Hypertrophic Cardiomyopathy 14

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Classifications

Harrison's Part

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Inheritance

1

Autosomal dominant HP:0000006

Where a mode of inheritance has been assigned to MYH6-attributed hypertrophic cardiomyopathy it is autosomal dominant transmission of a heterozygous missense allele, which is the mode ClinGen records for the relationship it then classified as Disputed. Segregation evidence is correspondingly thin: the Q1065H proband's two unaffected offspring did not carry the allele, and the elderly-onset series that produced the founding variant was explicitly selected for absent family history.

Autosomal dominant inheritance Penetrance: INCOMPLETE

Show evidence (2 references)

CGGV:assertion_ee5380a4-0dee-49aa-b911-141502648144-2023-07-12T020000.000Z SUPPORT Other

ClinGen records autosomal dominant as the mode of inheritance for the MYH6-HCM relationship, in the same row that classifies that relationship as Disputed.

PMID:15998695 SUPPORT Human Clinical

"A Q1065H mutation was detected in 1 of 21 HCM probands and was absent in 2 unaffected offspring."

The only segregation observation reported for an HCM-attributed MYH6 allele is the absence of Q1065H in two unaffected offspring of the proband.

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Mechanistic Hypotheses

1

Minor-ventricular-isoform sarcomere model of MYH6 hypertrophic cardiomyopathy

myh6_minor_ventricular_isoform_hcm EMERGING

Evidence balance 2 support

The proposed model is that a heterozygous missense allele in alpha-MHC alters the motor function of the minor myosin isoform of the human ventricle, and that this is sufficient to seed the same maladaptive hypertrophic remodeling that beta-MHC (MYH7) alleles produce. The model has never been tested directly. No functional study of any HCM-attributed human MYH6 allele has been published, ClinGen states outright that the disease mechanism is unknown, and the model has to explain why a lesion in the ventricle's minor isoform would produce a ventricular phenotype at all. The observed late-onset skew is consistent with a weak-effect allele requiring decades of accumulated remodeling, but that is a post-hoc reading, not a tested prediction. This hypothesis group is what every pathophysiology edge in this entry belongs to; the entry asserts no established MYH6 mechanism.

Pathograph links

MYH6 Missense Variant in Alpha-Myosin Heavy Chain -> Altered Sarcomere Motor Function DIRECT The proposed proximal consequence, by analogy with MYH7 missense disease. Asserted by analogy, not measured for any MYH6 HCM allele.

Alpha-MHC Is the Minor Myosin Isoform of the Human Ventricle -> Altered Sarcomere Motor Function INDIRECT UNKNOWN INTERMEDIATES This node is the standing tissue context rather than a lesion: it is the second input to any ventricular consequence of an MYH6 allele, and it sets the ceiling on how large that consequence can be. A node with no upstream is correct here — the isoform distribution is constitutive, not caused by the variant.

Altered Sarcomere Motor Function -> Maladaptive Ventricular Remodeling INDIRECT UNKNOWN INTERMEDIATES The remaining chain is the conserved hypertrophic remodeling pathway, which is well established for sarcomeric HCM generally. What is unestablished is that an MYH6 allele enters it.

Show evidence (2 references)

CGGV:assertion_ee5380a4-0dee-49aa-b911-141502648144-2023-07-12T020000.000Z SUPPORT Other

"The mechanism for disease remains unknown."

ClinGen's expert-panel judgement that no disease mechanism is established is the reason this is curated as a hypothesis rather than as pathophysiology.

PMID:6234108 SUPPORT Human Clinical

"myosin heavy chain alpha was found to be a major component of atrial myosin and a minor component of ventricular myosin"

Establishes the expression constraint the model must overcome: alpha-MHC is the minor ventricular isoform in the human heart.

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Discussions and Knowledge Gaps

4

Does any HCM-attributed human MYH6 missense allele alter alpha-myosin motor function, and if so is the effect large enough to matter in a ventricle where alpha-MHC is the minor isoform?

KNOWLEDGE GAP myh6_hcm_allele_functional_effect_unknown

Attached to

pathophysiology#Altered Sarcomere Motor Function mechanistic_hypotheses#myh6_minor_ventricular_isoform_hcm

This is the gap that keeps the gene-disease relationship Disputed rather than Limited or Moderate. ClinGen states that the mechanism for disease remains unknown, and the reason is that no functional characterisation of any HCM-attributed MYH6 allele has been published — the supporting functional literature it could find was about alpha-MHC's normal biochemistry, not about any patient allele. Because alpha-MHC is a minor ventricular isoform, a demonstrated functional effect would also need a dosage argument to explain a ventricular phenotype, so an assay showing a change is necessary but not sufficient. A patient-derived iPSC line carrying an MYH6 HCM allele already exists and has never been phenotyped as cardiomyocytes, which makes this an unusually tractable gap.

Proposed experiments

Cardiomyocyte phenotyping of the MYH6 G3755A patient iPSC line

exp_myh6_ipsc_cardiomyocyte_phenotyping

Differentiate the existing patient-derived iPSC line and an isogenic variant-corrected control to ventricular cardiomyocytes and compare contractile and sarcomeric readouts. An isogenic control is essential: the line is from a single patient, so any uncorrected comparison confounds the allele with genetic background.

Perturbations

Isogenic correction of the MYH6 G3755A allele

pathophysiology#MYH6 Missense Variant in Alpha-Myosin Heavy Chain

CRISPR correction of the patient allele to wild type in the derived iPSC line, giving an isogenic control that differs only at the variant site.

MYH6 hgnc:7576

Effect: DECREASED

Readouts

Sarcomere organisation in differentiated cardiomyocytes

pathophysiology#Altered Sarcomere Motor Function

Interpretation: Disorganisation in the variant line relative to its isogenic control would be the first functional evidence for any HCM-attributed MYH6 allele.

Would support

pathophysiology#Altered Sarcomere Motor Function

Would refute

pathophysiology#Altered Sarcomere Motor Function

Supporting outcome

Variant cardiomyocytes show altered contractile kinetics or sarcomere disorganisation relative to the isogenic control, with the effect abolished by correction of the allele.

Refuting outcome

Variant and isogenic-corrected cardiomyocytes are indistinguishable across contractile and sarcomeric readouts, indicating the allele has no measurable effect in a human ventricular-like cell.

Show evidence (3 references)

CGGV:assertion_ee5380a4-0dee-49aa-b911-141502648144-2023-07-12T020000.000Z SUPPORT Other

"The mechanism for disease remains unknown."

The expert-panel statement that defines this gap.

CGGV:assertion_ee5380a4-0dee-49aa-b911-141502648144-2023-07-12T020000.000Z SUPPORT Other

"The gene-disease association is supported by expression studies in the human heart"

Shows what the supporting functional literature actually consists of — normal-biology expression and biochemistry studies, not characterisation of any patient allele, which is precisely the gap.

PMID:33385793 SUPPORT In Vitro

"The generated iPSC line expressed pluripotency markers, exhibited a normal karyotype, presented the specific mutation, and demonstrated differentiation potential into three germ layers in vitro."

Establishes that a characterised patient-derived line carrying an MYH6 HCM allele already exists and is differentiation-competent, which is what makes this gap tractable.

The reference mouse models of hypertrophic cardiomyopathy carry their mutations in Myh6. Does that make them models of human MYH6 disease?

HUMAN MODEL MISMATCH myh6_mouse_myh6_r403q_is_myh7_disease

Attached to

pathophysiology#MYH6 Missense Variant in Alpha-Myosin Heavy Chain animal_models#alpha-MHC 403/+ mouse (Myh6 R403Q knock-in)

No, and the mismatch is a species-level isoform switch that is easy to miss because the gene symbol matches. The human ventricle runs predominantly on beta-MHC (MYH7) with alpha-MHC as a minor component; the mouse ventricle runs on alpha-MHC. To model a human MYH7 ventricular allele faithfully in a mouse, the field therefore put the human MYH7-derived R403Q substitution into mouse Myh6 — preserving the ventricular context by changing the gene. The resulting alpha-MHC 403/+ mouse and its descendants, including allele-specific silencing work targeting mutant Myh6 transcripts, form a large and influential literature indexed under Myh6 and hypertrophic cardiomyopathy that is substantively about MYH7 biology. This matters concretely for curation. A text- or database-driven search for MYH6 model evidence returns these mice first, and they look like strong support: the phenotype is convincing, the gene symbol is right, and the disease term is right. ClinGen reviewed them and declined to score them for exactly this reason. Any future strengthening of the MYH6-HCM relationship has to come from human alleles or from a model built on a human MYH6 allele, not from this body of work.

Show evidence (2 references)

CGGV:assertion_ee5380a4-0dee-49aa-b911-141502648144-2023-07-12T020000.000Z SUPPORT Other

"these mice models are not analogous to human MYH6"

ClinGen's explicit statement of the mismatch, and its stated ground for excluding the mouse literature from the MYH6 gene-disease evaluation.

PMID:6234108 SUPPORT Human Clinical

"heavy chain beta was found to be a major component of ventricular myosin and a minor component of atrial myosin"

Establishes the human side of the species isoform difference that creates the mismatch.

Is the late-onset skew of MYH6-attributed hypertrophic cardiomyopathy a property of the allele, or an artefact of how elderly-onset HCM cohorts are ascertained?

KNOWLEDGE GAP myh6_late_onset_skew_allele_or_ascertainment

Attached to

phenotypes#Late-Onset Presentation

The late-onset association is the most reproducible observation about this entity — it appears in the founding elderly-onset series and independently in a later cohort designed to contrast extreme ages at diagnosis. But the same cohorts show that elderly-onset HCM has a far lower genetic yield overall (23% versus 86% in the early-onset arm of the Italian series), which is the signature of a group enriched for phenocopies and for variants of small or absent effect. A weak-effect allele producing genuinely late disease and a benign variant surfacing in a low-yield cohort predict the same observation. Distinguishing them requires case-control allele-frequency comparison in age-stratified cohorts rather than more case series, and the answer bears directly on whether the Disputed classification should move in either direction. The nearest existing approach to that comparison is the ExAC-referenced burden analysis of 7,855 cardiomyopathy cases, which found MYH6 rare variation indistinguishable from background. It does not settle the question here, for a reason worth stating so it is not misread later: MYH6 appears only in that study's dilated cardiomyopathy panel and not in its hypertrophic panel, and the analysis was not age-stratified. So it constrains the gene's general credibility rather than answering the age question, which remains open.

Show evidence (1 reference)

PMID:27483260 SUPPORT Human Clinical

"The mutation detection rate was 85.7% (30/35) in the EO group and 22.9% (8/35) in the LO group."

Quantifies the low genetic yield of the late-onset arm in which MYH6 variants were exclusively found, which is the basis for the ascertainment alternative.

How much of the reported MYH6 hypertrophic cardiomyopathy signal survives once probands carrying a variant in an established HCM gene are excluded?

KNOWLEDGE GAP myh6_cooccurring_established_gene_variants

Attached to

pathophysiology#MYH6 Missense Variant in Alpha-Myosin Heavy Chain phenotypes#Sudden Cardiac Death

Co-occurrence is the dominant confounder in this literature rather than an occasional complication. ClinGen excluded reported MYH6 variants from scoring on the grounds that the proband also carried a variant in another HCM gene, in three separate publications — a Japanese family with a MYH6 frameshift alongside an MYH7 missense variant, a multi-omics pedigree study in which the MYH6 carrier also carried a TNNT2 variant, and part of the Italian NGS series. In each case the severe phenotype is at least as attributable to the established gene. What remains after those exclusions is three probands, and that residue is the whole quantitative basis of the entity.

Show evidence (2 references)

CGGV:assertion_ee5380a4-0dee-49aa-b911-141502648144-2023-07-12T020000.000Z SUPPORT Other

"but were not scored because probands have variants in another HCM gene"

States the exclusion criterion and, with the accompanying citation list, its scope across the reported literature.

PMID:34087240 SUPPORT INDIRECT Human Clinical

"The proband of Family 1 and his father carried TNNT2-rs397516484 and MYH6-rs372446459 missense mutations"

A worked instance of the confound: the MYH6 carriers in this pedigree also carry a TNNT2 variant, so the phenotype cannot be attributed to MYH6.

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Pathophysiology

5

MYH6 Missense Variant in Alpha-Myosin Heavy Chain

The proposed initiating lesion in CMH14 is a heterozygous missense variant in MYH6, encoding the alpha-cardiac myosin heavy chain. Four unique missense alleles have been reported in HCM probands with limited pathogenicity evidence. The reported alleles fall in conserved residues and are predicted to change the structure or chemical bonding of the protein, but no functional assay of any HCM-attributed MYH6 allele has been reported, and this node is therefore an attributed lesion rather than a demonstrated one.

