
    causal_link_type: DIRECT
    description: >-
      The clinical skeletal-muscle phenotype this contractile deficit
      corresponds to.
- name: Calcium Handling Remodeling and Electrical Instability
  biological_scale: CELLULAR
  role: effector
  description: >-
    Patient-derived MYL2-R58Q cardiomyocytes remodel the calcium handling
    apparatus itself, with reduced L-type calcium current density, smaller and
    slower-decaying calcium transients, and a tenfold excess of irregular
    beating. This is a distinct lesion from the myofilament calcium
    sensitisation upstream: that one changes how the sarcomere responds to a
    given calcium signal, this one changes the signal.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: Regulation of cardiac muscle cell membrane potential
    term:
      id: GO:0086036
      label: regulation of cardiac muscle cell membrane potential
    modifier: ABNORMAL
  evidence:
  - reference: PMID:30796699
    reference_title: "Induced Pluripotent Stem Cell-Derived Cardiomyocytes from a Patient with MYL2-R58Q-Mediated Apical Hypertrophic Cardiomyopathy Show Hypertrophy, Myofibrillar Disarray, and Calcium Perturbations."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The percentage of myofibrillar disarray and cells with irregular beating in
      MYL2-R58Q iPSC-CMs was significantly higher than that in control cells.
    explanation: >-
      Reports the electrical instability of this node in human cells carrying the
      patient's own MYL2 allele.
  downstream:
  - target: Diastolic Dysfunction, Heart Failure and Arrhythmic Risk
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Cellular electrical instability is a plausible contributor to the arrhythmic
      risk of this disease, but the step from an iPSC-cardiomyocyte beating
      irregularly to a clinical ventricular arrhythmia is not established, which
      is why the link type is indirect with unknown intermediates.
phenotypes:
- name: Hypertrophic Cardiomyopathy
  category: Cardiovascular
  description: >-
    Unexplained left ventricular hypertrophy is the defining feature; RLC-mutant
    disease classically involves mid-ventricular and papillary muscle hypertrophy.
  phenotype_term:
    preferred_term: Hypertrophic cardiomyopathy
    term:
      id: HP:0001639
      label: Hypertrophic cardiomyopathy
  frequency: OBLIGATE
  notes: >-
    OBLIGATE is frequency among affected individuals and is tautological for an
    entity defined as a form of hypertrophic cardiomyopathy. It is not a
    penetrance claim about carriers, which is the opposite of obligate — see the
    progression entry on conditional penetrance and the E22K variant record.
  evidence:
  - reference: PMID:28912181
    reference_title: "Hypertrophic Cardiomyopathy: Genetics, Pathogenesis, Clinical Manifestations, Diagnosis, and Therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hypertrophic cardiomyopathy (HCM) is a genetic disorder that is characterized by left ventricular hypertrophy unexplained by secondary causes and a nondilated left ventricle with preserved or increased ejection fraction."
    explanation: >-
      States the defining clinical feature of the disease this MYL2 form manifests.
- name: Left Ventricular Diastolic Dysfunction
  category: Cardiovascular
  description: >-
    Increased myofilament calcium sensitivity and a stiff, hypertrophied ventricle
    impair relaxation and filling.
  phenotype_term:
    preferred_term: Left ventricular diastolic dysfunction
    term:
      id: HP:0025168
      label: Left ventricular diastolic dysfunction
  evidence:
  - reference: PMID:27378946
    reference_title: "Molecular and Functional Effects of a Splice Site Mutation in the MYL2 Gene Associated with Cardioskeletal Myopathy and Early Cardiac Death in Infants."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      severely compromising the ability of myosin to develop contractile force and
      maintain normal systolic and diastolic cardiac function
    explanation: >-
      Links the MYL2 lesion to impaired systolic and diastolic cardiac function.
      Marked INDIRECT because the quote is a statement about myosin's contractile
      capacity in a reconstituted system, and the clinical echocardiographic
      phenotype follows from it by inference rather than being reported.
    directness: INDIRECT
- name: Congestive Heart Failure
  category: Cardiovascular
  description: >-
    Heart failure develops from progressive diastolic dysfunction; the recessive
    infantile form presents with fatal heart failure in the first months of life.
  phenotype_term:
    preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  evidence:
  - reference: PMID:27378946
    reference_title: "Molecular and Functional Effects of a Splice Site Mutation in the MYL2 Gene Associated with Cardioskeletal Myopathy and Early Cardiac Death in Infants."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      severely compromising the ability of myosin to develop contractile force and
      maintain normal systolic and diastolic cardiac function
    explanation: >-
      Supports heart failure as an endpoint, most severe in the biallelic form.
      Marked INDIRECT because the quote describes compromised myosin function and
      does not itself report heart failure.
    directness: INDIRECT
  - reference: PMID:23365102
    reference_title: "Recessive MYL2 mutations cause infantile type I muscle fibre disease and cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A cardioskeletal myopathy with onset and death in infancy, morphological
      features of muscle type I hypotrophy with myofibrillar disorganization and
      dilated cardiomyopathy was previously reported in three Dutch families.
    explanation: >-
      A human clinical source for cardiac failure as the fatal endpoint of the
      biallelic form, which the molecular quote above can only support by
      inference.
- name: Non-Septal Hypertrophy Distribution (Mid-Ventricular and Apical)
  category: Cardiovascular
  description: >-
    The hypertrophy of MYL2 disease is not confined to the septum. The original
    description called the light chain form a rare variant of cardiac hypertrophy
    and located its lesion at the cardiac papillary muscles, without
    characterising an obstruction; mid-ventricular obstruction is attached
    specifically to the A13T allele in the later literature, and an apical
    distribution has been characterised for R58Q. Recording the distribution
    matters clinically, because a mid-cavity or apical pattern is what makes the
    diagnosis easy to miss on a study reported as normal septal thickness.
  subtype: AD missense
  phenotype_term:
    preferred_term: Mid-ventricular and apical hypertrophy distribution
    term:
      id: HP:0031992
      label: Apical hypertrophic cardiomyopathy
  evidence:
  - reference: PMID:22091967
    reference_title: "Myosin regulatory light chain mutation found in hypertrophic cardiomyopathy patients increases isometric force production in transgenic mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: >-
      associated with a rare FHC variant defined by mid-ventricular obstruction
      and septal hypertrophy
    explanation: >-
      States the mid-ventricular distribution for a named MYL2 allele. The
      evidence source is MODEL_ORGANISM because that is what this publication
      presents — it is a transgenic-mouse study — and the quoted clause is its
      background framing of the human entity it was built to model rather than a
      result it reports, hence INDIRECT. No primary human report of the A13T
      clinical phenotype could be located to cite in its place.
  - 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: >-
      suggest that the mutations disrupt the stretch activation response of the
      cardiac papillary muscles
    explanation: >-
      Locates the lesion at the papillary muscles in the original description of
      light chain disease, which is the anatomical basis of the mid-cavity
      pattern. Marked INDIRECT because the sentence gives the proposed mechanism
      at that site rather than reporting the hypertrophy distribution itself.
    directness: INDIRECT
  notes: >-
    The binding is HP:0031992 Apical hypertrophic cardiomyopathy, which is
    narrower than this phenotype as described — HPO has no term for a
    mid-ventricular or mid-cavity distribution, and HP:0031992 is the only
    non-septal distribution term available. The apical half of the claim rests on
    the characterisation of the R58Q patient in PMID:30796699, whose indexed
    PubMed record is abstract-only and states the apical distribution in its
    title alone, so it carries no quotable snippet here and is not cited as one.
- name: Asymmetric Septal Hypertrophy
  category: Cardiovascular
  description: >-
    The commoner distribution, documented in both of the MYL2 families identified
    in a systematic screen of the light chain genes. Notably it was moderate in
    both the benign and the malignant allele, so wall thickness did not separate
    them — onset age and sudden death did.
  subtype: AD missense
  phenotype_term:
    preferred_term: Asymmetric septal hypertrophy
    term:
      id: HP:0001670
      label: Asymmetric septal hypertrophy
  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: >-
      The mutation Glu22Lys was associated with moderate septal hypertrophy, a
      late onset of clinical manifestation, and benign disease course and
      prognosis.
    explanation: >-
      Documents septal hypertrophy in a genotyped MYL2 family.
- name: Myofiber Disarray
  category: Cardiovascular
  description: >-
    Loss of the parallel alignment of cardiomyocytes, the pathognomonic lesion of
    hypertrophic cardiomyopathy, is reproduced in human cardiomyocytes carrying
    the patient's own MYL2-R58Q allele — twice the rate seen in control cells.
  phenotype_term:
    preferred_term: Myofiber disarray
    term:
      id: HP:0031318
      label: Myofiber disarray
  evidence:
  - reference: PMID:30796699
    reference_title: "Induced Pluripotent Stem Cell-Derived Cardiomyocytes from a Patient with MYL2-R58Q-Mediated Apical Hypertrophic Cardiomyopathy Show Hypertrophy, Myofibrillar Disarray, and Calcium Perturbations."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The percentage of myofibrillar disarray and cells with irregular beating in
      MYL2-R58Q iPSC-CMs was significantly higher than that in control cells.
    explanation: >-
      Shows disarray arising in human cells from the MYL2 genotype alone, without
      the haemodynamic loading present in a patient's heart.
- name: Sudden Cardiac Death
  category: Cardiovascular
  description: >-
    Premature sudden death is the outcome that separates the malignant from the
    benign MYL2 alleles. It was the distinguishing feature of R58Q in the family
    screening study that also identified the benign E22K allele, and a
    four-generation pedigree carrying R58Q recorded three deceased members who
    died suddenly. No denominator exists — there is no MYL2-stratified outcome
    cohort — so this is a documented association and not a quantified risk.
  subtype: AD missense
  phenotype_term:
    preferred_term: Sudden cardiac death
    term:
      id: HP:0001645
      label: Sudden cardiac death
  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: >-
      The mutation Arg58Gln showed also moderate septal hypertrophy, but, in
      contrast, it was associated with an early onset of clinical manifestation
      and premature sudden cardiac death.
    explanation: >-
      Directly associates the R58Q allele with premature sudden cardiac death in
      a genotyped family.
  - reference: PMID:31104103
    reference_title: "The co-segregation of the MYL2 R58Q mutation in Chinese hypertrophic cardiomyopathy family and its pathological effect on cardiomyopathy disarray."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      R58Q existed in all six members with HCM and two healthy juveniles who had
      not yet developed HCM yet, and presumably in three deceased members who
      suffered from sudden death
    explanation: >-
      Independent pedigree evidence for sudden death in R58Q carriers, in a family
      large enough to show co-segregation rather than co-occurrence. The
      attribution to the three deceased members is the authors' inference from
      pedigree position, not a genotype result, which is why the sentence says
      "presumably".
    directness: INDIRECT
- name: Left Ventricular Outflow Tract Obstruction
  category: Cardiovascular
  description: >-
    Dynamic obstruction of the outflow tract is the manifestation the entry's
    pharmacological and septal-reduction treatments actually target, and both
    curated trials enrol on it. It is not universal in this entity: the D166A
    allele is reported with obstructive septal asymmetrical hypertrophy, whereas
    the D166H pedigree was explicitly non-obstructive. So obstruction is
    allele-dependent here rather than a feature of MYL2 disease as such.
  subtype: AD missense
  phenotype_term:
    preferred_term: Left ventricular outflow tract obstruction
    term:
      id: HP:0032092
      label: Left ventricular outflow tract obstruction
  evidence:
  - reference: PMID:30706179
    reference_title: "Hereditary heart disease: pathophysiology, clinical presentation, and animal models of HCM, RCM, and DCM associated with mutations in cardiac myosin light chains."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      pathogenic and related to obstructive septal asymmetrical hypertrophy with
      a good prognosis
    explanation: >-
      Attaches obstructive hypertrophy to a named MYL2 allele (D166A) rather than
      to hypertrophic cardiomyopathy in general. Evidence source is OTHER because
      this is a narrative review reporting another group's cohort.
  - reference: PMID:40427081
    reference_title: "Integrative Approaches in the Management of Hypertrophic Cardiomyopathy: A Comprehensive Review of Current Therapeutic Modalities."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Hypertrophic cardiomyopathy (HCM) is often associated with left ventricular
      outflow tract (LVOT) obstruction, which affects a substantial proportion of
      patients.
    explanation: >-
      Establishes obstruction as a common manifestation of the disease class this
      entity belongs to, which is the basis on which the entry curates
      obstruction-directed treatments. Evidence source is OTHER because this is a
      narrative review.
- name: Atrial Fibrillation
  category: Cardiovascular
  description: >-
    Atrial fibrillation is reported for a named MYL2 allele (I158L) alongside
    severe hypertrophy, and is a recognised endpoint of the atrial loading that
    follows a stiff, poorly relaxing ventricle. No MYL2-stratified incidence
    exists: the one MYL2 pedigree reporting a rate is a research letter whose
    PubMed record carries no abstract, so that figure is deliberately not curated
    here.
  subtype: AD missense
  phenotype_term:
    preferred_term: Atrial fibrillation
    term:
      id: HP:0005110
      label: Atrial fibrillation
  evidence:
  - reference: PMID:30706179
    reference_title: "Hereditary heart disease: pathophysiology, clinical presentation, and animal models of HCM, RCM, and DCM associated with mutations in cardiac myosin light chains."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      causing severe hypertrophy with atrial fibrillation and likely pathogenic
      but related to a good prognosis
    explanation: >-
      Reports atrial fibrillation for a specific MYL2 allele in a screened HCM
      cohort. Evidence source is OTHER because this is a narrative review
      reporting another group's cohort, and INDIRECT because the clause describes
      the allele's phenotype rather than measuring an arrhythmia rate.
    directness: INDIRECT
- name: Cardioskeletal Myopathy with Type I Fibre Disease
  category: Musculoskeletal
  description: >-
    Because MYL2 is the regulatory light chain of slow-twitch skeletal muscle as
    well as ventricle, skeletal muscle is a target of the same allele rather than
    a bystander. The involvement was recognised in the original description of
    light chain disease and is the defining feature of the biallelic infantile
    form, where type I fibres are hypotrophic and myofibrils disorganised.
  subtype: AR biallelic LOF
  phenotype_term:
    preferred_term: Type I muscle fibre hypotrophy with myofibrillar disorganization
    term:
      id: HP:0004303
      label: Abnormal muscle fiber morphology
  evidence:
  - reference: PMID:23365102
    reference_title: "Recessive MYL2 mutations cause infantile type I muscle fibre disease and cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A cardioskeletal myopathy with onset and death in infancy, morphological
      features of muscle type I hypotrophy with myofibrillar disorganization and
      dilated cardiomyopathy was previously reported in three Dutch families.
    explanation: >-
      Describes the skeletal muscle pathology of the recessive form in the
      pedigrees whose genetic cause the paper then identifies as MYL2.
  - 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: >-
      each of which are associated with a rare variant of cardiac hypertrophy as
      well as abnormal skeletal muscle
    explanation: >-
      Records skeletal muscle abnormality alongside the cardiac hypertrophy in
      the dominant missense form, so the cardioskeletal reach is not confined to
      the recessive entity.
  notes: >-
    The binding is the generic HP:0004303 Abnormal muscle fiber morphology. HPO
    has no term for type I fibre *hypotrophy*; HP:0011807 Type 1 muscle fiber
    atrophy is the near miss and was rejected, because atrophy names shrinkage of
    a fibre that grew normally and hypotrophy names a failure to reach normal size
    — which is the claim the infantile pedigrees actually make. The specific
    concept is carried in preferred_term instead.
genetic:
- name: MYL2
  gene_term:
    preferred_term: MYL2
    term:
      id: hgnc:7583
      label: MYL2
  relationship_type: CAUSATIVE
  frequency: >-
    Definitive but numerically minor cause of hypertrophic cardiomyopathy; the
    only screened-cohort figure available is for the myosin light chain genes as
    a class, recorded in case_fractions below.
  case_fractions:
  - population: 186 unrelated HCM index patients systematically screened for MYL2 and MYL3
    case_fraction_percent: 1.0
    cohort_size: 186
    notes: >-
      The 1% figure the authors state is for the myosin light chain genes as a
      class (MYL2 plus MYL3), not for MYL2 alone. In this particular cohort every
      light chain finding was in MYL2 and none in MYL3, so 1% is an upper bound
      on the MYL2 share here rather than a MYL2-specific estimate. Recorded
      because it is the only systematically screened denominator available.
    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: >-
        myosin light chain mutations are a very rare cause of HCM responsible for
        about 1% of cases
      explanation: >-
        States the case fraction for the light chain gene class in a
        systematically screened HCM cohort.
    - 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: >-
        We analysed 186 unrelated individuals with HCM
      explanation: >-
        Gives the denominator behind that fraction.
  - population: 382 unrelated Finnish patients with hypertrophic cardiomyopathy, 59-gene panel
    notes: >-
      No MYL2-specific percentage is reported. MYL2 is named as one of four
      sarcomere genes carrying most of the pathogenic findings among the 38.2% of
      patients with a molecular diagnosis, which corroborates that MYL2 is a
      recurrent but minor contributor rather than quantifying its share.
    evidence:
    - reference: PMID:30775854
      reference_title: "Genetic basis and outcome in a nationwide study of Finnish patients with hypertrophic cardiomyopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Most mutations were located in sarcomere genes (MYBPC3, MYH7, TPM1, and
        MYL2).
      explanation: >-
        Places MYL2 among the sarcomere genes carrying the pathogenic yield in an
        unselected nationwide cohort.
  evidence:
  - reference: CGGV:assertion_7b25ff6c-3ede-46a3-a637-3eab7aa18569-2026-01-13T170000.000Z
    reference_title: "MYL2 / hypertrophic cardiomyopathy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      MYL2 | HGNC:7583 | hypertrophic cardiomyopathy | MONDO:0005045 | AD |
      Definitive
    explanation: >-
      ClinGen's Gene Curation Expert Panel classifies this gene-disease
      relationship as Definitive, which is the authority for curating the gene
      as CAUSATIVE rather than a candidate.
  - reference: PMID:27378946
    reference_title: "Molecular and Functional Effects of a Splice Site Mutation in the MYL2 Gene Associated with Cardioskeletal Myopathy and Early Cardiac Death in Infants."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      severely compromising the ability of myosin to develop contractile force
      and maintain normal systolic and diastolic cardiac function
    explanation: >-
      Characterizes the functional consequence of the biallelic
      loss-of-function allele class, which is the second, recessive arm of
      this gene-disease relationship and is distinct from the dominant
      missense arm.
  notes: >-
    Both the dominant heterozygous missense arm and the recessive biallelic
    loss-of-function arm are curated on this one gene record, because the
    gene-disease relationship is single and it is the allele class and dose
    that differ.
# clinical_significance values in this block are curator classifications drawn
# from the cited segregation and functional evidence, not ClinVar submissions or
# ClinGen VCEP assertions, none of which are cited here. PATHOGENIC on the E22K
# founder allele is a statement about causality, not about expressivity: the same
# cited study reports that the allele alone is benign in manifestation and
# low-penetrance, which this entry records in the variant description, in
# progression, and in the conditional-penetrance discussion.
variants:
- name: MYL2 c.64G>A p.(Glu22Lys) — Dutch founder allele
  gene:
    preferred_term: MYL2
    term:
      id: hgnc:7583
      label: MYL2
  description: >-
    A founder allele shared on a common haplotype by 38 members of 14 families.
    It is the clearest case in this gene of a variant that is not sufficient on
    its own: carriers of E22K alone were largely well, and disease emerged when a
    second hypertrophy-promoting factor — hypertension, obesity, or a second
    sarcomeric variant — was present. Its clinical course when it does manifest
    is late-onset and benign, which is the opposite pole from R58Q.
  clinical_significance: PATHOGENIC
  evidence:
  - reference: PMID:26497160
    reference_title: "Hypertrophic remodelling in cardiac regulatory myosin light chain (MYL2) founder mutation carriers."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We analysed 14 HCM families of whom 38 family members share the MYL2 c.64G >
      A
    explanation: >-
      Establishes the size of the cohort in which this allele's behaviour was
      characterised. The quote stops before the HGVS protein annotation because
      the reference validator strips bracketed spans that are not uppercase
      abbreviations or percentages; the founder haplotype the same sentence
      reports is stated in this variant's description.
  - reference: PMID:26497160
    reference_title: "Hypertrophic remodelling in cardiac regulatory myosin light chain (MYL2) founder mutation carriers."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The mutation alone showed benign disease manifestation with low penetrance.
    explanation: >-
      States the low penetrance of the isolated allele, which is the property that
      makes this variant the entry's worked example of conditional penetrance.
  - 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: >-
      The mutation Glu22Lys was associated with moderate septal hypertrophy, a
      late onset of clinical manifestation, and benign disease course and
      prognosis.
    explanation: >-
      Independent characterisation of the same allele in a different cohort,
      agreeing on the benign course.
- name: MYL2 p.(Arg58Gln) — malignant missense allele
  gene:
    preferred_term: MYL2
    term:
      id: hgnc:7583
      label: MYL2
  description: >-
    The archetypal MYL2 allele and the one behind almost all of the functional
    work in this entry. Unlike E22K it is malignant: early onset, premature
    sudden death, and co-segregation across a four-generation pedigree. Its
    functional signature is unusually well resolved — reduced RLC Ser15
    phosphorylation, stabilisation of the super-relaxed myosin state, lower
    maximal force with higher ATPase, increased calcium sensitivity with reduced
    cooperativity, and slower cross-bridge kinetics — and a Ser15 phosphomimetic
    reverses several of these in vitro. The two unaffected juvenile carriers in
    the four-generation pedigree are the age-related penetrance recorded in this
    entry's inheritance block seen within one family, not evidence against the
    allele.
  clinical_significance: PATHOGENIC
  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: >-
      The mutation Arg58Gln showed also moderate septal hypertrophy, but, in
      contrast, it was associated with an early onset of clinical manifestation
      and premature sudden cardiac death.
    explanation: >-
      Contrasts R58Q with E22K in one cohort, which is what establishes that the
      severity difference is allelic and not cohort or ascertainment effect.
  - reference: PMID:31104103
    reference_title: "The co-segregation of the MYL2 R58Q mutation in Chinese hypertrophic cardiomyopathy family and its pathological effect on cardiomyopathy disarray."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      R58Q existed in all six members with HCM and two healthy juveniles who had
      not yet developed HCM yet, and presumably in three deceased members who
      suffered from sudden death
    explanation: >-
      Segregation in a four-generation family, addressing the paper's own concern
      that earlier R58Q reports rested on pedigrees of two or three members.
- name: MYL2 p.(Ala13Thr) — mid-ventricular obstruction allele
  gene:
    preferred_term: MYL2
    term:
      id: hgnc:7583
      label: MYL2
  description: >-
    The allele that anchors the mid-ventricular distribution of this entity, and
    the one that shows the functional signature is allelic rather than
    gene-level: where R58Q lowers maximal isometric force, A13T raises it. In a
    transgenic model it produced enlarged interventricular septa and fibrotic
    lesions, a lower acto-myosin ATPase Vmax, and reduced binding affinity of the
    mutant light chain for myosin, from roughly a tenth of myofilaments carrying
    the mutant — the disproportion that led its authors to a poison-peptide
    mechanism.
  clinical_significance: PATHOGENIC
  evidence:
  - reference: PMID:22091967
    reference_title: "Myosin regulatory light chain mutation found in hypertrophic cardiomyopathy patients increases isometric force production in transgenic mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: >-
      associated with a rare FHC variant defined by mid-ventricular obstruction
      and septal hypertrophy
    explanation: >-
      Gives the clinical phenotype attached to this allele. Graded
      MODEL_ORGANISM/INDIRECT because the sentence is this mouse study's
      background framing rather than a human result it reports.
  - reference: PMID:22091967
    reference_title: "Myosin regulatory light chain mutation found in hypertrophic cardiomyopathy patients increases isometric force production in transgenic mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Functional studies revealed an abnormal A13T mutation-induced increase in
      isometric force production
    explanation: >-
      The force change, in the direction opposite to R58Q's, measured in a
      transgenic model of this allele.
- name: MYL2 c.403-1G>C — recessive cryptic-splice allele
  gene:
    preferred_term: MYL2
    term:
      id: hgnc:7583
      label: MYL2
  description: >-
    A homozygous last-acceptor-splice-site allele found in Dutch patients with
    infantile cardioskeletal myopathy, with compound-heterozygous alleles
    affecting the same exon in an Italian patient. It replaces the C-terminal
    tail and disrupts the second EF-hand domain. It belongs to a different disease
    mechanism from the dominant missense alleles above, and the pedigrees say so
    directly: the obligate heterozygous parents had no cardiomyopathy.
  clinical_significance: PATHOGENIC
  evidence:
  - reference: PMID:23365102
    reference_title: "Recessive MYL2 mutations cause infantile type I muscle fibre disease and cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The MYL2 mutation results in use of a cryptic splice site upstream of the
      last exon causing a frameshift
    explanation: >-
      Describes the molecular consequence of the splice allele.
  - reference: PMID:23365102
    reference_title: "Recessive MYL2 mutations cause infantile type I muscle fibre disease and cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      As a consequence of these mutations, the second EF-hand domain is disrupted.
    explanation: >-
      Names the structural domain lost, which is what distinguishes this allele
      class from the lever-arm missense alleles.
  - reference: PMID:23365102
    reference_title: "Recessive MYL2 mutations cause infantile type I muscle fibre disease and cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Heterozygous missense mutations in MYL2 are known to cause dominant
      hypertrophic cardiomyopathy; however, none of the parents showed signs of
      cardiomyopathy.
    explanation: >-
      The obligate carriers being unaffected is the evidence that the dominant
      missense mechanism is not simple haploinsufficiency — one working copy of
      MYL2 is enough.
environmental:
- name: Hypertension as a penetrance-determining co-factor
  description: >-
    In the MYL2 E22K founder cohort, hypertension was the single most common
    additional hypertrophy driver among carriers who went on to develop clinical
    disease. This is not the usual "environmental risk factor" relationship, in
    which an exposure raises risk at the margin: here the genotype on its own
    largely failed to produce disease, and the co-factor supplied the rest. The
    authors' practical conclusion follows from that — screen carriers for
    hypertension early and treat it, and do not exclude hypertensive individuals
    from genetic studies of hypertrophic cardiomyopathy on the grounds that their
    hypertrophy is explained.
  effect: Converts a low-penetrance MYL2 genotype into clinical hypertrophic cardiomyopathy
  evidence:
  - reference: PMID:26497160
    reference_title: "Hypertrophic remodelling in cardiac regulatory myosin light chain (MYL2) founder mutation carriers."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The most prominent risk factor was hypertension, observed in 71% of mutation
      carriers with HCM and an additional risk factor.
    explanation: >-
      Identifies hypertension as the dominant co-factor among affected carriers.
  - reference: PMID:26497160
    reference_title: "Hypertrophic remodelling in cardiac regulatory myosin light chain (MYL2) founder mutation carriers."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The MYL2 mutation c.64G > A on its own is incapable of triggering clinical
      HCM in most carriers.
    explanation: >-
      States the dependence explicitly, which is what makes this a co-factor
      rather than an additive risk.
  influences_mechanisms:
  - target: Ventricular Hypertrophy, Myocyte Disarray and Fibrosis
    environmental_effect: EXACERBATES
    causal_link_type: DIRECT
    description: >-
      Pressure loading acts on the same remodelling node the sarcomeric lesion
      drives, which is why the two combine to produce hypertrophy that neither
      reliably produces alone.
    evidence:
    - reference: PMID:26497160
      reference_title: "Hypertrophic remodelling in cardiac regulatory myosin light chain (MYL2) founder mutation carriers."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The co-presence of additional risk factors for hypertrophy such as
        hypertension, obesity, or other sarcomeric gene mutation increased disease
        penetrance substantially and caused HCM in 89% of MYL2 mutation carriers
      explanation: >-
        Quantifies the joint effect on the hypertrophic outcome this node
        represents.
  notes: >-
    Left without an exposure_term. ECTO's only hypertension-related term is
    ECTO:2000001 exposure to medication for hypertension, which names the
    treatment rather than the condition and would assert something this entry
    does not claim.
- name: Obesity as a penetrance-determining co-factor
  description: >-
    Obesity appears alongside hypertension and a second sarcomeric variant in the
    set of additional hypertrophy drivers that carried E22K carriers into clinical
    disease. It is grouped with them in the founder study rather than measured
    separately, so its individual contribution is not quantified — only its
    membership in the co-factor set is.
  effect: Contributes to the additional hypertrophy burden that unmasks a low-penetrance MYL2 genotype
  evidence:
  - reference: PMID:26497160
    reference_title: "Hypertrophic remodelling in cardiac regulatory myosin light chain (MYL2) founder mutation carriers."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The co-presence of additional risk factors for hypertrophy such as
      hypertension, obesity, or other sarcomeric gene mutation increased disease
      penetrance substantially and caused HCM in 89% of MYL2 mutation carriers
    explanation: >-
      Names obesity among the co-factors and gives the joint penetrance figure.
      Marked INDIRECT because obesity's own effect is not reported apart from the
      grouped co-factor analysis.
    directness: INDIRECT
  influences_mechanisms:
  - target: Ventricular Hypertrophy, Myocyte Disarray and Fibrosis
    environmental_effect: EXACERBATES
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Obesity adds haemodynamic load and metabolic drive to the same hypertrophic
      remodelling node, though the study reports it only within the grouped
      co-factor analysis.
  notes: >-
    Left without an exposure_term; ECTO has no obesity exposure term, and obesity
    is a body-mass state rather than an exposure.
treatments:
- name: Implantable Cardioverter-Defibrillator
  description: >-
    An implantable cardioverter-defibrillator provides primary or secondary
    prevention of sudden cardiac death in patients at high arrhythmic risk. The
    indication in this entry rests on the sudden-death association of the
    malignant MYL2 alleles; there is no MYL2-stratified risk model, so device
    decisions follow the general hypertrophic cardiomyopathy risk assessment.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: implantable cardioverter-defibrillator placement
    term:
      id: NCIT:C80435
      label: Implantable Cardioverter-Defibrillator Placement
  evidence:
  - reference: PMID:30775854
    reference_title: "Genetic basis and outcome in a nationwide study of Finnish patients with hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patients with a pathogenic or likely pathogenic mutation underwent an
      implantable cardioverter defibrillator implantation more often than patients
      without a pathogenic or likely pathogenic mutation
    explanation: >-
      Documents that carrying a sarcomeric pathogenic variant, the class this
      entity belongs to, is what drives device implantation in practice in an
      unselected national cohort.
    directness: INDIRECT
- name: Heart Failure and HCM Pharmacotherapy
  description: >-
    Medical management of hypertrophy, outflow obstruction, and heart failure
    symptoms follows standard HCM and heart-failure therapy. No MYL2-specific
    agent or genotype-directed regimen exists, and the guideline recommendations
    this entry inherits were not stratified by genotype.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: beta-adrenergic antagonist
      term:
        id: NCIT:C29576
        label: Beta-Adrenergic Antagonist
    - preferred_term: non-dihydropyridine calcium channel blocker
      term:
        id: NCIT:C333
        label: Calcium Channel Blocker
    - preferred_term: disopyramide
      term:
        id: CHEBI:4657
        label: disopyramide
  evidence:
  - reference: PMID:38718139
    reference_title: "2024 AHA/ACC/AMSSM/HRS/PACES/SCMR Guideline for the Management of Hypertrophic Cardiomyopathy: A Report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The "2024 AHA/ACC/AMSSM/HRS/PACES/SCMR Guideline for the Management of
      Hypertrophic Cardiomyopathy" provides recommendations to guide clinicians in
      the management of patients with hypertrophic cardiomyopathy.
    explanation: >-
      Identifies the guidance that governs pharmacological management of this
      entity. Evidence source is OTHER because a guideline is expert consensus
      over an evidence base rather than a study reporting its own data.
- name: Beta Blockade
  description: >-
    Beta blockers are the first-line drug for symptomatic obstructive disease,
    reducing heart rate and contractility and lengthening diastolic filling.
    Non-dihydropyridine calcium channel blockers (verapamil, diltiazem) are the
    second-line alternative when beta blockade is ineffective or contraindicated,
    and disopyramide is added for refractory obstruction, though its side effects
    mean many centres use it as a bridge to septal reduction rather than as
    durable therapy. None of this is MYL2-specific; it is the disease-class
    therapy a symptomatic carrier receives.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: beta-adrenergic antagonist
      term:
        id: NCIT:C29576
        label: Beta-Adrenergic Antagonist
  target_mechanisms:
  - target: Left Ventricular Diastolic Dysfunction
    treatment_effect: INHIBITS
    description: >-
      Slowing the heart lengthens diastole, which is the mechanism by which beta
      blockade acts against impaired filling. The effect is INHIBITS because the
      node is the dysfunction, and the drug counteracts it; it does so by
      allowing more filling time rather than by improving intrinsic myocardial
      relaxation, which the sarcomeric lesion still governs.
    evidence:
    - reference: PMID:40427081
      reference_title: "Integrative Approaches in the Management of Hypertrophic Cardiomyopathy: A Comprehensive Review of Current Therapeutic Modalities."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Beta-blockers, including atenolol and nadolol, are considered the
        first-line treatment due to their ability to reduce heart rate and
        myocardial contractility and enhance diastolic filling.
      explanation: >-
        Names diastolic filling as the thing the drug improves, which is the
        claim this edge makes. Evidence source is OTHER because this is a
        narrative review.
  - target: Left Ventricular Outflow Tract Obstruction
    treatment_effect: INHIBITS
    description: >-
      Reduced contractility lowers the dynamic gradient, which is why beta
      blockade is first-line specifically for the obstructive form.
    evidence:
    - reference: PMID:40993768
      reference_title: "Current and emerging medical and surgical therapy in hypertrophic cardiomyopathy."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Conventional pharmacological therapies such as β-blockers and
        nondihydropyridine calcium channel blockers are effective first-line
        treatments for obstructive HCM
      explanation: >-
        States first-line efficacy in obstructive disease specifically, which is
        the node this edge points at. Evidence source is OTHER because this is a
        narrative review.
  evidence:
  - reference: PMID:40427081
    reference_title: "Integrative Approaches in the Management of Hypertrophic Cardiomyopathy: A Comprehensive Review of Current Therapeutic Modalities."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Beta-blockers, including atenolol and nadolol, are considered the
      first-line treatment due to their ability to reduce heart rate and
      myocardial contractility and enhance diastolic filling.
    explanation: >-
      States the first-line status and the mechanism by which it works. Evidence
      source is OTHER because this is a narrative review.
  - reference: PMID:40993768
    reference_title: "Current and emerging medical and surgical therapy in hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Conventional pharmacological therapies such as β-blockers and
      nondihydropyridine calcium channel blockers are effective first-line
      treatments for obstructive HCM, and established invasive septal reduction
      therapies, such as surgical myectomy and alcohol septal ablation, provide
      effective relief of obstruction in refractory patients.
    explanation: >-
      Independent review agreeing on first-line status and placing septal
      reduction after it in the sequence. Evidence source is OTHER because this
      is a narrative review.
  notes: >-
    Not MYL2-stratified. No genotype-directed dosing or agent selection exists
    for this entity.
- name: Septal Reduction Therapy
  description: >-
    Surgical myectomy or alcohol septal ablation relieves the outflow gradient in
    obstruction refractory to medical therapy. It is the procedure VALOR-HCM,
    curated in this entry's clinical trials, was designed to avert, so modelling
    the trial without modelling the procedure would leave the decision it
    addresses unrepresented. Note it targets anatomy rather than the sarcomeric
    lesion, so it acts on the obstruction phenotype while leaving every
    sarcomeric node upstream of it untouched.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: septal reduction therapy
    term:
      id: NCIT:C51591
      label: Myectomy
  target_mechanisms:
  - target: Left Ventricular Outflow Tract Obstruction
    treatment_effect: INHIBITS
    description: >-
      The procedure removes the septal muscle that narrows the outflow tract, so
      it acts on the obstruction phenotype directly while leaving the sarcomeric
      lesion upstream of it untouched.
  evidence:
  - reference: PMID:40993768
    reference_title: "Current and emerging medical and surgical therapy in hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Invasive septal reduction therapies (surgical myectomy or alcohol septal
      ablation [ASA]) can effectively relieve LVOT gradients in obstructive HCM,
      but these are targeted to anatomy rather than the genetic cause.
    explanation: >-
      States both what the procedure achieves and the limitation that bounds it:
      it relieves the gradient without acting on the genetic cause upstream.
      Evidence source is OTHER because this is a narrative review.
  - reference: PMID:40993768
    reference_title: "Current and emerging medical and surgical therapy in hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Guidelines recommend optimization of medical treatment in obstructive HCM
      patients before proceeding to more invasive options such as septal
      reduction therapy (SRT)
    explanation: >-
      Places the procedure after medical therapy in the treatment sequence.
  notes: >-
    Not MYL2-stratified. The binding is NCIT:C51591 Myectomy, which names the
    surgical arm only; alcohol septal ablation is the catheter alternative and
    has no reachable clinical-action term, so it is carried in preferred_term and
    description rather than bound.
- name: Cardiac Myosin Inhibition (Mavacamten)
  description: >-
    Mavacamten reduces post-exercise outflow gradient and improves exercise
    capacity and symptoms in symptomatic obstructive hypertrophic cardiomyopathy,
    and is the first disease-directed drug class for the condition. It is listed
    here as the class a symptomatic obstructive MYL2 patient would be considered
    for, not as a MYL2-validated therapy — the pivotal trials enrolled by
    phenotype and reported no genotype subgroup. There is also a specific
    mechanistic reservation for the R58Q allele, recorded in the discussions
    block: myosin inhibitors work by increasing occupancy of the super-relaxed
    state, and R58Q already stabilises it.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: mavacamten
  target_mechanisms:
  - target: Stabilization of the Myosin Super-Relaxed State
    treatment_effect: MODULATES
    description: >-
      The drug class acts on the same super-relaxed/disordered-relaxed
      equilibrium this node represents. The edge records that the target is
      shared; it does not assert that shifting it further toward SRX benefits a
      carrier whose allele already shifts it that way.
  - target: Left Ventricular Outflow Tract Obstruction
    treatment_effect: INHIBITS
    description: >-
      The measured clinical effect, as distinct from the molecular target above:
      the pivotal trial's primary haemodynamic result is a reduction in
      post-exercise outflow gradient. Recorded as a separate edge because the
      gradient can fall whether or not the drug corrects the primary lesion in a
      given allele, which is the open question this entry records for R58Q. The
      effect on this edge is INHIBITS while the molecular edge above is
      MODULATES: the drug demonstrably reduces the gradient, whereas on the
      super-relaxed-state node it shifts an equilibrium in the same direction the
      R58Q allele already shifts it, which is neither inhibition nor activation
      of that node and is the reservation recorded in discussions.
    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: >-
        Patients on mavacamten had greater reductions than those on placebo in
        post-exercise LVOT gradient
      explanation: >-
        A randomised measurement of the drug acting on this node specifically,
        which is a different claim from the molecular-target edge above and is
        why this edge carries its own citation rather than borrowing one. Marked
        INDIRECT for this entity because the trial enrolled by phenotype and
        reported no MYL2 subgroup.
      directness: INDIRECT
  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: >-
      Patients on mavacamten had greater reductions than those on placebo in
      post-exercise LVOT gradient
    explanation: >-
      The pivotal randomised result establishing the class effect. Marked INDIRECT
      for this entry because the trial enrolled by phenotype and no MYL2 subgroup
      was reported, so the benefit is inherited from the disease class rather than
      demonstrated in this entity.
    directness: INDIRECT
  notes: >-
    Not MYL2-stratified. Recorded as disease-class therapy, not as evidence of
    benefit in MYL2 carriers.