Minor-ventricular-isoform sarcomere model of MYH6 hypertrophic cardiomyopathy

ventricular cardiomyocyte CL:0002131

MYH6 hgnc:7576

alpha-myosin heavy chain actin-based motor activity GO:0000146 ⚠ ABNORMAL

myocardium UBERON:0002349

Experimental models

MYH6 c.G3755A patient-derived iPSC line IPSC DERIVED MODEL The line carries the patient's own heterozygous MYH6 allele in a human genetic background, so it reproduces the initiating lesion of this entry exactly.

Animal models

alpha-MHC 403/+ mouse (Myh6 R403Q knock-in) Mouse fails to recapitulate The model does not represent the initiating lesion of this entry. It carries an MYH7-derived allele in the mouse ventricular myosin isoform, which is a different molecular claim from a human MYH6 missense allele in the human ventricle's minor isoform.

Downstream

Altered Sarcomere Motor Function The proposed proximal consequence, by analogy with MYH7 missense disease. Asserted by analogy, not measured for any MYH6 HCM allele.

Show evidence (3 references)

CGGV:assertion_ee5380a4-0dee-49aa-b911-141502648144-2023-07-12T020000.000Z SUPPORT Other

"Four unique heterozygous missense variants have been reported in humans with limited evidence to support their pathogenicity"

Establishes the class of lesion attributed to this entity, and simultaneously that the pathogenicity evidence for each is limited.

PMID:15998695 SUPPORT Human Clinical

"All MYH6 mutations were distributed in highly conserved residues, were predicted to change the structure or chemical bonds of alphaMyHC"

Supports the in-silico rationale offered for the reported alleles. The prediction is computational; no functional assay followed.

CGGV:assertion_ee5380a4-0dee-49aa-b911-141502648144-2023-07-12T020000.000Z REFUTE Other

"It has been associated with HCM in 3 probands in 2 publications."

Cited against the strength of this node, not for it. Three probands across two publications is the entire human genetic basis for attributing a hypertrophic phenotype to this gene.

Alpha-MHC Is the Minor Myosin Isoform of the Human Ventricle

In the human heart alpha-MHC is the dominant myosin of the atrium and only a minor component of ventricular myosin, while beta-MHC (MYH7) is the dominant ventricular isoform. This isoform distribution is the central difficulty for any MYH6 model of a ventricular hypertrophic phenotype, and it is also why the murine literature does not transfer: the mouse ventricle runs on alpha-MHC. The same study shows the distribution is not fixed — chronically overloaded human atria shift substantially toward beta-MHC, whereas hypertrophied ventricles change only slightly.

Minor-ventricular-isoform sarcomere model of MYH6 hypertrophic cardiomyopathy

ventricular cardiomyocyte CL:0002131 atrial cardiomyocyte CL:0002129

alpha-myosin heavy chain actin-based motor activity GO:0000146

heart left ventricle UBERON:0002084 left cardiac atrium UBERON:0002079

Downstream

Altered Sarcomere Motor Function This node is the standing tissue context rather than a lesion: it is the second input to any ventricular consequence of an MYH6 allele, and it sets the ceiling on how large that consequence can be. A node with no upstream is correct here — the isoform distribution is constitutive, not caused by the variant.

Show evidence (3 references)

PMID:6234108 SUPPORT Human Clinical

"myosin heavy chain alpha was found to be a major component of atrial myosin and a minor component of ventricular myosin, while heavy chain beta was found to be a major component of ventricular myosin and a minor component of atrial myosin"

Direct immunofluorescence measurement of the isoform distribution in human atrial and ventricular myocardium.

PMID:6234108 SUPPORT Human Clinical

"chronic exposure to hemodynamic overload can induce marked changes in the myosin heavy chain composition of human atria, whereas it affects only slightly that of the ventricles"

Shows the isoform distribution is load-responsive in the atrium but largely fixed in the ventricle, so ventricular hypertrophy does not recruit alpha-MHC into a larger role.

PMID:10388558 SUPPORT In Vitro

"functional diversity among MyHCs is likely to be accomplished by having small pockets of sequence diversity in an otherwise highly conserved molecule"

Explains why alpha- and beta-MHC are hard to separate functionally by sequence alone, which is part of why an MYH6 missense allele is difficult to interpret against the well-characterised MYH7 alleles.

Altered Sarcomere Motor Function

The hypothesised proximal consequence of an HCM-attributed MYH6 allele is a change in the actin-based motor behaviour of the affected myosin molecules within the ventricular sarcomere, by analogy with the well-characterised MYH7 missense alleles. This node carries no direct evidence for any human HCM-attributed MYH6 variant: no functional characterisation of such an allele has been published, which is one of the stated grounds for ClinGen's Disputed classification. It is retained as an explicit hypothesis node rather than dropped, so that the gap is visible and addressable.

Minor-ventricular-isoform sarcomere model of MYH6 hypertrophic cardiomyopathy

ventricular cardiomyocyte CL:0002131

cardiac muscle contraction GO:0060048 ⚠ ABNORMAL

alpha-myosin heavy chain actin-based motor activity GO:0000146 ⚠ ABNORMAL ATP hydrolysis activity GO:0016887 ⚠ ABNORMAL actin filament binding GO:0051015 ⚠ ABNORMAL

Downstream

Maladaptive Ventricular Remodeling The remaining chain is the conserved hypertrophic remodeling pathway, which is well established for sarcomeric HCM generally. What is unestablished is that an MYH6 allele enters it.

Show evidence (1 reference)

CGGV:assertion_ee5380a4-0dee-49aa-b911-141502648144-2023-07-12T020000.000Z NO_EVIDENCE Other

"The mechanism for disease remains unknown."

Recorded as NO_EVIDENCE rather than SUPPORT: ClinGen's review of the whole literature found nothing establishing a mechanism for this node. The node is an explicit hypothesis, and this is the citation that says so.

Maladaptive Ventricular Remodeling

Downstream of a sarcomeric insult the myocardium undergoes the conserved maladaptive remodeling programme of hypertrophic cardiomyopathy: cardiomyocyte hypertrophy, myocyte disarray, and interstitial fibrosis producing asymmetric wall thickening in a non-dilated ventricle. This chain is well established for sarcomeric HCM as a class and is imported here from the cardiomyopathy_maladaptive_remodeling module; the MYH6-specific claim is only that a MYH6 allele is what initiates it, which is the disputed step upstream.

ventricular cardiomyocyte CL:0002131 cardiac fibroblast CL:0002548

cardiac muscle hypertrophy in response to stress GO:0014898 ↑ INCREASED sarcomere organization GO:0045214 ↓ DECREASED

heart left ventricle UBERON:0002084 interventricular septum UBERON:0002094

Animal models

alpha-MHC 403/+ mouse (Myh6 R403Q knock-in) Mouse recapitulates For the conserved sarcomeric-HCM remodeling programme — disarray, hypertrophy, fibrosis, age-dependent progression — this model is faithful to human disease, which is why it became the reference HCM model.

Downstream

Left Ventricular Hypertrophy The remodeling programme is what produces the measurable wall thickening that defines the clinical entity.

Hypertrophic Cardiomyopathy Wall thickening in a non-dilated ventricle without another cause is the clinical diagnosis itself.

Progressive Contractile Dysfunction and Progression to Dilation

Show evidence (1 reference)

PMID:8614836 SUPPORT INDIRECT Model Organism

"myocyte disarray, hypertrophy, and fibrosis increased with age"

Establishes the histological content of the remodeling node in a sarcomeric HCM model. Graded INDIRECT deliberately: this mouse carries an MYH7-derived R403Q allele knocked into mouse Myh6, so it evidences the conserved remodeling programme but not the MYH6 attribution. See the HUMAN_MODEL_MISMATCH discussion.

Progressive Contractile Dysfunction and Progression to Dilation

In the single cohort that followed MYH6-attributed HCM carriers clinically, the reported course was not stable hypertrophy but progression toward chamber dilation, left ventricular dysfunction and refractory heart failure — the "burnt-out" end of the HCM spectrum. This is also the observation the same authors used to argue that MYH6 alleles produce a phenotypic continuum from hypertrophic to dilated cardiomyopathy, which is consistent with MYH6 being separately, if weakly, associated with dilated cardiomyopathy.

heart contraction GO:0060047 ↓ DECREASED relaxation of cardiac muscle GO:0055119 ↓ DECREASED

heart left ventricle UBERON:0002084

Downstream

Progression to Ventricular Dilation The observable chamber change produced by this mechanism node.

Congestive Heart Failure Refractory heart failure is the reported endpoint of the course.

Show evidence (2 references)

PMID:15998695 SUPPORT Human Clinical

"the HCM phenotype was characterized by progression toward dilation, left ventricular dysfunction, and refractory heart failure"

The only reported clinical course for an MYH6-attributed HCM carrier lineage.

PMID:15998695 SUPPORT Human Clinical

"This study suggests that mutations in MYH6 may cause a spectrum of phenotypes ranging from DCM to HCM."

States the phenotypic-continuum reading that this node encodes, and is the origin of the overlap between this entry and the MYH6 dilated cardiomyopathy entities.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

8

Cardiovascular 7

Left Ventricular Hypertrophy VERY_FREQUENT HP:0001712

Onset: LATE; mean 62.8y

Sequelae: Left Ventricular Outflow Tract Obstruction Left Ventricular Diastolic Dysfunction

Show evidence (1 reference)

PMID:11815426 SUPPORT Human Clinical

"Echocardiography demonstrated maximal left ventricular wall thickness of 19.9+/-3.8 mm"

Quantifies the hypertrophy in the cohort from which the founding MYH6 HCM variant was reported.

Hypertrophic Cardiomyopathy VERY_FREQUENT HP:0001639

Show evidence (1 reference)

PMID:27483260 SUPPORT Human Clinical

"The clinical diagnosis of HCM was based on the echocardiographic demonstration of a hypertrophied and not dilated left ventricle"

States the ascertainment criterion applied to the cohort in which MYH6 variants were found exclusively in the late-onset arm.

Left Ventricular Outflow Tract Obstruction FREQUENT HP:0032092

Show evidence (1 reference)

PMID:11815426 SUPPORT Human Clinical

"systolic anterior motion of the mitral valve (58%), and, in 11 individuals, left ventricular outflow tract gradients"

Reports systolic anterior motion and measurable outflow gradients in the cohort. This is the general elderly-HCM phenotype, not a MYH6-attributed one.

Congestive Heart Failure HP:0001635

Show evidence (1 reference)

PMID:15998695 SUPPORT Human Clinical

"progression toward dilation, left ventricular dysfunction, and refractory heart failure"

Refractory heart failure is the reported endpoint of the MYH6-attributed HCM course.

Sudden Cardiac Death HP:0001645

Deliberately left with no incoming pathograph edge. Sudden death in HCM arises from an arrhythmic substrate of myocyte disarray and fibrosis, but no such node is curated in this entry because no MYH6-specific evidence supports one, and the single reported death comes from a family carrying an MYH7 variant as well. Drawing an edge from the remodeling node would assert a mechanism for this entity that its literature does not contain.

Show evidence (1 reference)

PMID:35911064 SUPPORT INDIRECT Human Clinical

"Family members with the double variants demonstrated severe phenotypes, such as sudden cardiac-related death and heart failure."

Graded INDIRECT because the phenotype is attributed to the double MYH6/MYH7 genotype, so it does not establish sudden death as a consequence of the MYH6 allele alone.

Left Ventricular Diastolic Dysfunction HP:0025168

Show evidence (1 reference)

PMID:34087240 SUPPORT INDIRECT Human Clinical

"They presented with heart failure and abnormal electrocardiogram, accompanied by diastolic and systolic dysfunction and impaired myocardial work."

Reports diastolic and systolic dysfunction in the pedigrees carrying the MYH6 variant. INDIRECT because those carriers also carry a TNNT2 variant, so the finding cannot be attributed to MYH6 alone.

Progression to Ventricular Dilation Dilated cardiomyopathy HP:0001644

Sequelae: Congestive Heart Failure

Show evidence (1 reference)

PMID:15998695 SUPPORT Human Clinical

"the HCM phenotype was characterized by progression toward dilation, left ventricular dysfunction, and refractory heart failure"

Reports dilation as the observed course in the MYH6-attributed HCM carriers.

Other 1

Late-Onset Presentation VERY_FREQUENT

Deliberately carries no phenotype_term. The observation is an age-of-onset statement, and HPO encodes onset under HP:0003674 rather than as a phenotypic abnormality, so no term in the PhenotypeTerm enum names it. The structured onset data is recorded instead on the Left Ventricular Hypertrophy phenotype_term as an OnsetDescriptor (LATE, mean 62.8 years). This node is retained because the late-onset skew is the most reproducible observation about the entity and is the anchor for a knowledge gap.

Show evidence (3 references)

PMID:11815426 SUPPORT Human Clinical

"Initial symptoms occurred at 59.3 (+/-12.3) years, and diagnosis was made at 62.8 (+/-10.8) years."

Gives the age at onset and diagnosis in the elderly-onset cohort that yielded the founding alpha-MHC variant.

PMID:27483260 SUPPORT Human Clinical

"In fact, mutations in MYH6 were identified in the LO group only, whereas mutations in TNNT2 were identified in the EO group only."

Independent replication of the late-onset skew in a second cohort designed to contrast the extremes of age at diagnosis.

PMID:11815426 SUPPORT Human Clinical

"The distribution of mutations in elderly-onset disease is strikingly different (P<0.00001) from that of familial, early onset hypertrophic cardiomyopathy."

Establishes that the gene distribution behind elderly-onset HCM, which is where MYH6 appears, differs significantly from that of classic familial HCM.

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Genetic Associations

1

MYH6

Gene: MYH6 hgnc:7576 relationship_type: DISPUTED

Show evidence (7 references)

CGGV:assertion_ee5380a4-0dee-49aa-b911-141502648144-2023-07-12T020000.000Z SUPPORT Other

"MYH6 gene encodes alpha heavy chain subunit of cardiac myosin (MHC-α), which are actin-based molecular motors that convert chemical energy released from the hydrolysis of ATP."

ClinGen's statement of the gene product and its molecular function.

PMID:11815426 SUPPORT Human Clinical

"Rather, mutations in cardiac myosin binding protein-C, troponin I, and alpha-cardiac myosin heavy chain caused elderly-onset hypertrophic cardiomyopathy."

The founding claim that alpha-cardiac myosin heavy chain variants underlie elderly-onset HCM, which is the origin of the CMH14 entity.

PMID:27532257 REFUTE INDIRECT Human Clinical

"MYH6 121 60328 0.00143 1.06 (0.34-3.34) 0.06 (0.00-0.70)"

Case-excess burden testing against 60,706 ExAC reference samples puts MYH6 rare variation at essentially background level, with an odds ratio of 1.06 whose confidence interval spans 1 and an etiological fraction of 0.06. Scope note, because it is easy to overstate: this row sits in the paper's *dilated* cardiomyopathy panel, and MYH6 does not appear in its hypertrophic cardiomyopathy panel at all. It is therefore graded INDIRECT — it shows that MYH6 rare variation is not distinguishable from background in a large cardiomyopathy case series, which undermines the gene's general credibility as a cardiomyopathy gene without being a direct measurement of HCM burden.

+ 4 more references

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Medical Actions

6

Negative Inotropic Pharmacotherapy

Action: Pharmacotherapy NCIT:C15986

Agent: beta-adrenergic antagonist NCIT:C29576 calcium channel blocker NCIT:C333 disopyramide NCIT:C61730

Platform: Small molecule

First-line symptomatic therapy for obstructive HCM: a beta-blocker, with a non-dihydropyridine calcium channel blocker or disopyramide added or substituted when symptoms persist. Management in this entity is the management of hypertrophic cardiomyopathy — guideline algorithms branch on obstructive versus non-obstructive physiology and on sudden-death risk, not on genotype, and no MYH6-directed therapy exists or is in development.

Show evidence (1 reference)

PMID:38718139 SUPPORT Other

"provides recommendations to guide clinicians in the management of patients with hypertrophic cardiomyopathy"

Establishes the current AHA/ACC guideline as the source of management recommendations for HCM, which is how this entity is managed. Cited for the guideline's scope rather than for an individual drug recommendation, because the cached record is the structured abstract rather than the recommendation tables.

Cardiac Myosin Inhibition

Action: Pharmacotherapy NCIT:C15986

Agent: mavacamten CHEBI:756998 aficamten CHEBI:747213

Platform: Small molecule

Mavacamten and aficamten are allosteric cardiac myosin inhibitors that reduce actin-myosin cross-bridge formation and relieve dynamic outflow obstruction, each with a positive phase III trial in symptomatic obstructive HCM. Worth stating plainly for this entity: these drugs act on beta-cardiac myosin, the MYH7 product that dominates the human ventricle. They are not targeted at the alpha-myosin this entry is named for. That is not a reason to withhold them from a patient with obstructive HCM — the indication is physiological, not genotypic — but it does mean the one mechanistically targeted therapy in HCM targets the other myosin, which is the same isoform asymmetry that makes the MYH6 attribution doubtful in the first place.

Mechanism Target:

Alpha-MHC Is the Minor Myosin Isoform of the Human Ventricle — Linked to the isoform node rather than to the MYH6 lesion, because that is where the drugs actually act: they inhibit the beta-MHC that constitutes the bulk of ventricular myosin. The link records a mechanistic mismatch between the entity's named gene and its most specific available therapy.

Show evidence (1 reference)

PMID:32871100 SUPPORT Human Clinical

"mavacamten, a first-in-class cardiac myosin inhibitor"

Identifies the drug class as a direct cardiac myosin inhibitor, which is what makes the isoform it inhibits the relevant mechanistic detail.

Show evidence (1 reference)

PMID:32871100 SUPPORT Human Clinical

"We aimed to assess the efficacy and safety of mavacamten, a first-in-class cardiac myosin inhibitor, in symptomatic obstructive hypertrophic cardiomyopathy."

Establishes mavacamten's indication and mechanism in obstructive HCM.

Septal Reduction Therapy

Action: septal myectomy Ontology label: Myectomy NCIT:C51591

Platform: Surgery

Surgical septal myectomy, or alcohol septal ablation where surgery is unsuitable, for drug-refractory obstruction. Anatomical rather than genotype-directed.

Show evidence (1 reference)

PMID:38718139 SUPPORT Other

"provides recommendations to guide clinicians in the management of patients with hypertrophic cardiomyopathy"

Septal reduction for drug-refractory obstruction is a guideline recommendation for HCM generally; it is not genotype-directed.

Implantable Cardioverter-Defibrillator

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

Platform: Device

Primary-prevention ICD for patients meeting HCM sudden-death risk criteria. Risk stratification in HCM is clinical and imaging-based; a MYH6 variant carries no established risk weight and should not be used to modify it.

Show evidence (1 reference)

PMID:38718139 SUPPORT Other

"provides recommendations to guide clinicians in the management of patients with hypertrophic cardiomyopathy"

ICD placement follows the guideline's HCM sudden-death risk assessment, which uses clinical and imaging variables and assigns no weight to a MYH6 variant.

Heart Transplantation

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

Platform: Surgery

Reserved for end-stage disease. Relevant to this entity specifically because the one reported MYH6-attributed HCM lineage progressed to dilation and refractory heart failure rather than remaining stably hypertrophic.

Mechanism Target:

Progressive Contractile Dysfunction and Progression to Dilation — Addresses the terminal node of this entry's causal chain.

Show evidence (1 reference)

PMID:15998695 SUPPORT Human Clinical

"the HCM phenotype was characterized by progression toward dilation, left ventricular dysfunction, and refractory heart failure"

Establishes that this entity's reported course reaches the refractory heart failure state that transplantation addresses.

Show evidence (1 reference)

PMID:38718139 SUPPORT Other

"provides recommendations to guide clinicians in the management of patients with hypertrophic cardiomyopathy"

Transplantation for end-stage HCM is a guideline-recognised pathway.

Genetic Counseling and Family Screening

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

Platform: Behavioral / lifestyle

Counselling here is unusual in content, because the honest message is a negative one: a MYH6 variant found on an HCM panel is not a molecular diagnosis, cannot be used to include or exclude relatives, and does not replace clinical and imaging surveillance of first-degree relatives, which proceeds on the phenotype alone.

Show evidence (1 reference)

PMID:39971408 SUPPORT Other

"Nine (29%) genes were downgraded to disputed, further discouraging clinical reporting of variants in these genes."

Underpins the counselling message that a disputed-gene variant should not drive family testing decisions.

🔬

Diagnosis

1

Targeted hypertrophic cardiomyopathy gene panel

Molecular diagnosis in HCM uses a targeted gene panel on the proband. The consequence of the ClinGen reappraisal for this entity is negative rather than positive: because MYH6 is classified Disputed for HCM, a MYH6 variant returned by a panel that still carries the gene should not be reported as causative and should not be used for cascade testing in relatives. There is consequently no molecular test that establishes CMH14 in a proband — which is a statement about the entity, not about the patient, whose hypertrophy is real and is investigated and managed as hypertrophic cardiomyopathy either way.

The same conclusion was reached empirically, and years before the ClinGen reappraisal, by the Italian NGS cohort study, which argued from its own yield data for a narrow rather than a broad HCM panel.

Show evidence (2 references)

PMID:39971408 SUPPORT Other

"Nine (29%) genes were downgraded to disputed, further discouraging clinical reporting of variants in these genes."

States the reporting consequence of a disputed classification, which is what this diagnostic entry records for MYH6.

PMID:27483260 SUPPORT Human Clinical

"Our findings support the choice of a limited, well-selected panel of HCM genes as the best tool for diagnostic purposes."

Independent, pre-ClinGen support for a narrow HCM panel, reached from the same cohort in which MYH6 variants appeared only in the low-yield late-onset arm.

📊

Prevalence

1

Worldwide

Unknown Not yet documented

No population prevalence exists for the MYH6-attributed form of hypertrophic cardiomyopathy, and none can responsibly be derived while the gene-disease relationship is Disputed. The only quantitative anchors are yields within referral HCM cohorts: MYH6 accounted for 3 of 41 clinically selected variants (7.5%) in a 70-patient Italian NGS series, and a MYH6 allele was found in 1 of 21 HCM probands in an earlier candidate-gene screen. ClinGen judged the variant behind that second figure to be common in the population, so even these cohort yields overstate the disease-attributable fraction.

Show evidence (2 references)

PMID:27483260 SUPPORT Human Clinical

"TNNT2, CAV3 and MYH6 (3/41 = 7.5% each)"

Gives the MYH6 share of clinically selected variants in a 70-patient referral HCM cohort. A cohort variant share is not a population prevalence.

CGGV:assertion_ee5380a4-0dee-49aa-b911-141502648144-2023-07-12T020000.000Z SUPPORT Other

"or high frequency in the population (Carniel et al. 2005, PMID 15998695)"

ClinGen's reason for excluding the Carniel variants from scoring is why no prevalence band is asserted from that cohort's yield.

🔬

Clinical Trials

2

NCT03470545 PHASE_III COMPLETED

EXPLORER-HCM. Mavacamten versus placebo over 30 weeks in symptomatic obstructive HCM with an LVOT gradient of at least 50 mm Hg and NYHA class II-III symptoms. Enrolled on physiology, not genotype; no MYH6 stratum.

Target Phenotypes: Left ventricular outflow tract obstruction HP:0032092

Show evidence (1 reference)

PMID:32871100 SUPPORT Human Clinical

"patients with hypertrophic cardiomyopathy with an LVOT gradient of 50 mm Hg or greater and New York Heart Association (NYHA) class II-III symptoms were assigned (1:1) to receive mavacamten (starting at 5 mg) or placebo for 30 weeks"

States the trial's design, population and randomisation.

NCT05186818 PHASE_III COMPLETED

SEQUOIA-HCM. Aficamten versus placebo in symptomatic obstructive HCM. As with EXPLORER-HCM, enrolment is on obstructive physiology rather than genotype.

Target Phenotypes: Left ventricular outflow tract obstruction HP:0032092

Show evidence (1 reference)

PMID:38739079 SUPPORT Human Clinical

"In this phase 3, double-blind trial, we randomly assigned adults with symptomatic obstructive HCM to receive aficamten (starting dose, 5 mg; maximum dose, 20 mg) or placebo for 24 weeks"

States the trial's phase, design, population and intervention.

🧫

Experimental Models

1

MYH6 c.G3755A patient-derived iPSC line IPSC_DERIVED_MODEL

An induced pluripotent stem cell line derived from peripheral blood mononuclear cells of a 41-year-old man with hypertrophic cardiomyopathy carrying a heterozygous MYH6 G3755A variant. This is a resource report: the line was characterised for pluripotency, karyotype and the presence of the variant, but no cardiomyocyte phenotype was assayed, so it does not yet constitute functional evidence for the allele. It is the closest thing to a human model system that exists for this entity, and testing it is the experiment ClinGen's Disputed classification is waiting on.