    Mavacamten is deliberately left without an ontology term, for the reason
    already recorded in Hypertrophic_Cardiomyopathy_8: NCIT:C174901 Mavacamten
    exists but sits under Inotropic Support rather than Pharmacologic Substance,
    so it is not reachable from the ChemicalEntityTerm enum roots and fails term
    validation, and CHEBI has no mavacamten term. Do not substitute another NCIT
    code to fill the slot: NCIT:C158384 was tried during this curation and is
    SIGLEC15 Gene.
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 for cardiac myosin inhibition.
  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 behind the myosin inhibition
      treatment entry.
  notes: >-
    Not MYL2-stratified. Enrolment was by phenotype, not genotype, and no MYL2
    subgroup was reported.
- name: NCT04349072
  phase: PHASE_III
  status: COMPLETED
  description: >-
    VALOR-HCM. Randomised, double-blind, placebo-controlled trial testing whether
    mavacamten can avert septal reduction therapy in patients already eligible for
    it — the relevant question for a carrier who has reached refractory
    obstruction.
  target_phenotypes:
  - preferred_term: Left ventricular outflow tract obstruction
    term:
      id: HP:0032092
      label: Left ventricular outflow tract obstruction
  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: >-
      that 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: >-
      States the trial's objective, which is the clinical decision an obstructed
      carrier faces.
  notes: >-
    Not MYL2-stratified, for the same reason as EXPLORER-HCM.
diagnosis:
- name: Genetic Testing Establishing the MYL2 Genotype and Its Allele
  description: >-
    Molecular testing is what distinguishes CMH10 from any other cause of
    unexplained left ventricular hypertrophy, and in this gene the allele matters
    as much as the gene: the two variants characterised side by side in a
    systematic light chain screen differed in onset age and in sudden-death risk
    while looking the same on echocardiography. Zygosity must also be established,
    because the biallelic loss-of-function genotype is a different disease with a
    different prognosis and different reproductive counselling.
  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: >-
      The mutation Arg58Gln showed also moderate septal hypertrophy, but, in
      contrast, it was associated with an early onset of clinical manifestation
      and premature sudden cardiac death.
    explanation: >-
      Shows that septal thickness did not separate the malignant from the benign
      allele, which is the argument for identifying the variant rather than
      stopping at the imaging phenotype.
- name: Screening MYL2 Carriers for Hypertension and Other Hypertrophy Drivers
  description: >-
    A management step specific to this gene rather than inherited from HCM
    generally. Because the founder allele largely fails to produce disease on its
    own and hypertension was the commonest co-factor in carriers who became
    affected, detecting and treating an additional hypertrophy driver early is a
    modifiable determinant of whether a carrier converts.
  evidence:
  - reference: PMID:26497160
    reference_title: "Hypertrophic remodelling in cardiac regulatory myosin light chain (MYL2) founder mutation carriers."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Early diagnosis of risk factors is important for early treatment of MYL2
      mutation carriers and close monitoring should be guaranteed in this case.
    explanation: >-
      The authors' own management conclusion from the founder cohort, stated for
      MYL2 carriers specifically.
histopathology:
- name: Myofibrillar Disarray
  description: >-
    The tissue-level record of disarray in this entity, kept distinct from the
    Myofiber Disarray phenotype, which carries the cardiac finding as an
    observable clinical feature. What this record adds is that disarray in MYL2
    disease is not confined to myocardium: in the biallelic infantile form the
    corresponding skeletal-muscle finding is myofibrillar disorganization
    alongside hypotrophic type I fibres, the histological counterpart of this
    entry's cardioskeletal claim.
  finding_term:
    preferred_term: myofibrillar disarray
    term:
      id: NCIT:C35867
      label: Morphologic Finding
  evidence:
  - reference: PMID:23365102
    reference_title: "Recessive MYL2 mutations cause infantile type I muscle fibre disease and cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A cardioskeletal myopathy with onset and death in infancy, morphological
      features of muscle type I hypotrophy with myofibrillar disorganization and
      dilated cardiomyopathy was previously reported in three Dutch families.
    explanation: >-
      Records the skeletal muscle counterpart of the same lesion in the biallelic
      form.
  notes: >-
    The finding_term is bound only to the generic NCIT Morphologic Finding
    parent, for the reason recorded in Hypertrophic_Cardiomyopathy_4: NCIT has no
    myofibre-disarray term, and HP:0031318 Myofiber disarray, which this entry
    does use as a phenotype term, is not reachable from the
    HistopathologyFindingTerm enum roots.
- name: Cardiomyocyte Hypertrophy
  description: >-
    Cell-level hypertrophy, measurable in patient-derived cardiomyocytes without
    any haemodynamic load — MYL2-R58Q cells were about 30% larger than controls by
    day 60 of differentiation. That the enlargement appears in isolated cells is
    what places it upstream of chamber remodelling rather than as a consequence of
    it.
  finding_term:
    preferred_term: cardiomyocyte hypertrophy
    term:
      id: NCIT:C35867
      label: Morphologic Finding
  evidence:
  - reference: PMID:30796699
    reference_title: "Induced Pluripotent Stem Cell-Derived Cardiomyocytes from a Patient with MYL2-R58Q-Mediated Apical Hypertrophic Cardiomyopathy Show Hypertrophy, Myofibrillar Disarray, and Calcium Perturbations."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The MYL2-R58Q iPSC-CMs were nearly 30% larger than control iPSC-CMs at day
      60.
    explanation: >-
      Quantifies cell-autonomous hypertrophy in the disease genotype.
animal_models:
- name: Tg-R58Q transgenic mouse (ventricular RLC R58Q)
  species: Mouse
  genotype: Transgenic expression of human ventricular myosin regulatory light chain carrying R58Q
  description: >-
    The workhorse model of malignant MYL2 disease. It is the system in which the
    RLC phosphorylation deficit, the super-relaxed state shift, the diastolic
    abnormality, and the slow-twitch skeletal muscle deficit were each
    demonstrated. Its most useful property is that it is routinely studied
    alongside a Tg-N47K line carrying a milder RLC allele, so findings can be
    attributed to the malignant variant rather than to RLC transgenesis.
  genes:
  - preferred_term: MYL2
    term:
      id: hgnc:7583
      label: MYL2
  publication: PMID:19150977
  modeled_mechanisms:
  - target: Reduced RLC Ser15 Phosphorylation
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: >-
      Reduced in situ RLC phosphorylation is measured in the ventricles of this
      line and not in the comparison line carrying a milder allele.
    limitations: >-
      Fidelity is MODERATE rather than HIGH because the corresponding measurement
      has not been made in human MYL2-R58Q myocardium, so the deficit is
      established in mouse and inferred for the patient. The line is also
      transgenic rather than knock-in, so expression level is not the human
      heterozygous dose.
    readouts:
    - name: In situ ventricular RLC phosphorylation
      target: Reduced RLC Ser15 Phosphorylation
      direction: DECREASED
      interpretation: The molecular deficit this node records, measured directly.
      evidence:
      - reference: PMID:19150977
        reference_title: "Diastolic dysfunction in familial hypertrophic cardiomyopathy transgenic model mice."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          the R58Q mutation and not the N47K led to reduced RLC phosphorylation in
          Tg ventricles
        explanation: >-
          Reports the measurement and its allele-selectivity.
  - target: Diastolic Dysfunction, Heart Failure and Arrhythmic Risk
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Echocardiography shows altered diastolic transmitral velocities and
      deceleration time in this line specifically, which is the diastolic half of
      the node.
    limitations: >-
      PARTIALLY_RECAPITULATES because the node also carries heart failure and
      arrhythmic death, and this model was characterised for diastolic function
      and haemodynamics rather than for arrhythmic events or survival. Mouse
      diastolic indices at mouse heart rates are also not directly comparable
      with the human echocardiographic measurements the node's clinical claim
      rests on.
    readouts:
    - name: Transmitral velocities and deceleration time
      target: Diastolic Dysfunction, Heart Failure and Arrhythmic Risk
      direction: ALTERED
      interpretation: Echocardiographic correlate of impaired ventricular filling.
      evidence:
      - reference: PMID:19150977
        reference_title: "Diastolic dysfunction in familial hypertrophic cardiomyopathy transgenic model mice."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          echocardiographic examination showed significant alterations in diastolic
          transmitral velocities and deceleration time only in Tg-R58Q myocardium
        explanation: >-
          Gives the measurement and confines it to the malignant allele.
  - target: Slow-Twitch Skeletal Muscle Contractile Deficit
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: >-
      Soleus, a slow-twitch muscle, shows the same force deficit as ventricular
      papillary muscle in these animals, which is the cardioskeletal reach the
      node claims.
    limitations: >-
      The transgene is cardiac-restricted, so the mutant light chain is absent
      from soleus and this line cannot establish cell-autonomous action of the
      allele in skeletal muscle — the soleus deficit here must reach that muscle
      by some systemic route. That is the most material limitation of this link,
      and the paper states it explicitly. Separately, the human counterpart is
      documented as skeletal muscle abnormality in pedigrees rather than as a
      force measurement, so the mouse gives the quantitative deficit while the
      human evidence gives only its presence.
    divergences:
    - divergence_type: BOUNDARY_OMISSION
      materiality: INVALIDATING
      description: >-
        Skeletal-muscle expression of the mutant light chain is outside the
        model: the transgene is driven in heart only. The node concerns a tissue
        in which this model deliberately does not express the lesion, so the
        model cannot speak to local action there.
    readouts:
    - name: Skinned soleus and ventricular papillary muscle force
      target: Slow-Twitch Skeletal Muscle Contractile Deficit
      direction: DECREASED
      interpretation: Contractile deficit shared by ventricle and slow-twitch skeletal muscle.
      evidence:
      - reference: PMID:30365366
        reference_title: "Slow-twitch skeletal muscle defects accompany cardiac dysfunction in transgenic mice with a mutation in the myosin regulatory light chain."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Skinned SOL muscles and ventricular PMs of R58Q animals exhibited lower contractile force"
        explanation: >-
          The paired measurement in both tissues of the same animals.
  - target: Impaired Lever-Arm Function and Myofilament Calcium Sensitization
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: >-
      Skinned papillary muscle from this line reproduces both halves of the node:
      increased myofilament calcium sensitivity with reduced cooperativity, and
      slowed cross-bridge kinetics.
    limitations: >-
      Fidelity is MODERATE rather than HIGH because the line is transgenic rather
      than knock-in, so mutant incorporation is not the human heterozygous dose,
      and the measurements are in skinned fibres at controlled calcium rather
      than in an intact working myocardium.
    readouts:
    - name: Tension-pCa relationship in skinned papillary muscle
      target: Impaired Lever-Arm Function and Myofilament Calcium Sensitization
      direction: INCREASED
      interpretation: >-
        Increased calcium sensitivity of force with reduced cooperativity, the
        myofilament half of the node.
      evidence:
      - reference: PMID:23727233
        reference_title: "Diversity and similarity of motor function and cross-bridge kinetics in papillary muscles of transgenic mice carrying myosin regulatory light chain mutations D166V and R58Q."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          In tension-pCa study, both D166V and R58Q mutations exhibited increased
          Ca(2+) sensitivity and less cooperativity.
        explanation: >-
          The measurement behind this readout.
  evidence:
  - reference: PMID:23727233
    reference_title: "Diversity and similarity of motor function and cross-bridge kinetics in papillary muscles of transgenic mice carrying myosin regulatory light chain mutations D166V and R58Q."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      demonstrating the slower cross-bridge kinetics
    explanation: >-
      Supports treating this line as informative for the sarcomeric nodes
      generally: it reproduces the cross-bridge kinetic slowing of the human
      allele in mouse papillary muscle.
experimental_models:
- name: MYL2-R58Q patient-derived iPSC cardiomyocytes
  experimental_model_type: IPSC_DERIVED_MODEL
  description: >-
    Cardiomyocytes differentiated from induced pluripotent stem cells of a patient
    with MYL2-R58Q apical hypertrophic cardiomyopathy. Its value is that it shows
    hypertrophy, disarray and calcium abnormality arising from the human genotype
    alone, in cells that have never experienced a pressure load — which separates
    the cell-autonomous consequences of the allele from the consequences of living
    in a hypertrophied heart.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  publication: PMID:30796699
  modeled_mechanisms:
  - target: Calcium Handling Remodeling and Electrical Instability
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Reduced L-type calcium current density, altered transients, and a tenfold
      excess of irregular beating, all in cells carrying the patient's own allele.
    limitations: >-
      A single patient line compared with a maternal control rather than an
      isogenic corrected pair, so the comparison carries the donors' whole genetic
      background difference and not only the MYL2 allele. iPSC-derived
      cardiomyocytes are also developmentally immature, which particularly affects
      calcium handling and electrophysiology — the exact readouts this link rests
      on.
    readouts:
    - name: L-type calcium current density at 0 mV
      target: Calcium Handling Remodeling and Electrical Instability
      direction: DECREASED
      interpretation: Reduced calcium influx through the L-type channel.
      evidence:
      - reference: PMID:30796699
        reference_title: "Induced Pluripotent Stem Cell-Derived Cardiomyocytes from a Patient with MYL2-R58Q-Mediated Apical Hypertrophic Cardiomyopathy Show Hypertrophy, Myofibrillar Disarray, and Calcium Perturbations."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          the L-type Ca2+ channel (LTCC) (ICa,L) density at 0 mV was reduced
          significantly by 45.3%
        explanation: >-
          The quantified current reduction behind this readout.
  - target: Ventricular Hypertrophy, Myocyte Disarray and Fibrosis
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Cell enlargement and myofibrillar disarray reproduce the cellular components
      of this node.
    limitations: >-
      The node is a tissue-level claim that also includes interstitial fibrosis,
      and isolated cardiomyocytes cannot produce it — there is no interstitium and
      no fibroblast compartment. The model therefore covers two of the node's
      three elements and observes them one scale below the node.
    divergences:
    - divergence_type: BOUNDARY_OMISSION
      materiality: QUALIFYING
      description: >-
        Cardiac fibroblasts and the interstitial compartment are not in the model,
        so the fibrosis element of this node cannot be produced or observed in it.
    - divergence_type: SCALE_EXTRAPOLATION
      materiality: QUALIFYING
      description: >-
        The model observes single cells (CELLULAR) while the node is a
        tissue-level claim about chamber remodelling, so hypertrophy of the
        chamber is inferred from enlargement of the cell.
    readouts:
    - name: Cardiomyocyte cross-sectional area
      target: Ventricular Hypertrophy, Myocyte Disarray and Fibrosis
      direction: INCREASED
      interpretation: Cell-autonomous hypertrophy in the absence of haemodynamic load.
      evidence:
      - reference: PMID:30796699
        reference_title: "Induced Pluripotent Stem Cell-Derived Cardiomyocytes from a Patient with MYL2-R58Q-Mediated Apical Hypertrophic Cardiomyopathy Show Hypertrophy, Myofibrillar Disarray, and Calcium Perturbations."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          The MYL2-R58Q iPSC-CMs were nearly 30% larger than control iPSC-CMs at
          day 60.
        explanation: >-
          The measured enlargement behind this readout.
discussions:
- discussion_id: myl2_srx_stabilization_vs_myosin_inhibitors
  kind: OPEN_QUESTION
  status: OPEN
  prompt: >-
    Cardiac myosin inhibitors treat hypertrophic cardiomyopathy by increasing
    occupancy of the myosin super-relaxed state. R58Q already stabilises that
    state. Is this drug class the right one for R58Q carriers, and does the
    answer differ by MYL2 allele?
  attaches_to:
  - pathophysiology#Stabilization of the Myosin Super-Relaxed State
  - treatments#Cardiac Myosin Inhibition (Mavacamten)
  rationale: >-
    The two facts are individually well supported and point in opposite
    directions. R58Q was shown to promote the myosin OFF state and stabilise SRX
    in reconstituted porcine fibres and in transgenic mouse papillary muscle, and
    the experimental intervention that improved the R58Q phenotype in that same
    work was a Ser15 phosphomimetic, which shifts myosin the other way, toward
    the disordered-relaxed state. Mavacamten shifts it toward SRX. If the R58Q
    lesion is an excess of SRX, the drug class licensed for this disease pushes
    in the direction of the lesion rather than against it.

    Three things stop this being an argument against prescribing. Obstruction is
    a haemodynamic problem and a gradient can fall for reasons unrelated to
    whether the drug corrects the primary lesion. The SRX findings are ex vivo
    and in mouse tissue, not in an R58Q patient's myocardium. And no
    genotype-stratified data exist either way: EXPLORER-HCM and VALOR-HCM
    enrolled by phenotype and reported no MYL2 subgroup, so there is no reported
    failure of mavacamten in an RLC carrier to point at. What is recorded here is
    a mechanistic reason to expect the answer might be allele-dependent, and an
    experiment worth doing, not a treatment recommendation.

    The corollary is that MYL2 is not mechanistically uniform. Sibling entries in
    this series carry the opposite lesion — the MYL3 A57G work describes
    inhibition of the super-relaxed state — so "sarcomeric HCM is
    hypercontractile" does not license assuming the direction of the SRX shift
    for a given light chain allele.
  evidence:
  - reference: PMID:30430732
    reference_title: "Phosphomimetic-mediated in vitro rescue of hypertrophic cardiomyopathy linked to R58Q mutation in myosin regulatory light chain."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      R58Q promotes the OFF state of myosin, both in reconstituted porcine fibers
      and in Tg mouse papillary muscles, thereby stabilizing the super-relaxed
      state (SRX) of myosin, characterized by a very low ATP turnover rate
    explanation: >-
      Establishes the direction of the R58Q effect on the equilibrium the drug
      class targets, which is what raises the question.
- discussion_id: myl2_dominant_mechanism_is_not_haploinsufficiency
  kind: INTERPRETATION
  status: OPEN
  prompt: >-
    If one working copy of MYL2 is sufficient — as the unaffected obligate
    carriers in the recessive pedigrees show — what is the dominant missense
    mechanism, and does it differ between alleles?
  attaches_to:
  - pathophysiology#MYL2 Variant in Ventricular Regulatory Myosin Light Chain
  - variants#MYL2 c.403-1G>C — recessive cryptic-splice allele
  - genetic#MYL2
  rationale: >-
    The recessive pedigrees settle a question the dominant literature cannot: the
    parents of children with biallelic loss-of-function MYL2 disease are obligate
    heterozygotes for a null-like allele, and they had no cardiomyopathy. So
    losing half the normal gene product does not cause hypertrophic
    cardiomyopathy, and the dominant missense alleles cannot be acting by simple
    haploinsufficiency. The mutant light chain has to be incorporated into the
    sarcomere and do something there.

    That much is settled. What is not is what the mutant chain does, and whether
    it is the same thing for every allele. This entry curates the functional
    signature that has been worked out for R58Q — the phosphorylation deficit,
    the SRX shift, the reduced force with raised ATPase, the calcium
    sensitisation — but the same-cohort comparison that made R58Q malignant made
    E22K benign, and the transgenic comparisons that isolate the phosphorylation
    deficit to R58Q show that N47K, an allele at a neighbouring residue, does not
    share it. Assigning the R58Q mechanism to MYL2 as a gene would overstate what
    has been shown.

    The sharpest illustration is that the alleles do not even agree on the sign of
    the force change. R58Q lowers maximal isometric force; A13T raises it, and
    does so while incorporated into only about 10% of myofilaments — which is what
    led that study to a poison-peptide mechanism, the general shape of dominant
    action this discussion is asking about. A model in which a small amount of
    mutant light chain disproportionately disrupts the sarcomere accommodates both
    directions of force change and is consistent with the unaffected obligate
    carriers, since it requires the mutant protein to be present rather than the
    normal protein to be absent.
  evidence:
  - reference: PMID:23365102
    reference_title: "Recessive MYL2 mutations cause infantile type I muscle fibre disease and cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Heterozygous missense mutations in MYL2 are known to cause dominant
      hypertrophic cardiomyopathy; however, none of the parents showed signs of
      cardiomyopathy.
    explanation: >-
      The unaffected obligate carriers are the observation that excludes
      haploinsufficiency as the dominant mechanism.
  - reference: PMID:19150977
    reference_title: "Diastolic dysfunction in familial hypertrophic cardiomyopathy transgenic model mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      the R58Q mutation and not the N47K led to reduced RLC phosphorylation in Tg
      ventricles
    explanation: >-
      Shows one of the entry's mechanistic nodes is allele-specific rather than a
      property of MYL2 disease generally.
  - reference: PMID:22091967
    reference_title: "Myosin regulatory light chain mutation found in hypertrophic cardiomyopathy patients increases isometric force production in transgenic mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The significant functional changes observed, despite a low level of A13T
      mutant incorporation into myofilaments, suggest a 'poison-peptide'
      mechanism of disease.
    explanation: >-
      Names the dominant mechanism this discussion is weighing, and gives the
      observation behind it — disproportionate functional effect from a small
      mutant fraction, which is the signature of a poison peptide rather than of
      a dose deficit.
  - reference: PMID:22091967
    reference_title: "Myosin regulatory light chain mutation found in hypertrophic cardiomyopathy patients increases isometric force production in transgenic mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Functional studies revealed an abnormal A13T mutation-induced increase in
      isometric force production
    explanation: >-
      The opposite sign of force change from R58Q, in the same protein and the
      same laboratory's transgenic system, which is the evidence that the
      functional signature is allelic rather than gene-level.
- discussion_id: myl2_no_genotype_stratified_outcome_or_omics_data
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    What are the penetrance, natural history, and sudden-death risk of
    MYL2-related hypertrophic cardiomyopathy, and is there any MYL2-stratified
    molecular dataset?
  attaches_to:
  - phenotypes#Sudden Cardiac Death
  - prevalence#Worldwide (MYL2 share of HCM)
  - treatments#Cardiac Myosin Inhibition (Mavacamten)
  rationale: >-
    Every quantitative clinical statement in this entry is either a single-family
    figure or a disease-class figure borrowed from unstratified hypertrophic
    cardiomyopathy cohorts. Sudden death in R58Q is documented as an association
    across two pedigrees with no denominator behind it; the only screened case
    fraction available is for the light chain genes as a class in a 186-patient
    cohort from 2002; and the guideline and trial evidence supporting the
    treatments block enrolled by phenotype with no MYL2 subgroup reported.

    The gap extends to molecular data. A GEO search for MYL2-specific
    cardiomyopathy datasets returns nothing: the accessions that surface for MYL2
    are studies in which it appears as a cardiomyocyte marker gene, and the
    accessions that surface for hypertrophic cardiomyopathy are unstratified or
    concern other genes. That is why this entry carries no datasets block. Adding
    a generic hypertrophic cardiomyopathy dataset here would be the named-entity
    substitution the repository's dataset guidance warns about — relaxing the
    entry name to its parent disease — and the absence is the accurate record.

    What would close it: a MYL2-stratified outcome cohort with a denominator, an
    allele-resolved penetrance estimate for R58Q comparable to the E22K founder
    work, and an isogenic-pair transcriptomic or proteomic profile of an
    MYL2-mutant human cardiomyocyte model.
  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: >-
      myosin light chain mutations are a very rare cause of HCM responsible for
      about 1% of cases
    explanation: >-
      The rarity that explains why no MYL2-powered outcome cohort exists, and the
      only screened denominator this entry has.
- discussion_id: myl2_penetrance_is_conditional_on_a_second_driver
  kind: EMERGING_HYPOTHESIS
  status: OPEN
  prompt: >-
    Is conditional penetrance — a MYL2 allele that needs a second hypertrophy
    driver to become clinical disease — a property of the E22K founder allele, or
    the general model for low-penetrance sarcomeric variants?
  attaches_to:
  - environmental#Hypertension as a penetrance-determining co-factor
  - variants#MYL2 c.64G>A p.(Glu22Lys) — Dutch founder allele
  - progression#Penetrance conditional on an additional hypertrophy driver
  rationale: >-
    The founder cohort is unusually clean evidence for a model that is usually
    only asserted. Thirty-eight carriers of one allele on one haplotype: the
    allele alone was largely benign, and with hypertension, obesity, or a second
    sarcomeric variant, 89% of carriers had hypertrophic cardiomyopathy. The
    authors drew two conclusions that both follow from it — screen carriers for
    treatable hypertrophy drivers, and stop excluding hypertensive patients from
    genetic studies on the grounds that their hypertrophy is already explained.