Organism

human NCBITaxon:9606

Pathograph links

MYH6 Missense Variant in Alpha-Myosin Heavy Chain perturbs fidelity: unknown The line carries the patient's own heterozygous MYH6 allele in a human genetic background, so it reproduces the initiating lesion of this entry exactly.

Limitations: No differentiated-cardiomyocyte phenotype has been reported for this line — no contractility, sarcomere-organisation, or calcium-handling readout. It therefore establishes the lesion is modellable, not that it is pathogenic. Fidelity is UNKNOWN rather than HIGH for that reason.

Show evidence (1 reference)

PMID:33385793 SUPPORT In Vitro

"An induced pluripotent stem cell (iPSC) line was generated from peripheral blood mononuclear cells (PBMCs) of a 41-year-old male patient with hypertrophic cardiomyopathy who carries a G3755A heterozygote mutation in the MYH6 gene."

Establishes the existence and genotype of the line, and that it derives from an HCM patient carrying the MYH6 allele.

Show evidence (1 reference)

PMID:33385793 SUPPORT In Vitro

"The generated iPSC line expressed pluripotency markers, exhibited a normal karyotype, presented the specific mutation, and demonstrated differentiation potential into three germ layers in vitro."

Characterises the line itself — pluripotency, karyotype, presence of the MYH6 variant, and trilineage differentiation capacity — which is what qualifies it as a usable model system for this entity.

🐁

Animal Models

1

alpha-MHC 403/+ mouse (Myh6 R403Q knock-in)

The founding mouse model of familial hypertrophic cardiomyopathy, made by knocking an Arg403Gln substitution into the mouse alpha-cardiac myosin heavy chain gene. Heterozygotes develop myocyte disarray, hypertrophy and fibrosis that increase with age and closely resemble human familial HCM. This model is listed here for an unusual reason: to record that it is *not* evidence for this entry. The R403Q allele it carries is a human MYH7 allele. It was placed in mouse Myh6 because the mouse ventricle expresses alpha-MHC where the human ventricle expresses beta-MHC — a species substitution intended to model human MYH7 disease faithfully, not to model human MYH6 disease at all. ClinGen reviewed these mice and explicitly declined to score them as MYH6 evidence. Because a naive text search for "Myh6" plus "hypertrophic cardiomyopathy" retrieves this large and influential literature first, leaving it unrecorded would invite exactly the misattribution it represents.

Species

Mouse

Genotype

Myh6 R403Q heterozygous knock-in

Publication

PMID:8614836

Pathograph links

Maladaptive Ventricular Remodeling recapitulates fidelity: high For the conserved sarcomeric-HCM remodeling programme — disarray, hypertrophy, fibrosis, age-dependent progression — this model is faithful to human disease, which is why it became the reference HCM model.

Limitations: Faithful to sarcomeric HCM in general, not to MYH6 attribution in particular. The allele is MYH7-derived and the gene is the mouse's orthologous ventricular isoform, so the model speaks to the downstream remodeling node only.

Show evidence (1 reference)

PMID:8614836 SUPPORT Model Organism

"Cardiac histopathology and dysfunction in the alpha MHC 403/+ mice resembled human FHC."

Establishes that the model reproduces the histopathology and dysfunction of human familial HCM.

MYH6 Missense Variant in Alpha-Myosin Heavy Chain fails to recapitulate fidelity: low The model does not represent the initiating lesion of this entry. It carries an MYH7-derived allele in the mouse ventricular myosin isoform, which is a different molecular claim from a human MYH6 missense allele in the human ventricle's minor isoform.

Limitations: The species substitution that makes this model good for human MYH7 disease is exactly what makes it inapplicable to human MYH6: mouse ventricular myosin is alpha-MHC, human ventricular myosin is beta-MHC, so putting a beta-MHC allele into mouse alpha-MHC preserves the ventricular context while changing the gene. Reading it as MYH6 evidence inverts the intent.

Show evidence (2 references)

PMID:8614836 SUPPORT INDIRECT Model Organism

"A mouse model of familial hypertrophic cardiomyopathy (FHC) was generated by the introduction of an Arg 403 --> Gln mutation into the alpha cardiac myosin heavy chain (MHC) gene."

The construction described is an R403Q allele in alpha-MHC. R403Q is a human MYH7 allele, so this establishes the gene/allele mismatch that makes the model inapplicable to human MYH6.

+ 1 more reference

Show evidence (2 references)

PMID:8614836 SUPPORT Model Organism

"Homozygous alpha MHC 403/403 mice died 7 days after birth, and sedentary heterozygous alpha MHC 403/+ mice survived for 1 year."

Establishes the model's genotype-viability structure, and that the heterozygote — the arm analogous to human dominant disease — is the long-lived, phenotypable one.

CGGV:assertion_ee5380a4-0dee-49aa-b911-141502648144-2023-07-12T020000.000Z REFUTE Other

"these mice models are not analogous to human MYH6"

Cited as REFUTE against treating this model as informative for the present entity. It is the reason the model is listed with a FAILS_TO_RECAPITULATE link to the initiating lesion rather than as supporting evidence.

{ }

Source YAML

click to show

name: Hypertrophic Cardiomyopathy 14
creation_date: "2026-08-31T00:00:00Z"
synonyms:
- CMH14
- MYH6 hypertrophic cardiomyopathy
- alpha-myosin heavy chain hypertrophic cardiomyopathy
- cardiomyopathy, familial hypertrophic, 14
- cardiomyopathy, hypertrophic, 14
- hypertrophic cardiomyopathy caused by mutation in MYH6
description: >-
  Hypertrophic cardiomyopathy 14 (CMH14) is the MYH6-attributed node of the
  hypertrophic cardiomyopathy gene series. MYH6 encodes the alpha-cardiac myosin
  heavy chain (alpha-MHC), the fast-ATPase sarcomeric motor that sits immediately
  beside MYH7 in a tandem gene pair on chromosome 14q11.2 and differs from its
  neighbour mainly in small pockets of an otherwise highly conserved molecule.

  The entity must be read with an explicit validity caveat, and that caveat is the
  single most important thing about it. ClinGen's Hereditary Cardiovascular Disease
  Gene Curation Expert Panel classifies the MYH6-hypertrophic cardiomyopathy
  gene-disease relationship as **Disputed**, downgraded from Limited in July 2023.
  The association rests on three probands across two publications, four unique
  heterozygous missense variants with limited pathogenicity evidence, and no known
  disease mechanism; further reported variants were excluded from scoring either
  because the proband also carried a variant in an established HCM gene or because
  the variant is common in the population. Dismech therefore curates CMH14 as a
  real MONDO entity whose pathophysiology is a *hypothesis under dispute*, not an
  established mechanism, and every mechanism node below is scoped accordingly.
  The downgrade has a direct clinical consequence, published as a 2025 JACC
  reappraisal by the same expert panel: a variant in a disputed gene should not be
  reported clinically, so a MYH6 variant returned by a legacy broad HCM panel is
  not a molecular diagnosis of this entity and does not support cascade testing.

  The mechanistic reason the association is hard to establish is an expression
  argument. Alpha-MHC is the major myosin of the human atrium and only a minor
  component of the human ventricle, where beta-MHC (MYH7) predominates. A
  heterozygous missense allele in the minor ventricular isoform is therefore a
  weak candidate for a disease defined by ventricular hypertrophy, which is the
  reverse of the situation for MYH7. What phenotypic signal exists is consistent
  across two independent cohorts and is a *late-onset* one: MYH6 variants were
  found in an elderly-onset HCM series in which none of the classic MYH7, TNNT2 or
  TPM1 alleles appeared, and in a second cohort MYH6 variants were confined to the
  late-onset arm while TNNT2 variants were confined to the early-onset arm.

  Named-entity caution, in two directions. First, MYH6 is Definitively associated
  with congenital heart defects and Limited for dilated cardiomyopathy; dismech
  already curates MYH6 as a causative gene in Atrial_Septal_Defect and
  Dilated_Cardiomyopathy_1EE, and as a susceptibility gene in
  Familial_Sick_Sinus_Syndrome and Hypoplastic_Left_Heart_Syndrome. None of those
  is this entry. Second, and more subtly, the classic and highly
  successful mouse models of familial HCM carry an R403Q allele knocked into mouse
  *Myh6* — but the human R403Q is an *MYH7* allele, and the mouse ventricle
  expresses alpha-MHC where the human ventricle expresses beta-MHC. Those mice
  model human MYH7 disease in the mouse's orthologous ventricular isoform; ClinGen
  explicitly declined to score them as MYH6 evidence. Model-organism literature
  retrieved by a text search for "Myh6" and "hypertrophic cardiomyopathy" is
  therefore mostly *not* about this entity.
category: Genetic
notes: >-
  MONDO:0013197 is_a familial hypertrophic cardiomyopathy (MONDO:0024573) and
  carries these cross-references, read from OLS at curation time: OMIM:613251,
  MEDGEN:442484, UMLS:C2750467, MESH:C567684, DOID:0110320, GARD:0024907. They
  are recorded here rather than in `mappings:` because `DiseaseMappings` provides
  only `mondo_mappings`, `ncit_mappings`, `icd10cm_mappings` and
  `icd11f_mappings`, and none of these identifiers belongs to those vocabularies.
  An ICD-10-CM mapping was considered and left out: the candidate codes (I42.1
  obstructive / I42.2 other hypertrophic cardiomyopathy) are HCM-level rather
  than CMH14-level, and neither is present in `cache/icd10cm/terms.csv`, so
  binding one would assert a mapping this repository cannot currently validate. The stub recorded a single causal gene,
  MYH6 (hgnc:7576), and no MONDO descendants, so the entity is a leaf and the
  lump/split call is a straightforward DISEASE at the same granularity as the
  fifteen sibling Hypertrophic_Cardiomyopathy_<N> entries already curated.