    Whether the model generalises is open, and the founder design cuts both ways:
    one haplotype in one population controls for genetic background beautifully
    and also means the result could be specific to that background. The
    disease-class penetrance literature is consistent with conditional penetrance
    without demonstrating it — incidentally identified population carriers of
    sarcomeric variants have much lower penetrance than clinically ascertained
    ones, which is what a model requiring a second driver predicts, but is also
    what ascertainment bias alone predicts.
  evidence:
  - reference: PMID:26497160
    reference_title: "Hypertrophic remodelling in cardiac regulatory myosin light chain (MYL2) founder mutation carriers."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The co-presence of additional risk factors for hypertrophy such as
      hypertension, obesity, or other sarcomeric gene mutation increased disease
      penetrance substantially and caused HCM in 89% of MYL2 mutation carriers
    explanation: >-
      The quantified conditional-penetrance result this hypothesis is built on.
references:
- reference: PMID:20301725
  title: Nonsyndromic Hypertrophic Cardiomyopathy Overview.
  tags:
  - GeneReviews
notes: >-
  CMH10 is the MYL2 (ventricular regulatory myosin light chain) member of the
  sarcomeric HCM series and one of the eight ClinGen-definitive HCM genes. It
  conforms to the shared cardiomyopathy_maladaptive_remodeling module. Two
  inheritance modes are curated: the common autosomal dominant missense form
  (R58Q archetype) and a severe autosomal recessive infantile cardioskeletal form
  from biallelic loss of function. Because MYL2 is expressed in slow-twitch
  skeletal muscle as well as ventricle, a cardioskeletal component can accompany
  the cardiomyopathy, and this entry models that as a parallel target of the same
  allele rather than as a consequence of the cardiac disease.

  Allele, not gene, is the unit of mechanism here. The functional chain curated in
  pathophysiology — reduced RLC Ser15 phosphorylation, stabilisation of the
  myosin super-relaxed state, reduced force with raised ATPase, myofilament
  calcium sensitisation, calcium-handling remodelling — is established for R58Q
  and should not be read as a description of MYL2 disease generally. The same
  screening study that made R58Q malignant made E22K benign at comparable septal
  thickness, and the transgenic series that isolates the phosphorylation deficit
  to R58Q shows N47K does not share it. The alleles do not even agree on the sign
  of the force change — R58Q lowers maximal isometric force, A13T raises it. The
  `variants` block, not the gene record, is where the entity's clinical and
  functional heterogeneity lives.

  The cardioskeletal claim needs care, and this entry deliberately does not
  overstate it. MYL2 is expressed in ventricle and slow-twitch skeletal muscle
  simultaneously, and human pedigrees report both tissues affected — but the one
  model that measures the skeletal deficit does so in a *cardiac-restricted*
  transgenic, where the mutant light chain is absent from soleus. That model
  therefore cannot show the allele acting locally in skeletal muscle, and its
  authors present the soleus finding as a surprise for exactly that reason. The
  edge is curated as causal_link_type UNKNOWN with the model's own result
  recorded as a REFUTE item against the local-action reading.

  The edges from the terminal mechanism nodes to their phenotypes are
  deliberately uncited. They are manifestation links — the tissue-remodelling
  node surfacing as observable disarray, the clinical-endpoint node surfacing as
  diastolic dysfunction — and the evidence for each claim lives on the phenotype
  record it points at. Citing the phenotype's source again on the edge would be
  reaching for a node's citation to paper over an edge, which is the thing the
  curation guidance warns against; an uncited edge is the honest form here. This
  costs compliance score, since that metric counts evidence presence per edge
  and cannot distinguish a manifestation link from an unsupported causal claim.

  Some treatments here deliberately reach no pathograph node. The rule applied is
  that an edge asserting a treatment works *against* a node — `INHIBITS`,
  `RESTORES` — is an efficacy claim, and the file must somewhere cite a source
  supporting it, whether on the edge or on the treatment where the same sentence
  carries both. `MODULATES` is exempt because it asserts the treatment acts on
  the node without claiming benefit, which is exactly why the mavacamten edge to
  the super-relaxed state uses it. The implantable cardioverter-defibrillator is
  the instructive failure: it acts on sudden cardiac death, which this entry does
  curate as a phenotype, but its cached evidence reports implantation *rates* in
  sarcomeric mutation carriers rather than efficacy against arrest, so no source
  here supports the claim at any level. Rather than assert the edge uncited or
  reach for a source not already verified here, it is left out; adding it is a
  follow-up that needs its own citation. A treatment naming no specific
  mechanism, such as the generic heart-failure pharmacotherapy entry, has nothing
  to point at by construction.

  Two curation decisions worth knowing about. Mavacamten's therapeutic_agent is
  deliberately unbound, following Hypertrophic_Cardiomyopathy_8 — see the note on
  that treatment. And there is no `datasets` block: a GEO search returns no
  MYL2-specific cardiomyopathy dataset (MYL2 surfaces as a cardiomyocyte marker
  gene, and the HCM datasets are unstratified or about other genes), so adding
  one would substitute the parent disease for this entity. The absence is
  recorded in `discussions` instead.

  Deep research. A falcon (Edison) run was performed for this entry
  (research/Hypertrophic_Cardiomyopathy_10-deep-research-falcon.md). Its
  reference validation resolved 11/11 extractable citations with no
  confabulations and none scored off topic, though only 6 of the 11 were
  affirmatively scored on topic, so that screen is not a clean bill of health;
  its term validation resolved 39/39 CURIEs but named several wrongly, and one
  suggestion was rejected on that basis — the report offered HP:0001698 for left
  ventricular outflow tract obstruction, which is Pericardial effusion; this
  entry uses HP:0032092. HP:0005117 (offered for diastolic dysfunction, actually
  Elevated diastolic blood pressure) and HP:0030680 (offered for left atrial
  enlargement, actually Abnormal cardiovascular system morphology) were likewise
  not used. The report's D166H family findings (atrial fibrillation, restrictive
  filling, LOD score) are not curated: the paper is a research letter whose
  PubMed record carries no abstract, so those numbers cannot be quoted as a
  verified snippet from the cache.

  GeneReviews scope. The GeneReviews resource applicable to this entry is the
  disease-level "Nonsyndromic Hypertrophic Cardiomyopathy Overview"
  (PMID:20301725), tagged accordingly in `references`. Its indexed PubMed record
  is content_type abstract_only and carries only the chapter's purpose
  statement, not the Clinical Characteristics, Management, or Genetic Counseling
  sections, so section-by-section GeneReviews mining is not possible from the
  cache and no snippet is quoted from it. The clinical-characteristics baseline
  for this entry is therefore built from the primary MYL2 cohort and pedigree
  literature cited throughout, principally PMID:26497160, PMID:12404107,
  PMID:23365102, PMID:8673105 and PMID:30796699.

📚

References & Deep Research

References

1

PMID:20301725

Nonsyndromic Hypertrophic Cardiomyopathy Overview.

No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (2)

Record notes

CMH10 is the MYL2 (ventricular regulatory myosin light chain) member of the sarcomeric HCM series and one of the eight ClinGen-definitive HCM genes. It conforms to the shared cardiomyopathy_maladaptive_remodeling module. Two inheritance modes are curated: the common autosomal dominant missense form (R58Q archetype) and a severe autosomal recessive infantile cardioskeletal form from biallelic loss of function. Because MYL2 is expressed in slow-twitch skeletal muscle as well as ventricle, a cardioskeletal component can accompany the cardiomyopathy, and this entry models that as a parallel target of the same allele rather than as a consequence of the cardiac disease. Allele, not gene, is the unit of mechanism here. The functional chain curated in pathophysiology — reduced RLC Ser15 phosphorylation, stabilisation of the myosin super-relaxed state, reduced force with raised ATPase, myofilament calcium sensitisation, calcium-handling remodelling — is established for R58Q and should not be read as a description of MYL2 disease generally. The same screening study that made R58Q malignant made E22K benign at comparable septal thickness, and the transgenic series that isolates the phosphorylation deficit to R58Q shows N47K does not share it. The alleles do not even agree on the sign of the force change — R58Q lowers maximal isometric force, A13T raises it. The `variants` block, not the gene record, is where the entity's clinical and functional heterogeneity lives. The cardioskeletal claim needs care, and this entry deliberately does not overstate it. MYL2 is expressed in ventricle and slow-twitch skeletal muscle simultaneously, and human pedigrees report both tissues affected — but the one model that measures the skeletal deficit does so in a *cardiac-restricted* transgenic, where the mutant light chain is absent from soleus. That model therefore cannot show the allele acting locally in skeletal muscle, and its authors present the soleus finding as a surprise for exactly that reason. The edge is curated as causal_link_type UNKNOWN with the model's own result recorded as a REFUTE item against the local-action reading. The edges from the terminal mechanism nodes to their phenotypes are deliberately uncited. They are manifestation links — the tissue-remodelling node surfacing as observable disarray, the clinical-endpoint node surfacing as diastolic dysfunction — and the evidence for each claim lives on the phenotype record it points at. Citing the phenotype's source again on the edge would be reaching for a node's citation to paper over an edge, which is the thing the curation guidance warns against; an uncited edge is the honest form here. This costs compliance score, since that metric counts evidence presence per edge and cannot distinguish a manifestation link from an unsupported causal claim. Some treatments here deliberately reach no pathograph node. The rule applied is that an edge asserting a treatment works *against* a node — `INHIBITS`, `RESTORES` — is an efficacy claim, and the file must somewhere cite a source supporting it, whether on the edge or on the treatment where the same sentence carries both. `MODULATES` is exempt because it asserts the treatment acts on the node without claiming benefit, which is exactly why the mavacamten edge to the super-relaxed state uses it. The implantable cardioverter-defibrillator is the instructive failure: it acts on sudden cardiac death, which this entry does curate as a phenotype, but its cached evidence reports implantation *rates* in sarcomeric mutation carriers rather than efficacy against arrest, so no source here supports the claim at any level. Rather than assert the edge uncited or reach for a source not already verified here, it is left out; adding it is a follow-up that needs its own citation. A treatment naming no specific mechanism, such as the generic heart-failure pharmacotherapy entry, has nothing to point at by construction. Two curation decisions worth knowing about. Mavacamten's therapeutic_agent is deliberately unbound, following Hypertrophic_Cardiomyopathy_8 — see the note on that treatment. And there is no `datasets` block: a GEO search returns no MYL2-specific cardiomyopathy dataset (MYL2 surfaces as a cardiomyocyte marker gene, and the HCM datasets are unstratified or about other genes), so adding one would substitute the parent disease for this entity. The absence is recorded in `discussions` instead. Deep research. A falcon (Edison) run was performed for this entry (research/Hypertrophic_Cardiomyopathy_10-deep-research-falcon.md). Its reference validation resolved 11/11 extractable citations with no confabulations and none scored off topic, though only 6 of the 11 were affirmatively scored on topic, so that screen is not a clean bill of health; its term validation resolved 39/39 CURIEs but named several wrongly, and one suggestion was rejected on that basis — the report offered HP:0001698 for left ventricular outflow tract obstruction, which is Pericardial effusion; this entry uses HP:0032092. HP:0005117 (offered for diastolic dysfunction, actually Elevated diastolic blood pressure) and HP:0030680 (offered for left atrial enlargement, actually Abnormal cardiovascular system morphology) were likewise not used. The report's D166H family findings (atrial fibrillation, restrictive filling, LOD score) are not curated: the paper is a research letter whose PubMed record carries no abstract, so those numbers cannot be quoted as a verified snippet from the cache. GeneReviews scope. The GeneReviews resource applicable to this entry is the disease-level "Nonsyndromic Hypertrophic Cardiomyopathy Overview" (PMID:20301725), tagged accordingly in `references`. Its indexed PubMed record is content_type abstract_only and carries only the chapter's purpose statement, not the Clinical Characteristics, Management, or Genetic Counseling sections, so section-by-section GeneReviews mining is not possible from the cache and no snippet is quoted from it. The clinical-characteristics baseline for this entry is therefore built from the primary MYL2 cohort and pedigree literature cited throughout, principally PMID:26497160, PMID:12404107, PMID:23365102, PMID:8673105 and PMID:30796699.

Augment: Hypertrophic Cardiomyopathy 10 (MYL2) · 2026-09-06T06:21:04Z · View source

Augmented the existing CMH10 entry using a falcon (Edison) deep-research run plus targeted PubMed retrieval. Compliance 84.2% -> 91.7%; entry 430 -> ~1975 lines; 18 -> 79 verified evidence snippets. Deep research: just research-disorder falcon Hypertrophic_Cardiomyopathy_10 (709s, 23 citations, 1 artifact). The report carried no validation sections, so both were added retroactively with just validate-research-reference and just validate-research-terms. References: 11/11 extractable citations resolved, 0 unresolved, 0 off topic. Terms: 39/39 CURIEs resolved but several mis-named; three suggested HPO bindings were rejected after independent OAK lookup - HP:0001698 (offered for LVOT obstruction, actually Pericardial effusion; used HP:0032092), HP:0005117 (offered for diastolic dysfunction, actually Elevated diastolic blood pressure) and HP:0030680 (offered for left atrial enlargement, actually Abnormal cardiovascular system morphology). A fourth wrong term was caught outside the report: NCIT:C158384 is SIGLEC15 Gene, not mavacamten. Pathophysiology: four nodes added (Reduced RLC Ser15 Phosphorylation, Stabilization of the Myosin Super-Relaxed State, Slow-Twitch Skeletal Muscle Contractile Deficit, Calcium Handling Remodeling and Electrical Instability) and every pre-existing downstream edge given its own evidence (previously 0/3 cited). Existing node names and conforms_to targets were left untouched so foreign keys and module conformance hold. New sections: variants (E22K founder, R58Q, A13T, c.403-1G>C recessive splice), environmental (hypertension and obesity as penetrance-determining co-factors, both pathograph-linked via influences_mechanisms), progression, diagnosis, histopathology, animal_models (Tg-R58Q with three mechanism links and readouts), experimental_models (patient MYL2-R58Q iPSC-CM), clinical_trials (EXPLORER-HCM, VALOR-HCM, both flagged not-MYL2-stratified), discussions (4), genetic.case_fractions, and five phenotypes. Mavacamten treatment added. Deliberate omissions. No datasets block: GEO returns no MYL2-specific cardiomyopathy dataset (MYL2 hits are studies using it as a cardiomyocyte marker; HCM hits are unstratified or other genes), and adding a generic HCM dataset would be the named-entity substitution the dataset guidance warns about. Recorded as a KNOWLEDGE_GAP discussion instead. The report's De Bortoli D166H figures (AF 62%, restrictive filling 38%, LOD 5.35) are not curated: the paper is a research letter whose PubMed record carries no abstract, so those numbers have no verifiable snippet in the cache. Mavacamten's therapeutic_agent is left unbound following the precedent and reasoning already recorded in Hypertrophic_Cardiomyopathy_8. Self-review found that the apical-hypertrophy phenotype's core claim was carried only by its source's title (PMID:30796699 is abstract-only), which is not quotable. Rather than leave it thinly supported it was reframed as a non-septal distribution phenotype and re-evidenced from PMID:22091967, which states mid-ventricular obstruction for the MYL2 A13T allele. That paper also supplied the poison-peptide mechanism and the observation that A13T raises isometric force where R58Q lowers it, both of which were added to the dominant-mechanism discussion, plus an A13T variant record. Validation: just validate passes (79/79 snippets verified against cached references); just validate-terms passes; check-entity-refs, check-duplicate-keys, check-causal-targets, check-qualifier-terms, check-enum-values, check-snippet-length, check-title-snippets, check-snippet-grading, check-folded-hyphens and check-environmental-evidence all pass; just validate-disorders run over the changed file.

Falcon ▸

Hypertrophic Cardiomyopathy 10 (MYL2-related HCM): Research Report

Edison Scientific Literature 23 citations 2026-09-06T05:58:40.309019

Hypertrophic Cardiomyopathy 10 (MYL2-related HCM): Research Report

Executive summary and evidence scope

Hypertrophic cardiomyopathy 10 (HCM10) is a rare, principally autosomal-dominant sarcomeric cardiomyopathy caused by pathogenic variants in MYL2, which encodes ventricular/slow-skeletal myosin regulatory light chain 2 (RLC). It is characterized by otherwise unexplained left-ventricular hypertrophy (LVH), but expression is age-dependent and highly variable: carriers may remain phenotype-negative, develop apical or conventional HCM, or—depending on the allele—show restrictive physiology, atrial fibrillation (AF), heart failure, or sudden-death risk. MYL2 variants are rare relative to MYH7 and MYBPC3. Most clinical-management evidence therefore comes from unstratified HCM cohorts, not HCM10 specifically. (glavaski2023hypertrophiccardiomyopathygenetic pages 2-4, yadav2019hereditaryheartdisease pages 1-2)

The strongest subtype-specific human data concern p.Glu22Lys, p.Arg58Gln, and p.Asp166His. The following evidence map distinguishes those findings from generic HCM guidance.

Domain	MYL2-specific evidence	Quantitative finding	Evidence type	Key limitation
Founder allele and modifiers	MYL2 c.64G>A, p.Glu22Lys occurred in 14 HCM families sharing a founder haplotype. Hypertension, obesity, or another sarcomeric variant increased disease expression. (claes2016hypertrophicremodellingin pages 1-1, claes2016hypertrophicremodellingin pages 4-5)	38 carriers; HCM in 89% of carriers with an additional hypertrophy-promoting factor; hypertension in 71% of affected carriers with an additional factor.	Human family and segregation study	Low penetrance and generally mild phenotype when isolated; estimates may be founder-population dependent.
Familial restrictive phenotype	MYL2 c.496G>C, p.Asp166His segregated with HCM and was associated with restrictive filling, atrial enlargement, atrial fibrillation, heart failure, and embolic or arrhythmic events. (bortoli2020novelmissensevariant pages 1-4, bortoli2020novelmissensevariant pages 4-7)	12 additional carriers: 11 with HCM and 1 borderline; LOD 5.35; AF 62%; restrictive filling 38%; no LV outflow obstruction.	Human multigenerational family study with structural modelling	Single-family phenotype may reflect shared genetic or environmental modifiers; classified as likely pathogenic in the study.
Patient-cell phenotype	Patient-derived cardiomyocytes carrying MYL2 p.Arg58Gln (R58Q) reproduced hypertrophy, myofibrillar disarray, abnormal calcium handling, and irregular beating. (zhou2019inducedpluripotentstem pages 4-7, zhou2019inducedpluripotentstem pages 8-9)	Cell area 4100 ± 171 versus 3200 ± 144 μm²; disarray 42% versus 21%; irregular beating 30.3% versus 2.4%; L-type calcium-current density reduced 45.3%.	Human patient-derived iPSC cardiomyocytes and myectomy tissue	Single-patient line compared with a maternal control; cells were immature and not reported as an isogenic pair.
Phosphorylation rescue	In R58Q biochemical and muscle-fibre systems, a Ser15-to-Asp phosphomimetic restored actin interaction, ATPase activity, and force while shifting myosin toward the disordered-relaxed state. (yadav2019phosphomimetic‐mediatedinvitro pages 8-10)	MLCK phosphorylation increased maximal active isometric force by approximately 30% in prior R58Q trabecula experiments; phosphomimetic measures approached wild-type levels.	Recombinant protein, reconstituted porcine cardiac fibres, and transgenic-mouse tissue	Preclinical in vitro or ex vivo rescue only; no S15D-R58Q animal or human therapeutic study.
Contemporary clinical guidance	2023 ESC and 2024 AHA/ACC multisociety guidance supports phenotype-led imaging, genetic testing and counselling, cascade screening, sudden-death risk assessment, and treatment of eligible HCM. (sanghvi2025hypertrophiccardiomyopathymanagement pages 14-15, ramonfaur2024eighteen‐monthreal‐worldexperience pages 12-12)	Guideline-level recommendations; no MYL2-specific treatment-effect estimate was reported.	Evidence-based clinical-practice guidelines	Generic HCM evidence is not genotype-stratified for MYL2-HCM10 and does not establish variant-specific efficacy or prognosis.

Table: Compact evidence map linking major MYL2 variants to family, patient-cell, and functional findings. It distinguishes subtype-specific observations from contemporary HCM guidance that was not stratified by MYL2 genotype.

Evidence notation: “human” means affected families, myocardial tissue, or patient-derived cells; “model” means transgenic animals or engineered tissue; “in vitro” means biochemical or reconstituted-muscle experiments. PMID values were not available in the retrieved full texts; DOI URLs are supplied instead rather than risking incorrect PMID assignment.

1. Disease information

Definition

HCM10 is the MYL2-related subtype of hypertrophic cardiomyopathy, a primary myocardial disorder in which LV wall thickening is not explained solely by pressure loading, valvular disease, athletic remodeling, or infiltration. Histologic hallmarks shared with sarcomeric HCM are cardiomyocyte hypertrophy, myofibrillar disarray, and interstitial fibrosis. Preservation or elevation of ejection fraction is common early, despite impaired relaxation and diastolic filling. (glavaski2023hypertrophiccardiomyopathygenetic pages 2-4, yadav2019hereditaryheartdisease pages 1-2)

Identifiers and terminology

MONDO: MONDO:0012112, as specified in the target record.
OMIM disease: commonly catalogued as Cardiomyopathy, hypertrophic, 10 (CMH10/HCM10; OMIM 608758).
Causal gene: MYL2, commonly catalogued as OMIM 160781; HGNC-approved symbol MYL2.
Synonyms: hypertrophic cardiomyopathy 10; CMH10; MYL2-related hypertrophic cardiomyopathy; familial hypertrophic cardiomyopathy due to ventricular myosin regulatory light-chain variants; cardiac regulatory myosin light-chain cardiomyopathy.
MeSH: use the broader term Cardiomyopathy, Hypertrophic.
ICD-10-CM: I42.1 for obstructive HCM and I42.2 for other HCM; there is no MYL2-specific code.
ICD-11: code under hypertrophic cardiomyopathy; no gene-specific subdivision was established in the retrieved evidence.
Orphanet: use the broader familial/genetic HCM entry; a reliably verified HCM10-specific ORPHA identifier was not recovered.

The report synthesizes aggregated disease-level resources and published families, not individual EHR records. Some detailed phenotypes derive from single families or one patient-derived cell line and should not be interpreted as population-wide frequencies. (bortoli2020novelmissensevariant pages 1-4, bortoli2020novelmissensevariant pages 4-7, zhou2019inducedpluripotentstem pages 4-7)

2. Etiology

Causal factors and genetic risk

The initiating lesion is generally a heterozygous germline MYL2 variant affecting the myosin lever arm, phosphorylation-dependent regulation, or actin–myosin cycling. Reported HCM-associated substitutions include p.Ala13Thr, p.Phe18Leu, p.Glu22Lys, p.Asn47Lys, p.Arg58Gln, p.Pro95Ala, p.Lys104Glu, p.Asp166Val, and p.Asp166His, although contemporary pathogenicity must be evaluated variant by variant. MYL2 is a rare HCM gene and many historical assertions require re-evaluation under ACMG/AMP and ClinGen standards. (glavaski2023hypertrophiccardiomyopathygenetic pages 2-4, yadav2019hereditaryheartdisease pages 1-2)

Strong family evidence:

c.64G>A, p.Glu22Lys (E22K): 38 carriers from 14 families shared a founder haplotype. The allele alone showed low penetrance and usually mild expression. With hypertension, obesity, or another sarcomeric variant, HCM occurred in 89% of carriers; hypertension was present in 71% of affected carriers who had an additional risk factor. This is direct human evidence for gene–environment/genetic-background interaction. (claes2016hypertrophicremodellingin pages 1-1, claes2016hypertrophicremodellingin pages 4-5)
c.496G>C, p.Asp166His (D166H): absent from gnomAD at publication, classified by the investigators as likely pathogenic, and segregated with disease at LOD 5.35. Of 12 additional carriers, 11 had HCM and one had borderline wall thickness. Structural modeling placed the altered conserved terminal residue against the bent myosin lever arm. (bortoli2020novelmissensevariant pages 1-4)
p.Arg58Gln (R58Q): associated with apical HCM and reproduced disease-related cellular abnormalities in patient-derived cardiomyocytes. (zhou2019inducedpluripotentstem pages 4-7)

Environmental and lifestyle modifiers

Hypertension, obesity, diabetes, renal dysfunction, sleep apnea, alcohol exposure, cardiac loading, and physical activity can modify the broader HCM phenotype, but only hypertension/obesity were directly evaluated in an MYL2 founder cohort. These factors are modifiers, not primary causes of HCM10. (claes2016hypertrophicremodellingin pages 1-1, claes2016hypertrophicremodellingin pages 4-5, hao2026hypertrophiccardiomyopathycomprehensive pages 8-9)

No infectious agent, toxin, radiation, or occupational exposure is established as a cause of HCM10. There is no validated genetic “protective allele.” Clinically useful protective measures are control of blood pressure and obesity, avoidance of dehydration or drugs that worsen obstruction where relevant, and longitudinal surveillance. Immunization has no disease-specific preventive role.

3. Phenotypes

Phenotype	Characteristics and frequency	Suggested HPO term
LV hypertrophy	Variable; asymmetric, apical, or relatively mild in restrictive disease. E22K may remain subclinical without modifiers.	HP:0001712, Left ventricular hypertrophy
Apical HCM	Documented with R58Q; chronic, variably symptomatic.	HP:0001712 plus apical localization annotation
Diastolic dysfunction/restrictive filling	D166H family: restrictive filling in 38%, sometimes with maximum wall thickness ≤15 mm.	HP:0005117, Elevated filling pressure/diastolic dysfunction; HP:0002092 where restrictive cardiomyopathy is coded
Atrial enlargement	D166H mean left-atrial diameter rose from 45±12 to 54±14 mm.	HP:0030680, Left atrial enlargement; HP:0006698, Biatrial enlargement
Atrial fibrillation	D166H family: 62%, approximately three times the rate cited for general HCM. Episodic or persistent.	HP:0005110
Ventricular arrhythmia/SCD risk	Nonsustained VT in the R58Q index patient; ventricular fibrillation and death occurred in the D166H pedigree. Frequency is not generalizable.	HP:0004756; HP:0001663; HP:0001645
LV outflow-tract obstruction	Common in generic HCM but absent in the reported D166H family.	HP:0001698
Heart failure/exercise intolerance	Dyspnea, restrictive physiology, pulmonary hypertension, end-stage disease, and transplantation occurred in severe family members.	HP:0001635; HP:0001648; HP:0002094; HP:0003236
Syncope/chest pain/palpitations	Recognized HCM symptoms, but MYL2-specific frequencies are unavailable.	HP:0001279; HP:0001681; HP:0001962
Histopathology	Cardiomyocyte hypertrophy, myofibrillar disarray, interstitial/pericellular fibrosis.	HP:0001639; HP:0005144; HP:0001685

The D166H family’s AF and restrictive pattern may be allele-specific or reflect shared modifiers; the authors explicitly cautioned against broad generalization from one pedigree. (bortoli2020novelmissensevariant pages 1-4, bortoli2020novelmissensevariant pages 4-7)

Quality of life: symptoms can limit exercise, work, and daily activity and increase anxiety concerning arrhythmia and familial risk. No MYL2-specific EQ-5D, SF-36, KCCQ, or HCMSQ dataset was found. Generic HCM trials show that gradient and symptom reduction can improve patient-reported health, but this has not been separately demonstrated in HCM10.

4. Genetic and molecular information

Gene and protein

MYL2 encodes the ventricular and slow-twitch skeletal-muscle myosin RLC. RLC wraps around an IQ motif in the MYH7 neck/lever arm, stabilizes lever-arm stiffness, and tunes force generation and actin–myosin kinetics. Its N terminus contains an EF-hand-like divalent-cation-binding region and a conserved Ser15 phosphorylation site regulated by cardiac myosin light-chain kinase. (yadav2019phosphomimetic‐mediatedinvitro pages 8-10, yadav2019hereditaryheartdisease pages 1-2)

Variant interpretation

Most established HCM10 alleles are heterozygous missense, germline variants, consistent with dominant inheritance and a poison-peptide/altered-function mechanism rather than simple haploinsufficiency.
p.Asp166His was absent from gnomAD in the 2020 report and classified likely pathogenic by its authors; current ClinVar submissions and population releases should be checked at implementation time. (bortoli2020novelmissensevariant pages 1-4)
p.Glu22Lys has strong founder/segregation evidence but reduced penetrance; classification should account for ancestry, phenotype, and coexisting hypertrophy drivers. (claes2016hypertrophicremodellingin pages 1-1)
p.Arg58Gln has human phenotype, tissue, iPSC, mouse, and biochemical functional support. (yadav2019phosphomimetic‐mediatedinvitro pages 8-10, zhou2019inducedpluripotentstem pages 4-7)
A homozygous c.403-1G>C splice variant causes a distinct infantile cardioskeletal myopathy with type-I fiber disease and early cardiac death. This recessive syndrome should not be conflated with dominant HCM10.

No recurrent pathogenic chromosomal deletion, translocation, inversion, aneuploidy, somatic MYL2 driver, or repeat expansion defines HCM10. CMA, karyotyping, FISH, and repeat-expansion assays are therefore not first-line tests.

Modifiers and epigenetics

Other sarcomeric variants, hypertension, and obesity demonstrably modify E22K penetrance. Broader HCM work implicates polygenic background and epigenetic regulation, but no validated MYL2-specific modifier gene, methylation signature, or clinical epigenomic biomarker is established. (claes2016hypertrophicremodellingin pages 1-1, claes2016hypertrophicremodellingin pages 4-5)

5. Environmental information

HCM10 is not environmentally acquired. Relevant exposures act by changing ventricular load, energetics, or arrhythmia susceptibility:

Hypertension: strongest directly demonstrated MYL2 modifier.
Obesity/metabolic disease: may increase hypertrophic loading and symptom burden.
Exercise: does not cause the mutation; intensity should be individualized through shared decision-making rather than universal prohibition.
Alcohol, dehydration, stimulants, and vasodilating agents: may aggravate arrhythmia or dynamic obstruction in susceptible patients, although no MYL2-specific effect size exists.
Smoking: increases general cardiovascular risk but is not a proven HCM10 penetrance determinant.
Infection: not etiologic; myocarditis remains a differential diagnosis.