  Curation precedent: this entry follows Hypertrophic_Cardiomyopathy_25 (TCAP),
  which is likewise ClinGen Disputed and is curated as a real entity carrying an
  explicit dispute rather than omitted. Two further siblings rest on Limited
  relationships (NEXN in CMH20, TTN in CMH9). Curating a contested entity is
  deliberate: the alternative is that the OMIM-derived name circulates with no
  record anywhere of how thin its evidence is.
classifications:
  harrisons_chapter:
  - classification_value: CARDIOVASCULAR
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
disease_term:
  preferred_term: hypertrophic cardiomyopathy 14
  term:
    id: MONDO:0013197
    label: hypertrophic cardiomyopathy 14
parents:
- Hypertrophic Cardiomyopathy
- Genetic Disorder
inheritance:
- name: Autosomal dominant
  description: >-
    Where a mode of inheritance has been assigned to MYH6-attributed hypertrophic
    cardiomyopathy it is autosomal dominant transmission of a heterozygous
    missense allele, which is the mode ClinGen records for the relationship it
    then classified as Disputed. Segregation evidence is correspondingly thin: the
    Q1065H proband's two unaffected offspring did not carry the allele, and the
    elderly-onset series that produced the founding variant was explicitly
    selected for absent family history.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  penetrance: INCOMPLETE
  evidence:
  - reference: CGGV:assertion_ee5380a4-0dee-49aa-b911-141502648144-2023-07-12T020000.000Z
    reference_title: "MYH6 / hypertrophic cardiomyopathy (Disputed)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MYH6 | HGNC:7576 | hypertrophic cardiomyopathy | MONDO:0005045 | AD | Disputed | SOP9 | Hereditary Cardiovascular Disease Gene Curation Expert Panel"
    explanation: >-
      ClinGen records autosomal dominant as the mode of inheritance for the
      MYH6-HCM relationship, in the same row that classifies that relationship as
      Disputed.
  - reference: PMID:15998695
    reference_title: "Alpha-myosin heavy chain: a sarcomeric gene associated with dilated and hypertrophic phenotypes of cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A Q1065H mutation was detected in 1 of 21 HCM probands and was absent in 2 unaffected offspring."
    explanation: >-
      The only segregation observation reported for an HCM-attributed MYH6 allele
      is the absence of Q1065H in two unaffected offspring of the proband.
prevalence:
- population: Worldwide
  measure_type: UNKNOWN
  prevalence_class: NOT_YET_DOCUMENTED
  notes: >-
    No population prevalence exists for the MYH6-attributed form of hypertrophic
    cardiomyopathy, and none can responsibly be derived while the gene-disease
    relationship is Disputed. The only quantitative anchors are yields within
    referral HCM cohorts: MYH6 accounted for 3 of 41 clinically selected variants
    (7.5%) in a 70-patient Italian NGS series, and a MYH6 allele was found in 1 of
    21 HCM probands in an earlier candidate-gene screen. ClinGen judged the
    variant behind that second figure to be common in the population, so even
    these cohort yields overstate the disease-attributable fraction.
  evidence:
  - reference: PMID:27483260
    reference_title: "A Next-Generation Sequencing Approach to Identify Gene Mutations in Early- and Late-Onset Hypertrophic Cardiomyopathy Patients of an Italian Cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "TNNT2, CAV3 and MYH6 (3/41 = 7.5% each)"
    explanation: >-
      Gives the MYH6 share of clinically selected variants in a 70-patient
      referral HCM cohort. A cohort variant share is not a population prevalence.
  - reference: CGGV:assertion_ee5380a4-0dee-49aa-b911-141502648144-2023-07-12T020000.000Z
    reference_title: "MYH6 / hypertrophic cardiomyopathy (Disputed)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "or high frequency in the population (Carniel et al. 2005, PMID 15998695)"
    explanation: >-
      ClinGen's reason for excluding the Carniel variants from scoring is why no
      prevalence band is asserted from that cohort's yield.
mechanistic_hypotheses:
- hypothesis_group_id: myh6_minor_ventricular_isoform_hcm
  hypothesis_label: Minor-ventricular-isoform sarcomere model of MYH6 hypertrophic cardiomyopathy
  status: EMERGING
  description: >-
    The proposed model is that a heterozygous missense allele in alpha-MHC alters
    the motor function of the minor myosin isoform of the human ventricle, and
    that this is sufficient to seed the same maladaptive hypertrophic remodeling
    that beta-MHC (MYH7) alleles produce. The model has never been tested
    directly. No functional study of any HCM-attributed human MYH6 allele has been
    published, ClinGen states outright that the disease mechanism is unknown, and
    the model has to explain why a lesion in the ventricle's minor isoform would
    produce a ventricular phenotype at all. The observed late-onset skew is
    consistent with a weak-effect allele requiring decades of accumulated
    remodeling, but that is a post-hoc reading, not a tested prediction. This
    hypothesis group is what every pathophysiology edge in this entry belongs to;
    the entry asserts no established MYH6 mechanism.
  evidence:
  - reference: CGGV:assertion_ee5380a4-0dee-49aa-b911-141502648144-2023-07-12T020000.000Z
    reference_title: "MYH6 / hypertrophic cardiomyopathy (Disputed)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The mechanism for disease remains unknown."
    explanation: >-
      ClinGen's expert-panel judgement that no disease mechanism is established is
      the reason this is curated as a hypothesis rather than as pathophysiology.
  - reference: PMID:6234108
    reference_title: "Myosin types in the human heart. An immunofluorescence study of normal and hypertrophied atrial and ventricular myocardium."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "myosin heavy chain alpha was found to be a major component of atrial myosin and a minor component of ventricular myosin"
    explanation: >-
      Establishes the expression constraint the model must overcome: alpha-MHC is
      the minor ventricular isoform in the human heart.
pathophysiology:
- name: MYH6 Missense Variant in Alpha-Myosin Heavy Chain
  biological_scale: MOLECULAR
  role: trigger
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Primary Cardiomyocyte Insult"
  description: >-
    The proposed initiating lesion in CMH14 is a heterozygous missense variant in
    MYH6, encoding the alpha-cardiac myosin heavy chain. Four unique missense
    alleles have been reported in HCM probands with limited pathogenicity
    evidence. The reported alleles fall in conserved residues and are predicted to
    change the structure or chemical bonding of the protein, but no functional
    assay of any HCM-attributed MYH6 allele has been reported, and this node is
    therefore an attributed lesion rather than a demonstrated one.
  genes:
  - preferred_term: MYH6
    term:
      id: hgnc:7576
      label: MYH6
  molecular_functions:
  - preferred_term: alpha-myosin heavy chain actin-based motor activity
    term:
      id: GO:0000146
      label: microfilament motor activity
    modifier: ABNORMAL
  cell_types:
  - preferred_term: ventricular cardiomyocyte
    term:
      id: CL:0002131
      label: regular ventricular cardiac myocyte
  locations:
  - preferred_term: myocardium
    term:
      id: UBERON:0002349
      label: myocardium
  evidence:
  - reference: CGGV:assertion_ee5380a4-0dee-49aa-b911-141502648144-2023-07-12T020000.000Z
    reference_title: "MYH6 / hypertrophic cardiomyopathy (Disputed)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Four unique heterozygous missense variants have been reported in humans with limited evidence to support their pathogenicity"
    explanation: >-
      Establishes the class of lesion attributed to this entity, and simultaneously
      that the pathogenicity evidence for each is limited.
  - reference: PMID:15998695
    reference_title: "Alpha-myosin heavy chain: a sarcomeric gene associated with dilated and hypertrophic phenotypes of cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All MYH6 mutations were distributed in highly conserved residues, were predicted to change the structure or chemical bonds of alphaMyHC"
    explanation: >-
      Supports the in-silico rationale offered for the reported alleles. The
      prediction is computational; no functional assay followed.
  - reference: CGGV:assertion_ee5380a4-0dee-49aa-b911-141502648144-2023-07-12T020000.000Z
    reference_title: "MYH6 / hypertrophic cardiomyopathy (Disputed)"
    supports: REFUTE
    evidence_source: OTHER
    snippet: "It has been associated with HCM in 3 probands in 2 publications."
    explanation: >-
      Cited against the strength of this node, not for it. Three probands across
      two publications is the entire human genetic basis for attributing a
      hypertrophic phenotype to this gene.
  downstream:
  - target: Altered Sarcomere Motor Function
    causal_link_type: DIRECT
    hypothesis_groups:
    - myh6_minor_ventricular_isoform_hcm
    description: >-
      The proposed proximal consequence, by analogy with MYH7 missense disease.
      Asserted by analogy, not measured for any MYH6 HCM allele.
    evidence:
    - reference: CGGV:assertion_ee5380a4-0dee-49aa-b911-141502648144-2023-07-12T020000.000Z
      reference_title: "MYH6 / hypertrophic cardiomyopathy (Disputed)"
      supports: NO_EVIDENCE
      evidence_source: OTHER
      snippet: "The mechanism for disease remains unknown."
      explanation: >-
        Recorded against this edge as NO_EVIDENCE rather than omitted. ClinGen's
        review of the whole literature found nothing establishing that an MYH6
        allele alters sarcomere motor function, so this edge is asserted by
        analogy with MYH7 and is the disputed step of the chain.
- name: Alpha-MHC Is the Minor Myosin Isoform of the Human Ventricle
  biological_scale: TISSUE
  description: >-
    In the human heart alpha-MHC is the dominant myosin of the atrium and only a
    minor component of ventricular myosin, while beta-MHC (MYH7) is the dominant
    ventricular isoform. This isoform distribution is the central difficulty for
    any MYH6 model of a ventricular hypertrophic phenotype, and it is also why the
    murine literature does not transfer: the mouse ventricle runs on alpha-MHC.
    The same study shows the distribution is not fixed — chronically overloaded
    human atria shift substantially toward beta-MHC, whereas hypertrophied
    ventricles change only slightly.
  molecular_functions:
  - preferred_term: alpha-myosin heavy chain actin-based motor activity
    term:
      id: GO:0000146
      label: microfilament motor activity
  cell_types:
  - preferred_term: ventricular cardiomyocyte
    term:
      id: CL:0002131
      label: regular ventricular cardiac myocyte
  - preferred_term: atrial cardiomyocyte
    term:
      id: CL:0002129
      label: regular atrial cardiac myocyte
  locations:
  - preferred_term: heart left ventricle
    term:
      id: UBERON:0002084
      label: heart left ventricle
  - preferred_term: left cardiac atrium
    term:
      id: UBERON:0002079
      label: left cardiac atrium
  evidence:
  - reference: PMID:6234108
    reference_title: "Myosin types in the human heart. An immunofluorescence study of normal and hypertrophied atrial and ventricular myocardium."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "myosin heavy chain alpha was found to be a major component of atrial myosin and a minor component of ventricular myosin, while heavy chain beta was found to be a major component of ventricular myosin and a minor component of atrial myosin"
    explanation: >-
      Direct immunofluorescence measurement of the isoform distribution in human
      atrial and ventricular myocardium.
  - reference: PMID:6234108
    reference_title: "Myosin types in the human heart. An immunofluorescence study of normal and hypertrophied atrial and ventricular myocardium."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "chronic exposure to hemodynamic overload can induce marked changes in the myosin heavy chain composition of human atria, whereas it affects only slightly that of the ventricles"
    explanation: >-
      Shows the isoform distribution is load-responsive in the atrium but largely
      fixed in the ventricle, so ventricular hypertrophy does not recruit alpha-MHC
      into a larger role.
  - reference: PMID:10388558
    reference_title: "Comparative sequence analysis of the complete human sarcomeric myosin heavy chain family: implications for functional diversity."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "functional diversity among MyHCs is likely to be accomplished by having small pockets of sequence diversity in an otherwise highly conserved molecule"
    explanation: >-
      Explains why alpha- and beta-MHC are hard to separate functionally by
      sequence alone, which is part of why an MYH6 missense allele is difficult to
      interpret against the well-characterised MYH7 alleles.
  downstream:
  - target: Altered Sarcomere Motor Function
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - myh6_minor_ventricular_isoform_hcm
    description: >-
      This node is the standing tissue context rather than a lesion: it is the
      second input to any ventricular consequence of an MYH6 allele, and it sets
      the ceiling on how large that consequence can be. A node with no upstream is
      correct here — the isoform distribution is constitutive, not caused by the
      variant.
    evidence:
    - reference: PMID:6234108
      reference_title: "Myosin types in the human heart. An immunofluorescence study of normal and hypertrophied atrial and ventricular myocardium."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "myosin heavy chain alpha was found to be a major component of atrial myosin and a minor component of ventricular myosin"
      explanation: >-
        The measurement establishing that a lesion in alpha-MHC acts, in the human
        ventricle, on a minor isoform, which is what this edge contributes.
- name: Altered Sarcomere Motor Function
  biological_scale: MOLECULAR
  description: >-
    The hypothesised proximal consequence of an HCM-attributed MYH6 allele is a
    change in the actin-based motor behaviour of the affected myosin molecules
    within the ventricular sarcomere, by analogy with the well-characterised MYH7
    missense alleles. This node carries no direct evidence for any human
    HCM-attributed MYH6 variant: no functional characterisation of such an allele
    has been published, which is one of the stated grounds for ClinGen's Disputed
    classification. It is retained as an explicit hypothesis node rather than
    dropped, so that the gap is visible and addressable.
  molecular_functions:
  - preferred_term: alpha-myosin heavy chain actin-based motor activity
    term:
      id: GO:0000146
      label: microfilament motor activity
    modifier: ABNORMAL
  - preferred_term: ATP hydrolysis activity
    term:
      id: GO:0016887
      label: ATP hydrolysis activity
    modifier: ABNORMAL
  - preferred_term: actin filament binding
    term:
      id: GO:0051015
      label: actin filament binding
    modifier: ABNORMAL
  biological_processes:
  - preferred_term: cardiac muscle contraction
    term:
      id: GO:0060048
      label: cardiac muscle contraction
    modifier: ABNORMAL
  cell_types:
  - preferred_term: ventricular cardiomyocyte
    term:
      id: CL:0002131
      label: regular ventricular cardiac myocyte
  evidence:
  - reference: CGGV:assertion_ee5380a4-0dee-49aa-b911-141502648144-2023-07-12T020000.000Z
    reference_title: "MYH6 / hypertrophic cardiomyopathy (Disputed)"
    supports: NO_EVIDENCE
    evidence_source: OTHER
    snippet: "The mechanism for disease remains unknown."
    explanation: >-
      Recorded as NO_EVIDENCE rather than SUPPORT: ClinGen's review of the whole
      literature found nothing establishing a mechanism for this node. The node is
      an explicit hypothesis, and this is the citation that says so.
  downstream:
  - target: Maladaptive Ventricular Remodeling
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - myh6_minor_ventricular_isoform_hcm
    description: >-
      The remaining chain is the conserved hypertrophic remodeling pathway, which
      is well established for sarcomeric HCM generally. What is unestablished is
      that an MYH6 allele enters it.
    evidence:
    - reference: PMID:8614836
      reference_title: "A mouse model of familial hypertrophic cardiomyopathy."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "Cardiac dysfunction preceded histopathologic changes, and myocyte disarray, hypertrophy, and fibrosis increased with age."
      explanation: >-
        Supports the edge from a sarcomeric motor lesion to maladaptive
        remodeling, and establishes its temporal ordering. INDIRECT because the
        allele is MYH7-derived in mouse Myh6, so it evidences the conserved step
        rather than the MYH6 attribution.
- name: Maladaptive Ventricular Remodeling
  biological_scale: TISSUE
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Ventricular Remodeling"
  description: >-
    Downstream of a sarcomeric insult the myocardium undergoes the conserved
    maladaptive remodeling programme of hypertrophic cardiomyopathy: cardiomyocyte
    hypertrophy, myocyte disarray, and interstitial fibrosis producing asymmetric
    wall thickening in a non-dilated ventricle. This chain is well established for
    sarcomeric HCM as a class and is imported here from the
    cardiomyopathy_maladaptive_remodeling module; the MYH6-specific claim is only
    that a MYH6 allele is what initiates it, which is the disputed step upstream.
  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: sarcomere organization
    term:
      id: GO:0045214
      label: sarcomere organization
    modifier: DECREASED
  cell_types:
  - preferred_term: ventricular cardiomyocyte
    term:
      id: CL:0002131
      label: regular ventricular cardiac myocyte
  - preferred_term: cardiac fibroblast
    term:
      id: CL:0002548
      label: fibroblast of cardiac tissue
  locations:
  - preferred_term: heart left ventricle
    term:
      id: UBERON:0002084
      label: heart left ventricle
  - preferred_term: interventricular septum
    term:
      id: UBERON:0002094
      label: interventricular septum
  evidence:
  - reference: PMID:8614836
    reference_title: "A mouse model of familial hypertrophic cardiomyopathy."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "myocyte disarray, hypertrophy, and fibrosis increased with age"
    explanation: >-
      Establishes the histological content of the remodeling node in a sarcomeric
      HCM model. Graded INDIRECT deliberately: this mouse carries an MYH7-derived
      R403Q allele knocked into mouse Myh6, so it evidences the conserved
      remodeling programme but not the MYH6 attribution. See the
      HUMAN_MODEL_MISMATCH discussion.
  downstream:
  - target: Left Ventricular Hypertrophy
    causal_link_type: DIRECT
    description: >-
      The remodeling programme is what produces the measurable wall thickening
      that defines the clinical entity.
    evidence:
    - reference: PMID:8614836
      reference_title: "A mouse model of familial hypertrophic cardiomyopathy."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "myocyte disarray, hypertrophy, and fibrosis increased with age"
      explanation: >-
        Links the remodeling node to hypertrophy as its tissue-level output.
        INDIRECT because the model's allele is MYH7-derived.
  - target: Hypertrophic Cardiomyopathy
    causal_link_type: DIRECT
    description: >-
      Wall thickening in a non-dilated ventricle without another cause is the
      clinical diagnosis itself.
    evidence:
    - reference: PMID:27483260
      reference_title: "A Next-Generation Sequencing Approach to Identify Gene Mutations in Early- and Late-Onset Hypertrophic Cardiomyopathy Patients of an Italian Cohort."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The clinical diagnosis of HCM was based on the echocardiographic demonstration of a hypertrophied and not dilated left ventricle"
      explanation: >-
        States the diagnostic rule that turns the remodeling outcome into the
        named clinical entity.
  - target: Progressive Contractile Dysfunction and Progression to Dilation
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:15998695
      reference_title: "Alpha-myosin heavy chain: a sarcomeric gene associated with dilated and hypertrophic phenotypes of cardiomyopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "the HCM phenotype was characterized by progression toward dilation, left ventricular dysfunction, and refractory heart failure"
      explanation: >-
        Reports the transition from the hypertrophic remodeling state to dilation
        and contractile failure in the MYH6-attributed carriers themselves, which
        is the step this edge encodes.
- name: Progressive Contractile Dysfunction and Progression to Dilation
  biological_scale: ORGANISM
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Progressive Contractile Dysfunction"
  description: >-
    In the single cohort that followed MYH6-attributed HCM carriers clinically,
    the reported course was not stable hypertrophy but progression toward chamber
    dilation, left ventricular dysfunction and refractory heart failure — the
    "burnt-out" end of the HCM spectrum. This is also the observation the same
    authors used to argue that MYH6 alleles produce a phenotypic continuum from
    hypertrophic to dilated cardiomyopathy, which is consistent with MYH6 being
    separately, if weakly, associated with dilated cardiomyopathy.
  biological_processes:
  - preferred_term: heart contraction
    term:
      id: GO:0060047
      label: heart contraction
    modifier: DECREASED
  - preferred_term: relaxation of cardiac muscle
    term:
      id: GO:0055119
      label: relaxation of cardiac muscle
    modifier: DECREASED
  locations:
  - preferred_term: heart left ventricle
    term:
      id: UBERON:0002084
      label: heart left ventricle
  evidence:
  - reference: PMID:15998695
    reference_title: "Alpha-myosin heavy chain: a sarcomeric gene associated with dilated and hypertrophic phenotypes of cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the HCM phenotype was characterized by progression toward dilation, left ventricular dysfunction, and refractory heart failure"
    explanation: >-
      The only reported clinical course for an MYH6-attributed HCM carrier
      lineage.
  - reference: PMID:15998695
    reference_title: "Alpha-myosin heavy chain: a sarcomeric gene associated with dilated and hypertrophic phenotypes of cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This study suggests that mutations in MYH6 may cause a spectrum of phenotypes ranging from DCM to HCM."
    explanation: >-
      States the phenotypic-continuum reading that this node encodes, and is the
      origin of the overlap between this entry and the MYH6 dilated
      cardiomyopathy entities.
  downstream:
  - target: Progression to Ventricular Dilation
    causal_link_type: DIRECT
    description: >-
      The observable chamber change produced by this mechanism node.
    evidence:
    - reference: PMID:15998695
      reference_title: "Alpha-myosin heavy chain: a sarcomeric gene associated with dilated and hypertrophic phenotypes of cardiomyopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "This study suggests that mutations in MYH6 may cause a spectrum of phenotypes ranging from DCM to HCM."
      explanation: >-
        The phenotypic-continuum claim that this edge, from mechanism to observed
        dilation, encodes.
  - target: Congestive Heart Failure
    causal_link_type: DIRECT
    description: >-
      Refractory heart failure is the reported endpoint of the course.
    evidence:
    - reference: PMID:15998695
      reference_title: "Alpha-myosin heavy chain: a sarcomeric gene associated with dilated and hypertrophic phenotypes of cardiomyopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "progression toward dilation, left ventricular dysfunction, and refractory heart failure"
      explanation: >-
        Names heart failure as the terminus of the reported clinical course.
phenotypes:
- category: Cardiac
  name: Left Ventricular Hypertrophy
  description: >-
    Asymmetric left ventricular wall thickening in a non-dilated ventricle is the
    defining phenotype of the HCM series and the diagnostic entry criterion for
    every cohort in which an MYH6 allele has been reported. In the elderly-onset
    series that produced the founding MYH6 variant, maximal wall thickness
    averaged 19.9 mm.
  phenotype_term:
    preferred_term: Left ventricular hypertrophy
    term:
      id: HP:0001712
      label: Left ventricular hypertrophy
    onset:
      onset_category: LATE
      mean_age_years: 62.8
      notes: >-
        Mean age at diagnosis in the elderly-onset cohort that yielded the
        founding alpha-MHC variant; mean age at first symptom in that series was
        59.3 years.
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:11815426
    reference_title: "Sarcomere protein gene mutations in hypertrophic cardiomyopathy of the elderly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Echocardiography demonstrated maximal left ventricular wall thickness of 19.9+/-3.8 mm"
    explanation: >-
      Quantifies the hypertrophy in the cohort from which the founding MYH6 HCM
      variant was reported.
  sequelae:
  - target: Left Ventricular Outflow Tract Obstruction
    description: >-
      Septal thickening with systolic anterior motion of the mitral valve is what
      generates the dynamic outflow gradient.
    evidence:
    - reference: PMID:11815426
      reference_title: "Sarcomere protein gene mutations in hypertrophic cardiomyopathy of the elderly."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "systolic anterior motion of the mitral valve (58%), and, in 11 individuals, left ventricular outflow tract gradients"
      explanation: >-
        Reports systolic anterior motion and measurable outflow gradients
        co-occurring with the hypertrophy in the same cohort, which is the
        observed form of this edge.
  - target: Left Ventricular Diastolic Dysfunction
    description: >-
      A hypertrophied, stiffened ventricle fills poorly.
    evidence:
    - reference: PMID:34087240
      reference_title: "Identification of three novel pathogenic mutations in sarcomere genes associated with familial hypertrophic cardiomyopathy based on multi-omics study."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "accompanied by diastolic and systolic dysfunction and impaired myocardial work"
      explanation: >-
        Reports diastolic dysfunction alongside the hypertrophic phenotype.
        INDIRECT: the carriers also carry a TNNT2 variant.
- category: Cardiac
  name: Hypertrophic Cardiomyopathy
  description: >-
    The clinical entity itself: a hypertrophied, non-dilated left ventricle in the
    absence of another cardiac or systemic cause, which is the criterion by which
    every reported MYH6 carrier was ascertained.
  phenotype_term:
    preferred_term: Hypertrophic cardiomyopathy
    term:
      id: HP:0001639
      label: Hypertrophic cardiomyopathy
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:27483260
    reference_title: "A Next-Generation Sequencing Approach to Identify Gene Mutations in Early- and Late-Onset Hypertrophic Cardiomyopathy Patients of an Italian Cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical diagnosis of HCM was based on the echocardiographic demonstration of a hypertrophied and not dilated left ventricle"
    explanation: >-
      States the ascertainment criterion applied to the cohort in which MYH6
      variants were found exclusively in the late-onset arm.
- category: Cardiac
  name: Late-Onset Presentation
  description: >-
    The most reproducible feature of MYH6-attributed HCM is when it is found
    rather than what it looks like. Two independent cohorts converge: the founding
    variant came from a series selected for elderly onset, in which initial
    symptoms occurred at a mean of 59 years and diagnosis at 63 years with no
    family history of cardiomyopathy; and in a later Italian series MYH6 variants
    appeared only in the late-onset arm, while TNNT2 variants appeared only in the
    early-onset arm. Whether this reflects a genuinely weak-effect allele or the
    lower genetic yield and higher phenocopy rate of elderly HCM cohorts is not
    resolved, and is the reason a Disputed relationship can still show a
    consistent phenotypic skew.
  notes: >-
    Deliberately carries no phenotype_term. The observation is an age-of-onset
    statement, and HPO encodes onset under HP:0003674 rather than as a phenotypic
    abnormality, so no term in the PhenotypeTerm enum names it. The structured
    onset data is recorded instead on the Left Ventricular Hypertrophy
    phenotype_term as an OnsetDescriptor (LATE, mean 62.8 years). This node is
    retained because the late-onset skew is the most reproducible observation
    about the entity and is the anchor for a knowledge gap.
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:11815426
    reference_title: "Sarcomere protein gene mutations in hypertrophic cardiomyopathy of the elderly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Initial symptoms occurred at 59.3 (+/-12.3) years, and diagnosis was made at 62.8 (+/-10.8) years."
    explanation: >-
      Gives the age at onset and diagnosis in the elderly-onset cohort that
      yielded the founding alpha-MHC variant.
  - reference: PMID:27483260
    reference_title: "A Next-Generation Sequencing Approach to Identify Gene Mutations in Early- and Late-Onset Hypertrophic Cardiomyopathy Patients of an Italian Cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In fact, mutations in MYH6 were identified in the LO group only, whereas mutations in TNNT2 were identified in the EO group only."
    explanation: >-
      Independent replication of the late-onset skew in a second cohort designed
      to contrast the extremes of age at diagnosis.
  - reference: PMID:11815426
    reference_title: "Sarcomere protein gene mutations in hypertrophic cardiomyopathy of the elderly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The distribution of mutations in elderly-onset disease is strikingly different (P<0.00001) from that of familial, early onset hypertrophic cardiomyopathy."
    explanation: >-
      Establishes that the gene distribution behind elderly-onset HCM, which is
      where MYH6 appears, differs significantly from that of classic familial HCM.
- category: Cardiac
  name: Left Ventricular Outflow Tract Obstruction
  description: >-
    Dynamic outflow tract obstruction with systolic anterior motion of the mitral
    valve, as seen in the elderly-onset HCM cohort from which the founding MYH6
    variant was reported. Recorded as a cohort-level feature of the clinical
    context rather than a MYH6-specific finding.
  phenotype_term:
    preferred_term: Left ventricular outflow tract obstruction
    term:
      id: HP:0032092
      label: Left ventricular outflow tract obstruction
  frequency: FREQUENT
  evidence:
  - reference: PMID:11815426
    reference_title: "Sarcomere protein gene mutations in hypertrophic cardiomyopathy of the elderly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "systolic anterior motion of the mitral valve (58%), and, in 11 individuals, left ventricular outflow tract gradients"
    explanation: >-
      Reports systolic anterior motion and measurable outflow gradients in the
      cohort. This is the general elderly-HCM phenotype, not a MYH6-attributed one.
- category: Cardiac
  name: Congestive Heart Failure
  description: >-
    Progression to refractory heart failure was the reported course in the
    MYH6-attributed HCM lineage, and heart failure was also a presenting feature
    in the family carrying a MYH6 frameshift alongside an MYH7 missense variant.
  phenotype_term:
    preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  evidence:
  - reference: PMID:15998695
    reference_title: "Alpha-myosin heavy chain: a sarcomeric gene associated with dilated and hypertrophic phenotypes of cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "progression toward dilation, left ventricular dysfunction, and refractory heart failure"
    explanation: >-
      Refractory heart failure is the reported endpoint of the MYH6-attributed HCM
      course.
- category: Cardiac
  name: Sudden Cardiac Death
  description: >-
    Sudden cardiac-related death was reported in a Japanese family carrying a MYH6
    frameshift variant together with an MYH7 missense variant. Attribution is
    explicitly confounded: the authors present the severity as a property of the
    double genotype, and ClinGen excluded this family from MYH6 scoring precisely
    because a variant in an established HCM gene was also present.
  notes: >-
    Deliberately left with no incoming pathograph edge. Sudden death in HCM
    arises from an arrhythmic substrate of myocyte disarray and fibrosis, but no
    such node is curated in this entry because no MYH6-specific evidence supports
    one, and the single reported death comes from a family carrying an MYH7
    variant as well. Drawing an edge from the remodeling node would assert a
    mechanism for this entity that its literature does not contain.
  phenotype_term:
    preferred_term: Sudden cardiac death
    term:
      id: HP:0001645
      label: Sudden cardiac death
  evidence:
  - reference: PMID:35911064
    reference_title: "A double heterozygous variant in MYH6 and MYH7 associated with hypertrophic cardiomyopathy in a Japanese Family."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Family members with the double variants demonstrated severe phenotypes, such as sudden cardiac-related death and heart failure."
    explanation: >-
      Graded INDIRECT because the phenotype is attributed to the double MYH6/MYH7
      genotype, so it does not establish sudden death as a consequence of the MYH6
      allele alone.
- category: Cardiac
  name: Left Ventricular Diastolic Dysfunction
  description: >-
    Impaired ventricular filling from a thickened, stiff ventricle. Reported in
    MYH6 variant carriers in a multi-omics pedigree study alongside systolic
    dysfunction and impaired myocardial work, though those carriers also carried a
    TNNT2 variant.
  phenotype_term:
    preferred_term: Left ventricular diastolic dysfunction
    term:
      id: HP:0025168
      label: Left ventricular diastolic dysfunction
  evidence:
  - reference: PMID:34087240
    reference_title: "Identification of three novel pathogenic mutations in sarcomere genes associated with familial hypertrophic cardiomyopathy based on multi-omics study."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "They presented with heart failure and abnormal electrocardiogram, accompanied by diastolic and systolic dysfunction and impaired myocardial work."
    explanation: >-
      Reports diastolic and systolic dysfunction in the pedigrees carrying the
      MYH6 variant. INDIRECT because those carriers also carry a TNNT2 variant, so
      the finding cannot be attributed to MYH6 alone.
- category: Cardiac
  name: Progression to Ventricular Dilation
  description: >-
    Unlike the stable hypertrophy typical of sarcomeric HCM, the reported
    MYH6-attributed carriers progressed toward chamber dilation and systolic
    failure — the "burnt-out" phase of the HCM spectrum. This is also the
    observation behind the claim that MYH6 alleles span a phenotypic continuum
    from hypertrophic to dilated cardiomyopathy.
  phenotype_term:
    preferred_term: Dilated cardiomyopathy
    term:
      id: HP:0001644
      label: Dilated cardiomyopathy
  evidence:
  - reference: PMID:15998695
    reference_title: "Alpha-myosin heavy chain: a sarcomeric gene associated with dilated and hypertrophic phenotypes of cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the HCM phenotype was characterized by progression toward dilation, left ventricular dysfunction, and refractory heart failure"
    explanation: >-
      Reports dilation as the observed course in the MYH6-attributed HCM carriers.
  sequelae:
  - target: Congestive Heart Failure
    description: >-
      Dilation with systolic dysfunction is what produces the refractory heart
      failure endpoint.
    evidence:
    - reference: PMID:15998695
      reference_title: "Alpha-myosin heavy chain: a sarcomeric gene associated with dilated and hypertrophic phenotypes of cardiomyopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "progression toward dilation, left ventricular dysfunction, and refractory heart failure"
      explanation: >-
        States dilation, dysfunction and heart failure as one reported sequence,
        which is the ordering this edge encodes.
genetic:
- name: MYH6
  gene_term:
    preferred_term: MYH6
    term:
      id: hgnc:7576
      label: MYH6
  relationship_type: DISPUTED
  notes: >-
    MYH6 encodes the alpha-cardiac myosin heavy chain, the actin-based sarcomeric
    motor that is the dominant myosin of the human atrium and a minor component of
    the human ventricle. It lies in a tandem pair with MYH7 on chromosome 14q11.2.
    Its attribution as a cause of hypertrophic cardiomyopathy is ClinGen Disputed;
    its attribution to congenital heart defects is ClinGen Definitive, and to
    dilated cardiomyopathy Limited. The reported HCM alleles are heterozygous
    missense changes, with one frameshift reported in a family that also carried an
    MYH7 missense variant.