The E22K founder study provides the clearest real-world gene–environment observation: the variant often required an additional hypertrophy-promoting exposure or genotype for overt disease. (claes2016hypertrophicremodellingin pages 1-1)

6. Mechanism and pathophysiology

Ordered causal chain

A heterozygous MYL2 missense variant alters ventricular RLC structure or phosphorylation-dependent regulation, which leads to abnormal support of the MYH7 lever arm. (bortoli2020novelmissensevariant pages 1-4, yadav2019phosphomimetic‐mediatedinvitro pages 8-10)
Altered lever-arm mechanics lead to variant-specific changes in actin binding, ATPase activity, cross-bridge recruitment/detachment, force, and myofilament calcium responsiveness. These changes are demonstrated in biochemical and transgenic systems but are not identical for every allele. (yadav2019phosphomimetic‐mediatedinvitro pages 8-10)
R58Q branch: reduced phosphorylation and excessive stabilization of the ATP-conserving super-relaxed state lead to fewer working myosin heads and abnormal force kinetics; this was experimentally improved by Ser15 phosphomimicry. (yadav2019phosphomimetic‐mediatedinvitro pages 8-10)
D166H branch: deformation near the bent lever arm is predicted to lead to abnormal cross-bridge geometry; this remains structural inference rather than direct kinetic demonstration. (bortoli2020novelmissensevariant pages 1-4)
Sarcomere inefficiency and altered mechanosensing lead to compensatory hypertrophic signaling and energetic stress; specific downstream MAPK/mTOR/PI3K attribution in human HCM10 remains incompletely demonstrated.
Calcium-handling remodeling leads to prolonged calcium decay and electrical instability. R58Q iPSC-cardiomyocytes showed reduced L-type calcium current, abnormal transients, and irregular beating. (zhou2019inducedpluripotentstem pages 4-7, zhou2019inducedpluripotentstem pages 8-9)
Chronic cardiomyocyte stress leads to cellular hypertrophy, sarcomere disarray, and fibrosis, which result in impaired relaxation, ventricular stiffness, and—in some alleles—apical or restrictive remodeling. (bortoli2020novelmissensevariant pages 4-7, zhou2019inducedpluripotentstem pages 4-7)
Obstructive branch: hypertrophy plus mitral–septal geometry may result in LV outflow obstruction; this is common in general HCM but was absent in the D166H family. Nonobstructive/restrictive branch: atrial-pressure loading leads to atrial enlargement, AF, pulmonary hypertension, embolism, and heart failure. (bortoli2020novelmissensevariant pages 1-4, bortoli2020novelmissensevariant pages 4-7)
Fibrosis, disarray, calcium instability, and chamber remodeling lead to ventricular arrhythmia, sudden death, or end-stage heart failure in a minority of affected patients. The relative contribution of each pathway in HCM10 is inferred from combined human and model evidence.

Key experimental findings

Human R58Q iPSC-cardiomyocytes: cell area was 4100±171 versus 3200±144 μm²; disarray occurred in 42% versus 21%; irregular beating in 30.3% versus 2.4%; L-type calcium-current density fell 45.3% at 0 mV; and calcium-transient decay was prolonged (1.8±0.3 versus 1.3±0.2 seconds). Myectomy tissue showed hypertrophy, disarray, and interstitial/pericellular fibrosis. (zhou2019inducedpluripotentstem pages 4-7)

R58Q biochemical rescue: R58Q reduced rigor actin affinity, ATPase Vmax, and maximal isometric force and favored the super-relaxed state. An S15D phosphomimetic shifted myosin toward the disordered-relaxed state and restored force and ATPase behavior toward wild type; MLCK phosphorylation increased maximal force by approximately 30% in prior trabecular experiments. This is preclinical, not a demonstrated therapy. (yadav2019phosphomimetic‐mediatedinvitro pages 8-10)

Short source excerpts supporting these conclusions include: “Myosin regulatory light chain phosphorylation is important for cardiac muscle mechanics/function” and the R58Q iPSC study title’s summary that cells “show hypertrophy, myofibrillar disarray, and calcium perturbations.” (yadav2019phosphomimetic‐mediatedinvitro pages 8-10, dolder2025experimentalmodelsof pages 36-36)

Suggested ontology annotations

GO biological process: cardiac muscle contraction (GO:0060048); actin–myosin filament sliding (GO:0033275); regulation of cardiac muscle contraction (GO:0055117); muscle filament sliding (GO:0030049); calcium-ion homeostasis (GO:0055074); cardiac muscle hypertrophy (GO:0003300); response to oxidative stress (GO:0006979).
GO cellular component: sarcomere (GO:0030017); myosin complex (GO:0016459); A band (GO:0031672); myofibril (GO:0030016); contractile fiber (GO:0043292).
Cell Ontology: cardiac muscle cell/cardiomyocyte (CL:0000746); ventricular cardiac muscle cell (CL:0002131); cardiac fibroblast (use current CL release); endothelial cell (CL:0000115); cardiac-resident macrophage only as a secondary remodeling cell, not a primary target.

No subtype-specific single-cell atlas, spatial transcriptomic dataset, lipidomic signature, CRISPR screen, or integrated human multi-omics study was identified. Available transcriptomic/proteomic findings are largely mouse or generic HCM and should not be treated as HCM10 biomarkers.

7. Anatomical structures affected

Primary organ/system: heart and cardiovascular system.
Primary sites: left-ventricular myocardium, interventricular septum, or LV apex; atria become secondarily enlarged with restrictive filling/AF.
Secondary sites: mitral valve/LV outflow tract in obstructive disease; pulmonary circulation in advanced diastolic failure; cerebral/systemic circulation through AF-related embolism.
Tissues/cells: ventricular myocardium and cardiomyocytes are primary; interstitial fibroblasts contribute to fibrosis; microvascular and conduction-system remodeling are secondary.
Subcellular localization: thick filament, myosin neck/lever arm, sarcomere, myofibril; downstream calcium-handling machinery and mitochondria may remodel.
Lateralization: not left/right-sided in the usual sense; ventricular hypertrophy is often asymmetric rather than unilateral.

Suggested anatomy terms include UBERON:0000948 heart, UBERON:0002084 heart left ventricle, UBERON:0002094 interventricular septum, and ventricular myocardium terms from the current UBERON release.

8. Temporal development

Dominant HCM10 is generally chronic and lifelong at the genetic level, with insidious, age-dependent phenotypic emergence. Onset ranges from childhood to late adulthood; a normal study at one age does not establish lifelong nonpenetrance. E22K may remain mild until an additional loading or genetic factor appears. D166H showed progression toward atrial enlargement, AF, restrictive physiology, and advanced heart failure in some relatives. (bortoli2020novelmissensevariant pages 1-4, claes2016hypertrophicremodellingin pages 1-1)

For sarcomeric HCM overall—not MYL2 alone—a 2024 meta-analysis found 57% penetrance among nonproband relatives, mean diagnosis age 38 years, and 15% phenotypic conversion over about eight years beginning at a mean age of 16. Incidentally identified population carriers had much lower penetrance, approximately 11%. The paper concluded that penetrance is “highly variable and influenced by currently undefined and context-dependent genetic and environmental factors.” These estimates must not be entered as HCM10-specific frequencies. (hao2026hypertrophiccardiomyopathycomprehensive pages 8-9)

There is no spontaneous genetic remission. Symptoms or obstruction may improve with treatment, but surveillance remains necessary. Critical intervention windows include presymptomatic cascade detection, emergence of hypertrophy or arrhythmia, pregnancy planning, and transition from pediatric to adult care.

9. Inheritance and population

Inheritance: usually autosomal dominant, with a 50% transmission probability from a heterozygous parent.
Penetrance: incomplete, age-dependent, allele- and context-dependent. E22K is a particularly clear example of low penetrance without additional risk factors. (claes2016hypertrophicremodellingin pages 1-1)
Expressivity: highly variable, ranging from no hypertrophy to apical HCM, restrictive filling, arrhythmia, or advanced heart failure.
Anticipation: not established.
Germline mosaicism: biologically possible but no characteristic HCM10 rate is known.
Founder effect: demonstrated for E22K in 14 related founder-haplotype families. (claes2016hypertrophicremodellingin pages 1-1)
Consanguinity: not relevant to usual dominant HCM10, but important in recessive MYL2 infantile myopathy.
Sex: no reliable MYL2-specific sex ratio. Generic HCM is genetically expected to affect both sexes, although ascertainment and expression differ.

No robust prevalence, incidence, carrier-frequency, ethnicity-specific frequency, or geographic distribution has been established for HCM10. Generic clinically apparent HCM is often estimated near 1:500, while broader imaging/genomic definitions yield higher estimates; these figures must not be assigned to MYL2-HCM10. MYL2 constitutes only a small minority of molecularly diagnosed HCM. (glavaski2023hypertrophiccardiomyopathygenetic pages 2-4)

10. Diagnostics

Clinical workflow

History and examination: dyspnea, chest pain, palpitations, syncope, exercise intolerance, family HCM/SCD, hypertension, skeletal weakness, and a three-generation pedigree.
ECG and ambulatory monitoring: LVH/repolarization abnormalities, conduction disease, AF, nonsustained VT, or other arrhythmia. The D166H family included first-degree AV block and left anterior hemiblock. (bortoli2020novelmissensevariant pages 4-7)
Transthoracic echocardiography: maximal wall thickness, distribution of hypertrophy, systolic/diastolic function, left-atrial size, systolic anterior mitral motion, and resting/provoked LVOT gradient.
CMR: useful when echocardiography is equivocal, for apical disease, wall-thickness definition, apical aneurysm, and late-gadolinium-enhancement fibrosis assessment.
Exercise testing: functional capacity and provoked obstruction when clinically appropriate.
Laboratory biomarkers: BNP/NT-proBNP and troponin may support severity assessment but are neither HCM10-specific nor diagnostic.
Biopsy: not routine; when available, may show hypertrophy, disarray, and fibrosis. It is reserved mainly for unresolved infiltrative/metabolic differentials.

Contemporary practice should follow the 2023 ESC cardiomyopathy guideline and 2024 AHA/ACC multisociety HCM guideline. A systematic comparison found broad agreement on echocardiography, genetic testing, family screening, and medical/invasive management, but differences in CMR use and SCD-risk frameworks. (sanghvi2025hypertrophiccardiomyopathymanagement pages 14-15, ramonfaur2024eighteen‐monthreal‐worldexperience pages 12-12)

Clinical criteria and differential diagnosis

In adults, otherwise unexplained maximal LV wall thickness around ≥15 mm generally supports HCM; lower thresholds may be meaningful in first-degree relatives or genotype-positive individuals. Pediatric interpretation uses body-size-adjusted z scores. Exclude hypertensive remodeling, aortic stenosis, athlete’s heart, amyloidosis, Fabry disease, glycogen-storage disease, mitochondrial disease, RASopathies, and myocarditis.

Genetic testing

Test an affected proband using a validated cardiomyopathy panel that includes MYL2 and other definitive HCM genes, with deletion/duplication analysis where technically appropriate.
Confirm a pathogenic/likely pathogenic result and offer targeted cascade testing to relatives with pre- and post-test genetic counseling.
Do not use a VUS for predictive testing or irreversible clinical decisions.
If panel testing is negative despite strong familial disease, updated panel reanalysis, WES, or WGS may detect overlooked coding, splice, structural, or deep-intronic variants. WGS/WES are adjuncts, not substitutes for careful phenotype and variant interpretation.
CMA, FISH, karyotype, mtDNA, and repeat-expansion tests are indicated only when syndromic clues or another diagnosis warrants them.
RNA sequencing can clarify suspected splice variants but is not routine diagnostic testing.

Genetic results are most actionable for etiologic confirmation, cascade screening, and reproductive counseling; current SCD decisions remain phenotype-led. (sanghvi2025hypertrophiccardiomyopathymanagement pages 14-15)

11. Outcome and prognosis

The course ranges from asymptomatic longevity to AF, embolic stroke, ventricular arrhythmia, restrictive or systolic heart failure, transplantation, and sudden death. D166H is associated within one pedigree with high AF/restrictive burden and adverse outcomes, but it does not establish an MYL2-wide prognosis. (bortoli2020novelmissensevariant pages 1-4, bortoli2020novelmissensevariant pages 4-7)

Generic optimally treated HCM mortality is reported at <1% annually, with near-normal life expectancy possible when recognized and managed appropriately; this is not an HCM10-specific survival estimate. Prognostic assessment should incorporate prior cardiac arrest/VT, unexplained syncope, family SCD, maximal wall thickness, apical aneurysm, LVEF <50%, nonsustained VT, LVOT obstruction, atrial size, symptoms, and CMR fibrosis—not genotype alone. (sanghvi2025hypertrophiccardiomyopathymanagement pages 14-15, kasiakogias2025exploringthecurrent pages 10-11)

Important morbidity includes reduced exercise capacity, anxiety, device burden, AF/stroke, heart-failure hospitalization, and treatment adverse effects. No validated MYL2-specific prognostic biomarker or calculator exists.

12. Treatment

There is no approved MYL2-genotype-specific therapy. Management follows the clinical HCM phenotype.

Phenotype-directed algorithm

Asymptomatic genotype-positive/phenotype-negative: surveillance, risk-factor treatment, family counseling; no prophylactic HCM drug is proven.
Symptomatic obstructive HCM: a nonvasodilating beta blocker is generally first line; verapamil or diltiazem is an alternative in suitable patients. Persistent symptoms may prompt disopyramide, a cardiac myosin inhibitor, or expert-center septal reduction.
Mavacamten: a reversible cardiac myosin inhibitor for eligible symptomatic obstructive HCM; requires serial echocardiography because excessive suppression can reduce LVEF. MYL2-specific efficacy has not been established.
Nonobstructive symptoms: cautious diuresis for congestion and conventional management of AF or systolic dysfunction; evidence for myosin inhibitors is less certain.
AF: anticoagulation and rhythm/rate management according to HCM guidance; thromboembolic risk is clinically important regardless of conventional CHA₂DS₂-VASc thresholds.
SCD prevention: implantable cardioverter-defibrillator after cardiac arrest/sustained VT and for selected high-risk primary-prevention patients.
Refractory obstruction: surgical septal myectomy or alcohol septal ablation at experienced centers.
End-stage disease: guideline-directed heart-failure care and transplant evaluation.

Suggested NCIT annotations include beta-adrenergic blocking agent, calcium-channel blocker, antiarrhythmic agent, anticoagulant therapy, implantable cardioverter-defibrillator placement, septal myectomy, alcohol septal ablation, and heart transplantation; verify preferred NCIT concept codes against the current release.

Current implementation and experimental therapy

A 2024 racially diverse real-world cohort of 66 obstructive-HCM patients treated with mavacamten reported ≥1 NYHA-class improvement in 72% after at least six months, an average 80±46-mmHg reduction in peak LVOT gradient, elimination of significant obstruction in 79.1%, and temporary discontinuation for LVEF <50% in three patients. These results were not MYL2-stratified. (ramonfaur2024eighteen‐monthreal‐worldexperience pages 12-12)

Ongoing or recent programs include mavacamten long-term extension NCT03723655, VALOR-HCM NCT04349072, and aficamten phase 2/3 studies. Retrieved current implementation studies include NCT06116968, NCT06146660, NCT06023186, NCT06551129, and NCT06549608. No trial specifically targets MYL2-HCM10.

RLC Ser15 phosphomimicry is an experimental mechanism-directed concept: S15D rescued R58Q abnormalities in reconstituted porcine fibers, but no human gene-, RNA-, or protein-replacement therapy has demonstrated safety or efficacy. (yadav2019phosphomimetic‐mediatedinvitro pages 8-10)

13. Prevention

Primary prevention: the inherited variant cannot presently be prevented after conception. Reproductive options include genetic counseling, prenatal diagnosis, and preimplantation genetic testing when a familial pathogenic variant is established.
Secondary prevention: cascade genetic testing plus ECG/echocardiographic surveillance of first-degree relatives; CMR or rhythm monitoring according to phenotype.
Tertiary prevention: blood-pressure and weight control, individualized exercise advice, AF anticoagulation, arrhythmia surveillance, ICD placement when indicated, and timely treatment of obstruction or heart failure.
Behavioral measures: maintain hydration, avoid unreviewed stimulants/performance-enhancing agents, and address obesity, sleep apnea, smoking, and hypertension.
Public health: clinician and family education and access to specialist cardiomyopathy/genetic services are more relevant than population-wide screening because HCM10 is rare.

No vaccine, antimicrobial prophylaxis, newborn biochemical screen, or population carrier-screening program is indicated specifically for HCM10.

14. Other species and natural disease

MYL2 orthologs are evolutionarily conserved across vertebrates, including mouse (Myl2), rat, pig, zebrafish, dog, and cat. No well-established naturally occurring veterinary disease equivalent specifically caused by an orthologous MYL2 HCM10 variant was identified in the retrieved literature. Consequently, breed-specific VBO terms, veterinary prevalence, and zoonotic transmission are not applicable. HCM10 is noninfectious and has no zoonotic potential.

Porcine cardiac fibers are useful for protein-reconstitution experiments because their sarcomeric mechanics are experimentally tractable, but this is an induced ex vivo system, not natural porcine HCM. (yadav2019phosphomimetic‐mediatedinvitro pages 8-10)

15. Model organisms and experimental systems

Available models

Patient-derived R58Q iPSC-cardiomyocytes: reproduced cellular hypertrophy, disarray, calcium abnormalities, and irregular beating. Strength: human genetic background and direct patient relevance. Limitations: one patient, maternal rather than isogenic control, and immature iPSC-CM physiology. (zhou2019inducedpluripotentstem pages 4-7, zhou2019inducedpluripotentstem pages 8-9)
Humanized transgenic mice: R58Q, E22K, N47K, and other RLC variants have been expressed in mouse hearts to study relaxation, calcium sensitivity, force, phosphorylation, energetics, and remodeling. Strength: intact-organ physiology and longitudinal study. Limitations: species-specific myosin isoforms, heart rate, transgene dosage, and allele-specific phenotypic divergence. (yadav2019hereditaryheartdisease pages 1-2, dolder2025experimentalmodelsof pages 36-36)
Reconstituted porcine papillary fibers/myosin: permit controlled replacement with mutant or phosphomimetic RLC and direct force, ATPase, actin-binding, and SRX/DRX measurements. Limitation: lacks chronic cellular remodeling and systemic physiology. (yadav2019phosphomimetic‐mediatedinvitro pages 8-10)
Human myectomy tissue: validates hypertrophy, disarray, fibrosis, and—as emerging work suggests—variant-dependent myosin energetic states. Limitation: late-stage surgical tissue is biased toward severe disease.

Best uses

These systems support variant classification, causal-mechanism testing, calcium/contractility assays, and preclinical evaluation of phosphorylation or myosin-modulating therapies. Future priorities are CRISPR-corrected isogenic iPSC pairs, engineered heart tissue with adult-like maturation, single-cell/spatial profiling, and allele-specific testing of myosin-inhibitor response.

Knowledge-base conclusions

Core assertion: HCM10 is a rare, dominantly inherited, germline MYL2 sarcomeric cardiomyopathy with incomplete, age- and context-dependent penetrance.
Highest-confidence human genotype–phenotype links: E22K founder disease strongly modified by hypertension/obesity/second variants; R58Q-associated apical HCM with cellular calcium and structural abnormalities; D166H-associated restrictive/AF-predominant familial disease. (bortoli2020novelmissensevariant pages 1-4, claes2016hypertrophicremodellingin pages 1-1, zhou2019inducedpluripotentstem pages 4-7)
Mechanistic core: altered RLC lever-arm regulation, phosphorylation, myosin-state equilibrium, force/ATPase kinetics, and calcium handling precede hypertrophy, disarray, fibrosis, diastolic dysfunction, and arrhythmia. Effects are variant-specific, so a universal “hypercontractility” mechanism should not be assigned uncritically. (yadav2019phosphomimetic‐mediatedinvitro pages 8-10)
Clinical implementation: diagnosis, risk stratification, treatment, and prevention currently follow 2023 ESC/2024 AHA/ACC HCM guidance; no MYL2-specific drug or validated genotype-only risk algorithm exists. (sanghvi2025hypertrophiccardiomyopathymanagement pages 14-15, ramonfaur2024eighteen‐monthreal‐worldexperience pages 12-12)
Major gaps: subtype-specific prevalence, incidence, lifetime penetrance, sex/ancestry effects, prospective natural history, quality-of-life estimates, treatment response, pharmacogenomics, single-cell/spatial omics, natural veterinary disease, and clinical gene/RNA therapy remain unavailable or inadequately studied.

References

(glavaski2023hypertrophiccardiomyopathygenetic pages 2-4): Mila Glavaški, Lazar Velicki, and Nataša Vučinić. Hypertrophic cardiomyopathy: genetic foundations, outcomes, interconnections, and their modifiers. Aug 2023. URL: https://doi.org/10.3390/medicina59081424, doi:10.3390/medicina59081424. This article has 48 citations.
(yadav2019hereditaryheartdisease pages 1-2): Sunil Yadav, Yoel H. Sitbon, Katarzyna Kazmierczak, and Danuta Szczesna-Cordary. Hereditary heart disease: pathophysiology, clinical presentation, and animal models of hcm, rcm, and dcm associated with mutations in cardiac myosin light chains. Pflügers Archiv - European Journal of Physiology, 471:683-699, Jan 2019. URL: https://doi.org/10.1007/s00424-019-02257-4, doi:10.1007/s00424-019-02257-4. This article has 50 citations.
(claes2016hypertrophicremodellingin pages 1-1): Godelieve R.F. Claes, Florence H.J. van Tienen, Patrick Lindsey, Ingrid P.C. Krapels, Apollonia T.J.M. Helderman-van den Enden, Marije B. Hoos, Yvette E.G. Barrois, Johanna W.H. Janssen, Aimée D.C. Paulussen, Jan-Willem E.M. Sels, Simone H.H. Kuijpers, J. Peter van Tintelen, Maarten P. van den Berg, Wilfred F. Heesen, Pablo Garcia-Pavia, Andreas Perrot, Imke Christiaans, Simone Salemink, Carlo L.M. Marcelis, Hubert J.M. Smeets, Han G. Brunner, Paul G.A. Volders, and Arthur van den Wijngaard. Hypertrophic remodelling in cardiac regulatory myosin light chain (myl2) founder mutation carriers. European heart journal, 37 23:1815-22, Jun 2016. URL: https://doi.org/10.1093/eurheartj/ehv522, doi:10.1093/eurheartj/ehv522. This article has 95 citations and is from a highest quality peer-reviewed journal.
(claes2016hypertrophicremodellingin pages 4-5): Godelieve R.F. Claes, Florence H.J. van Tienen, Patrick Lindsey, Ingrid P.C. Krapels, Apollonia T.J.M. Helderman-van den Enden, Marije B. Hoos, Yvette E.G. Barrois, Johanna W.H. Janssen, Aimée D.C. Paulussen, Jan-Willem E.M. Sels, Simone H.H. Kuijpers, J. Peter van Tintelen, Maarten P. van den Berg, Wilfred F. Heesen, Pablo Garcia-Pavia, Andreas Perrot, Imke Christiaans, Simone Salemink, Carlo L.M. Marcelis, Hubert J.M. Smeets, Han G. Brunner, Paul G.A. Volders, and Arthur van den Wijngaard. Hypertrophic remodelling in cardiac regulatory myosin light chain (myl2) founder mutation carriers. European heart journal, 37 23:1815-22, Jun 2016. URL: https://doi.org/10.1093/eurheartj/ehv522, doi:10.1093/eurheartj/ehv522. This article has 95 citations and is from a highest quality peer-reviewed journal.
(bortoli2020novelmissensevariant pages 1-4): Marzia De Bortoli, Riccardo Vio, Cristina Basso, Martina Calore, Giovanni Minervini, Annalisa Angelini, Paola Melacini, Libero Vitiello, Giovanni Vazza, Gaetano Thiene, Silvio Tosatto, Domenico Corrado, Sabino Iliceto, Alessandra Rampazzo, and Chiara Calore. Novel missense variant in myl2 gene associated with hypertrophic cardiomyopathy showing high incidence of restrictive physiology. Circulation: Genomic and Precision Medicine, Apr 2020. URL: https://doi.org/10.1161/circgen.119.002824, doi:10.1161/circgen.119.002824. This article has 23 citations.
(bortoli2020novelmissensevariant pages 4-7): Marzia De Bortoli, Riccardo Vio, Cristina Basso, Martina Calore, Giovanni Minervini, Annalisa Angelini, Paola Melacini, Libero Vitiello, Giovanni Vazza, Gaetano Thiene, Silvio Tosatto, Domenico Corrado, Sabino Iliceto, Alessandra Rampazzo, and Chiara Calore. Novel missense variant in myl2 gene associated with hypertrophic cardiomyopathy showing high incidence of restrictive physiology. Circulation: Genomic and Precision Medicine, Apr 2020. URL: https://doi.org/10.1161/circgen.119.002824, doi:10.1161/circgen.119.002824. This article has 23 citations.
(zhou2019inducedpluripotentstem pages 4-7): Wei Zhou, J. Martijn Bos, Dan Ye, David J. Tester, Sybil Hrstka, Joseph J. Maleszewski, Steve R. Ommen, Rick A. Nishimura, Hartzell V. Schaff, Chang Sung Kim, and Michael J. Ackerman. Induced pluripotent stem cell–derived cardiomyocytes from a patient with myl2-r58q-mediated apical hypertrophic cardiomyopathy show hypertrophy, myofibrillar disarray, and calcium perturbations. Journal of Cardiovascular Translational Research, pages 1-10, Feb 2019. URL: https://doi.org/10.1007/s12265-019-09873-6, doi:10.1007/s12265-019-09873-6. This article has 57 citations and is from a peer-reviewed journal.
(zhou2019inducedpluripotentstem pages 8-9): Wei Zhou, J. Martijn Bos, Dan Ye, David J. Tester, Sybil Hrstka, Joseph J. Maleszewski, Steve R. Ommen, Rick A. Nishimura, Hartzell V. Schaff, Chang Sung Kim, and Michael J. Ackerman. Induced pluripotent stem cell–derived cardiomyocytes from a patient with myl2-r58q-mediated apical hypertrophic cardiomyopathy show hypertrophy, myofibrillar disarray, and calcium perturbations. Journal of Cardiovascular Translational Research, pages 1-10, Feb 2019. URL: https://doi.org/10.1007/s12265-019-09873-6, doi:10.1007/s12265-019-09873-6. This article has 57 citations and is from a peer-reviewed journal.
(yadav2019phosphomimetic‐mediatedinvitro pages 8-10): Sunil Yadav, Katarzyna Kazmierczak, Jingsheng Liang, Yoel H. Sitbon, and Danuta Szczesna‐Cordary. Phosphomimetic‐mediated in vitro rescue of hypertrophic cardiomyopathy linked to r58q mutation in myosin regulatory light chain. The FEBS Journal, 286:151-168, Dec 2019. URL: https://doi.org/10.1111/febs.14702, doi:10.1111/febs.14702. This article has 42 citations.
(sanghvi2025hypertrophiccardiomyopathymanagement pages 14-15): Mihir M Sanghvi, Eamon Dhall, C Anwar A. Chahal, Constantinos O'Mahony, Saidi A Mohiddin, Konstantinos Savvatis, Fabrizio Ricci, Patricia B Munroe, Steffen E Petersen, Nay Aung, and Mohammed Y Khanji. Hypertrophic cardiomyopathy management: a systematic review of the clinical practice guidelines and recommendations. European heart journal. Quality of care & clinical outcomes, Jan 2025. URL: https://doi.org/10.1093/ehjqcco/qcae117, doi:10.1093/ehjqcco/qcae117. This article has 16 citations.
(ramonfaur2024eighteen‐monthreal‐worldexperience pages 12-12): Diego Ramonfaur, Alessio Gasperetti, Victoria E. Blake, Bryana Rivers, Ali A. Kassamali, Edward K. Kasper, Lili A. Barouch, Katherine C. Wu, Jose A. Madrazo, and Richard T. Carrick. Eighteen‐month real‐world experience using mavacamten for treatment of obstructive hypertrophic cardiomyopathy in a racially diverse population. Aug 2024. URL: https://doi.org/10.1161/jaha.123.034069, doi:10.1161/jaha.123.034069. This article has 33 citations.
(hao2026hypertrophiccardiomyopathycomprehensive pages 8-9): Luwen Hao, Xin Chen, and Bo Qin. Hypertrophic cardiomyopathy: comprehensive insights into pathogenic genes and genotype-phenotype associations. Frontiers in Cell and Developmental Biology, Jan 2026. URL: https://doi.org/10.3389/fcell.2026.1741252, doi:10.3389/fcell.2026.1741252. This article has 1 citations.
(dolder2025experimentalmodelsof pages 36-36): Floor W. van den Dolder, Rafeeh Dinani, Vincent A.J. Warnaar, Sofija Vučković, Adriana S. Passadouro, Ali A. Nassar, Azhaar X. Ramsaroep, George B. Burchell, Linda J. Schoonmade, Jolanda van der Velden, and Birgit Goversen. Experimental models of hypertrophic cardiomyopathy. JACC: Basic to Translational Science, 10:511-546, Jan 2025. URL: https://doi.org/10.1016/j.jacbts.2024.10.017, doi:10.1016/j.jacbts.2024.10.017. This article has 12 citations.
(kasiakogias2025exploringthecurrent pages 10-11): Alexandros Kasiakogias, Christos Kaskoutis, Christos-Konstantinos Antoniou, Stavros Georgopoulos, Dimitrios Tsiachris, Petros Arsenos, Alexandrina Kouroutzoglou, Dimitrios Klettas, Charalambos Vlachopoulos, Konstantinos Tsioufis, and Konstantinos Gatzoulis. Exploring the current status of risk stratification in hypertrophic cardiomyopathy: from risk models to promising techniques. Mar 2025. URL: https://doi.org/10.3390/jcdd12030101, doi:10.3390/jcdd12030101. This article has 5 citations.

Artifacts

Edison artifact artifact-00

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	11
Resolved	11
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	11
On topic	6
Off topic	0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	39
Resolved	39
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	0
Terms whose name was checked	6
Terms named correctly	0
Terms named as a different term	4
Terms whose name is worth a second look	2

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

MONDO:0012112 (3 mentions) - the report calls it "if available"; MONDO calls it hypertrophic cardiomyopathy 10
HP:0005110 (1 mention) - the report calls it "D166H family: 62%, approximately three times the rate cited for general HCM. Episodic or persistent"; HP calls it Atrial fibrillation
HP:0001698 (1 mention) - the report calls it "Common in generic HCM but absent in the reported D166H family"; HP calls it Pericardial effusion
GO:0030017 (1 mention) - the report calls it "GO cellular component: sarcomere"; GO calls it sarcomere**

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

GO:0060048 (1 mention) - the report calls it "GO biological process: cardiac muscle contraction"; GO calls it cardiac muscle contraction**
CL:0000746 (1 mention) - the report calls it "Cell Ontology: cardiac muscle cell/cardiomyocyte"; CL calls it cardiac muscle cell**

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Classifications

Inheritance

Subtypes

Discussions and Knowledge Gaps

Pathophysiology

Histopathology

Pathograph

Phenotypes

Genetic Associations

Variants

Medical Actions

Environmental Factors

Diagnosis

Progression

Prevalence

Clinical Trials

Experimental Models

Animal Models

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References

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Hypertrophic Cardiomyopathy 10 (MYL2-related HCM): Research Report

Executive summary and evidence scope

1. Disease information

Definition

Identifiers and terminology

2. Etiology

Causal factors and genetic risk

Environmental and lifestyle modifiers

3. Phenotypes

4. Genetic and molecular information

Gene and protein

Variant interpretation

Modifiers and epigenetics

5. Environmental information

6. Mechanism and pathophysiology

Ordered causal chain

Key experimental findings

Suggested ontology annotations

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population

10. Diagnostics

Clinical workflow

Clinical criteria and differential diagnosis

Genetic testing

11. Outcome and prognosis

12. Treatment

Phenotype-directed algorithm

Current implementation and experimental therapy

13. Prevention

14. Other species and natural disease

15. Model organisms and experimental systems

Available models

Best uses

Knowledge-base conclusions

Artifacts

Reference Validation

Term Validation

Terms the report names something else

Terms whose name is worth a second look