    Variant-level record, which for a disputed entity is the argument rather than
    a detail. The alleles attributed to HCM are p.Gln1065His (Carniel 2005,
    excluded from ClinGen scoring as too common in the population), the
    alpha-cardiac myosin heavy chain missense variant reported in the
    elderly-onset series (Niimura 2002), c.G3755A (Wang 2020, the iPSC line
    donor), rs372446459 (Liu 2021, co-occurring with a TNNT2 variant), and
    p.Lys364fs (Suzuki 2022, co-occurring with an MYH7 missense variant). Set
    against these, the best-supported human MYH6 variant of any kind is
    p.Arg721Trp, and its phenotype is sick sinus syndrome rather than
    hypertrophy.
  evidence:
  - reference: CGGV:assertion_ee5380a4-0dee-49aa-b911-141502648144-2023-07-12T020000.000Z
    reference_title: "MYH6 / hypertrophic cardiomyopathy (Disputed)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MYH6 gene encodes alpha heavy chain subunit of cardiac myosin (MHC-α), which are actin-based molecular motors that convert chemical energy released from the hydrolysis of ATP."
    explanation: >-
      ClinGen's statement of the gene product and its molecular function.
  - reference: PMID:11815426
    reference_title: "Sarcomere protein gene mutations in hypertrophic cardiomyopathy of the elderly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Rather, mutations in cardiac myosin binding protein-C, troponin I, and alpha-cardiac myosin heavy chain caused elderly-onset hypertrophic cardiomyopathy."
    explanation: >-
      The founding claim that alpha-cardiac myosin heavy chain variants underlie
      elderly-onset HCM, which is the origin of the CMH14 entity.
  - reference: PMID:27532257
    reference_title: "Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples."
    supports: REFUTE
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "MYH6 121 60328 0.00143 1.06 (0.34-3.34) 0.06 (0.00-0.70)"
    explanation: >-
      Case-excess burden testing against 60,706 ExAC reference samples puts MYH6
      rare variation at essentially background level, with an odds ratio of 1.06
      whose confidence interval spans 1 and an etiological fraction of 0.06.
      Scope note, because it is easy to overstate: this row sits in the paper's
      *dilated* cardiomyopathy panel, and MYH6 does not appear in its hypertrophic
      cardiomyopathy panel at all. It is therefore graded INDIRECT — it shows that
      MYH6 rare variation is not distinguishable from background in a large
      cardiomyopathy case series, which undermines the gene's general credibility
      as a cardiomyopathy gene without being a direct measurement of HCM burden.
  - reference: PMID:27532257
    reference_title: "Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples."
    supports: REFUTE
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "these are in fact genes that have the highest background"
    explanation: >-
      The authors' own reading of that result: genes implicated through candidate
      studies rather than linkage, MYH6 among them, show little excess burden and
      instead carry the highest background variation. Stated in the paper about
      reported contributors to dilated cardiomyopathy, hence INDIRECT here.
  - reference: PMID:39971408
    reference_title: "Genes Associated With Hypertrophic Cardiomyopathy: A Reappraisal by the ClinGen Hereditary Cardiovascular Disease Gene Curation Expert Panel."
    supports: REFUTE
    evidence_source: OTHER
    snippet: "Nine (29%) genes were downgraded to disputed, further discouraging clinical reporting of variants in these genes."
    explanation: >-
      The peer-reviewed publication of the ClinGen reappraisal round that moved
      MYH6 from Limited to Disputed, and its stated consequence for reporting.
      Cited as REFUTE against MYH6 as a reportable HCM gene. Note the abstract
      gives the count of downgraded genes rather than naming them; that MYH6 is
      one of the nine comes from the ClinGen assertion record cited above, which
      records the same expert panel and the same Limited-to-Disputed transition.
  - reference: PMID:21378987
    reference_title: "A rare variant in MYH6 is associated with high risk of sick sinus syndrome."
    supports: NO_EVIDENCE
    evidence_source: HUMAN_CLINICAL
    snippet: "associates with sick sinus syndrome with an odds ratio = 12.53"
    explanation: >-
      Recorded as NO_EVIDENCE for the hypertrophic claim, because it is about a
      different phenotype. It is here for calibration: this is what a
      well-supported MYH6 genotype-phenotype association looks like — a
      population-scale effect size with an odds ratio of 12.53 — against which the
      three-proband hypertrophic claim can be judged.
  - reference: CGGV:assertion_44f4a5ee-8b1d-44b7-87ca-967968d8c0c4-2023-05-09T040000.000Z
    reference_title: "MYH6 / MYH-6 related congenital heart defects (Definitive)"
    supports: NO_EVIDENCE
    evidence_source: OTHER
    snippet: "MYH6 | HGNC:7576 | MYH-6 related congenital heart defects | MONDO:0800442 | AD | Definitive"
    explanation: >-
      Recorded as NO_EVIDENCE for the hypertrophic claim: this assertion is about a
      different MYH6 phenotype entirely. It is cited to make the named-entity
      hazard explicit — MYH6's Definitive disease association is congenital heart
      defects, not hypertrophic cardiomyopathy, and literature searches on the gene
      return that relationship first.
treatments:
- name: Negative Inotropic Pharmacotherapy
  description: >-
    First-line symptomatic therapy for obstructive HCM: a beta-blocker, with a
    non-dihydropyridine calcium channel blocker or disopyramide added or
    substituted when symptoms persist. Management in this entity is the
    management of hypertrophic cardiomyopathy — guideline algorithms branch on
    obstructive versus non-obstructive physiology and on sudden-death risk, not
    on genotype, and no MYH6-directed therapy exists or is in development.
  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: calcium channel blocker
      term:
        id: NCIT:C333
        label: Calcium Channel Blocker
    - preferred_term: disopyramide
      term:
        id: NCIT:C61730
        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: "provides recommendations to guide clinicians in the management of patients with hypertrophic cardiomyopathy"
    explanation: >-
      Establishes the current AHA/ACC guideline as the source of management
      recommendations for HCM, which is how this entity is managed. Cited for the
      guideline's scope rather than for an individual drug recommendation, because
      the cached record is the structured abstract rather than the recommendation
      tables.
- name: Cardiac Myosin Inhibition
  description: >-
    Mavacamten and aficamten are allosteric cardiac myosin inhibitors that
    reduce actin-myosin cross-bridge formation and relieve dynamic outflow
    obstruction, each with a positive phase III trial in symptomatic obstructive
    HCM.

    Worth stating plainly for this entity: these drugs act on beta-cardiac
    myosin, the MYH7 product that dominates the human ventricle. They are not
    targeted at the alpha-myosin this entry is named for. That is not a reason to
    withhold them from a patient with obstructive HCM — the indication is
    physiological, not genotypic — but it does mean the one mechanistically
    targeted therapy in HCM targets the other myosin, which is the same isoform
    asymmetry that makes the MYH6 attribution doubtful in the first place.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: mavacamten
      term:
        id: CHEBI:756998
        label: mavacamten
    - preferred_term: aficamten
      term:
        id: CHEBI:747213
        label: aficamten
  target_mechanisms:
  - target: Alpha-MHC Is the Minor Myosin Isoform of the Human Ventricle
    description: >-
      Linked to the isoform node rather than to the MYH6 lesion, because that is
      where the drugs actually act: they inhibit the beta-MHC that constitutes
      the bulk of ventricular myosin. The link records a mechanistic mismatch
      between the entity's named gene and its most specific available therapy.
    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: "mavacamten, a first-in-class cardiac myosin inhibitor"
      explanation: >-
        Identifies the drug class as a direct cardiac myosin inhibitor, which is
        what makes the isoform it inhibits the relevant mechanistic detail.
  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: "We aimed to assess the efficacy and safety of mavacamten, a first-in-class cardiac myosin inhibitor, in symptomatic obstructive hypertrophic cardiomyopathy."
    explanation: >-
      Establishes mavacamten's indication and mechanism in obstructive HCM.
- name: Septal Reduction Therapy
  description: >-
    Surgical septal myectomy, or alcohol septal ablation where surgery is
    unsuitable, for drug-refractory obstruction. Anatomical rather than
    genotype-directed.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: septal myectomy
    term:
      id: NCIT:C51591
      label: Myectomy
  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: "provides recommendations to guide clinicians in the management of patients with hypertrophic cardiomyopathy"
    explanation: >-
      Septal reduction for drug-refractory obstruction is a guideline recommendation for HCM generally; it is not genotype-directed.
- name: Implantable Cardioverter-Defibrillator
  description: >-
    Primary-prevention ICD for patients meeting HCM sudden-death risk criteria.
    Risk stratification in HCM is clinical and imaging-based; a MYH6 variant
    carries no established risk weight and should not be used to modify it.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: implantable cardioverter-defibrillator placement
    term:
      id: NCIT:C80435
      label: Implantable Cardioverter-Defibrillator Placement
  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: "provides recommendations to guide clinicians in the management of patients with hypertrophic cardiomyopathy"
    explanation: >-
      ICD placement follows the guideline's HCM sudden-death risk assessment, which uses clinical and imaging variables and assigns no weight to a MYH6 variant.
- name: Heart Transplantation
  description: >-
    Reserved for end-stage disease. Relevant to this entity specifically because
    the one reported MYH6-attributed HCM lineage progressed to dilation and
    refractory heart failure rather than remaining stably hypertrophic.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: heart transplantation
    term:
      id: NCIT:C15246
      label: Heart Transplantation
  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: "provides recommendations to guide clinicians in the management of patients with hypertrophic cardiomyopathy"
    explanation: >-
      Transplantation for end-stage HCM is a guideline-recognised pathway.
  target_mechanisms:
  - target: Progressive Contractile Dysfunction and Progression to Dilation
    description: >-
      Addresses the terminal node of this entry's causal chain.
    evidence:
    - reference: PMID:15998695
      reference_title: "Alpha-myosin heavy chain: a sarcomeric gene associated with dilated and hypertrophic phenotypes of cardiomyopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "the HCM phenotype was characterized by progression toward dilation, left ventricular dysfunction, and refractory heart failure"
      explanation: >-
        Establishes that this entity's reported course reaches the refractory
        heart failure state that transplantation addresses.
- name: Genetic Counseling and Family Screening
  description: >-
    Counselling here is unusual in content, because the honest message is a
    negative one: a MYH6 variant found on an HCM panel is not a molecular
    diagnosis, cannot be used to include or exclude relatives, and does not
    replace clinical and imaging surveillance of first-degree relatives, which
    proceeds on the phenotype alone.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:39971408
    reference_title: "Genes Associated With Hypertrophic Cardiomyopathy: A Reappraisal by the ClinGen Hereditary Cardiovascular Disease Gene Curation Expert Panel."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Nine (29%) genes were downgraded to disputed, further discouraging clinical reporting of variants in these genes."
    explanation: >-
      Underpins the counselling message that a disputed-gene variant should not
      drive family testing decisions.
clinical_trials:
- name: NCT03470545
  phase: PHASE_III
  status: COMPLETED
  description: >-
    EXPLORER-HCM. Mavacamten versus placebo over 30 weeks in symptomatic
    obstructive HCM with an LVOT gradient of at least 50 mm Hg and NYHA class
    II-III symptoms. Enrolled on physiology, not genotype; no MYH6 stratum.
  target_phenotypes:
  - preferred_term: Left ventricular outflow tract obstruction
    term:
      id: HP:0032092
      label: Left ventricular outflow tract obstruction
  evidence:
  - reference: PMID:32871100
    reference_title: "Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "patients with hypertrophic cardiomyopathy with an LVOT gradient of 50 mm Hg or greater and New York Heart Association (NYHA) class II-III symptoms were assigned (1:1) to receive mavacamten (starting at 5 mg) or placebo for 30 weeks"
    explanation: >-
      States the trial's design, population and randomisation.
- name: NCT05186818
  phase: PHASE_III
  status: COMPLETED
  description: >-
    SEQUOIA-HCM. Aficamten versus placebo in symptomatic obstructive HCM. As with
    EXPLORER-HCM, enrolment is on obstructive physiology rather than genotype.
  target_phenotypes:
  - preferred_term: Left ventricular outflow tract obstruction
    term:
      id: HP:0032092
      label: Left ventricular outflow tract obstruction
  evidence:
  - reference: PMID:38739079
    reference_title: "Aficamten for Symptomatic Obstructive Hypertrophic Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In this phase 3, double-blind trial, we randomly assigned adults with symptomatic obstructive HCM to receive aficamten (starting dose, 5 mg; maximum dose, 20 mg) or placebo for 24 weeks"
    explanation: >-
      States the trial's phase, design, population and intervention.

diagnosis:
- name: Targeted hypertrophic cardiomyopathy gene panel
  description: >-
    Molecular diagnosis in HCM uses a targeted gene panel on the proband. The
    consequence of the ClinGen reappraisal for this entity is negative rather
    than positive: because MYH6 is classified Disputed for HCM, a MYH6 variant
    returned by a panel that still carries the gene should not be reported as
    causative and should not be used for cascade testing in relatives. There is
    consequently no molecular test that establishes CMH14 in a proband — which is
    a statement about the entity, not about the patient, whose hypertrophy is
    real and is investigated and managed as hypertrophic cardiomyopathy either
    way.
  notes: >-
    The same conclusion was reached empirically, and years before the ClinGen
    reappraisal, by the Italian NGS cohort study, which argued from its own yield
    data for a narrow rather than a broad HCM panel.
  evidence:
  - reference: PMID:39971408
    reference_title: "Genes Associated With Hypertrophic Cardiomyopathy: A Reappraisal by the ClinGen Hereditary Cardiovascular Disease Gene Curation Expert Panel."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Nine (29%) genes were downgraded to disputed, further discouraging clinical reporting of variants in these genes."
    explanation: >-
      States the reporting consequence of a disputed classification, which is what
      this diagnostic entry records for MYH6.
  - reference: PMID:27483260
    reference_title: "A Next-Generation Sequencing Approach to Identify Gene Mutations in Early- and Late-Onset Hypertrophic Cardiomyopathy Patients of an Italian Cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our findings support the choice of a limited, well-selected panel of HCM genes as the best tool for diagnostic purposes."
    explanation: >-
      Independent, pre-ClinGen support for a narrow HCM panel, reached from the
      same cohort in which MYH6 variants appeared only in the low-yield
      late-onset arm.
experimental_models:
- name: MYH6 c.G3755A patient-derived iPSC line
  experimental_model_type: IPSC_DERIVED_MODEL
  description: >-
    An induced pluripotent stem cell line derived from peripheral blood
    mononuclear cells of a 41-year-old man with hypertrophic cardiomyopathy
    carrying a heterozygous MYH6 G3755A variant. This is a resource report: the
    line was characterised for pluripotency, karyotype and the presence of the
    variant, but no cardiomyocyte phenotype was assayed, so it does not yet
    constitute functional evidence for the allele. It is the closest thing to a
    human model system that exists for this entity, and testing it is the
    experiment ClinGen's Disputed classification is waiting on.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  evidence:
  - reference: PMID:33385793
    reference_title: "Generation of an IPSC line from a patient with hypertrophic cardiomyopathy carrying a mutation in MYH6 gene."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The generated iPSC line expressed pluripotency markers, exhibited a normal karyotype, presented the specific mutation, and demonstrated differentiation potential into three germ layers in vitro."
    explanation: >-
      Characterises the line itself — pluripotency, karyotype, presence of the
      MYH6 variant, and trilineage differentiation capacity — which is what
      qualifies it as a usable model system for this entity.
  modeled_mechanisms:
  - target: MYH6 Missense Variant in Alpha-Myosin Heavy Chain
    relationship: PERTURBS
    fidelity: UNKNOWN
    description: >-
      The line carries the patient's own heterozygous MYH6 allele in a human
      genetic background, so it reproduces the initiating lesion of this entry
      exactly.
    limitations: >-
      No differentiated-cardiomyocyte phenotype has been reported for this line —
      no contractility, sarcomere-organisation, or calcium-handling readout. It
      therefore establishes the lesion is modellable, not that it is pathogenic.
      Fidelity is UNKNOWN rather than HIGH for that reason.
    evidence:
    - reference: PMID:33385793
      reference_title: "Generation of an IPSC line from a patient with hypertrophic cardiomyopathy carrying a mutation in MYH6 gene."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "An induced pluripotent stem cell (iPSC) line was generated from peripheral blood mononuclear cells (PBMCs) of a 41-year-old male patient with hypertrophic cardiomyopathy who carries a G3755A heterozygote mutation in the MYH6 gene."
      explanation: >-
        Establishes the existence and genotype of the line, and that it derives
        from an HCM patient carrying the MYH6 allele.
animal_models:
- name: alpha-MHC 403/+ mouse (Myh6 R403Q knock-in)
  species: Mouse
  genotype: Myh6 R403Q heterozygous knock-in
  publication: PMID:8614836
  description: >-
    The founding mouse model of familial hypertrophic cardiomyopathy, made by
    knocking an Arg403Gln substitution into the mouse alpha-cardiac myosin heavy
    chain gene. Heterozygotes develop myocyte disarray, hypertrophy and fibrosis
    that increase with age and closely resemble human familial HCM.

    This model is listed here for an unusual reason: to record that it is *not*
    evidence for this entry. The R403Q allele it carries is a human MYH7 allele.
    It was placed in mouse Myh6 because the mouse ventricle expresses alpha-MHC
    where the human ventricle expresses beta-MHC — a species substitution intended
    to model human MYH7 disease faithfully, not to model human MYH6 disease at
    all. ClinGen reviewed these mice and explicitly declined to score them as MYH6
    evidence. Because a naive text search for "Myh6" plus "hypertrophic
    cardiomyopathy" retrieves this large and influential literature first, leaving
    it unrecorded would invite exactly the misattribution it represents.
  evidence:
  - reference: PMID:8614836
    reference_title: "A mouse model of familial hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Homozygous alpha MHC 403/403 mice died 7 days after birth, and sedentary heterozygous alpha MHC 403/+ mice survived for 1 year."
    explanation: >-
      Establishes the model's genotype-viability structure, and that the
      heterozygote — the arm analogous to human dominant disease — is the
      long-lived, phenotypable one.
  - reference: CGGV:assertion_ee5380a4-0dee-49aa-b911-141502648144-2023-07-12T020000.000Z
    reference_title: "MYH6 / hypertrophic cardiomyopathy (Disputed)"
    supports: REFUTE
    evidence_source: OTHER
    snippet: "these mice models are not analogous to human MYH6"
    explanation: >-
      Cited as REFUTE against treating this model as informative for the present
      entity. It is the reason the model is listed with a FAILS_TO_RECAPITULATE
      link to the initiating lesion rather than as supporting evidence.
  modeled_mechanisms:
  - target: Maladaptive Ventricular Remodeling
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      For the conserved sarcomeric-HCM remodeling programme — disarray,
      hypertrophy, fibrosis, age-dependent progression — this model is faithful to
      human disease, which is why it became the reference HCM model.
    limitations: >-
      Faithful to sarcomeric HCM in general, not to MYH6 attribution in
      particular. The allele is MYH7-derived and the gene is the mouse's
      orthologous ventricular isoform, so the model speaks to the downstream
      remodeling node only.
    evidence:
    - reference: PMID:8614836
      reference_title: "A mouse model of familial hypertrophic cardiomyopathy."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Cardiac histopathology and dysfunction in the alpha MHC 403/+ mice resembled human FHC."
      explanation: >-
        Establishes that the model reproduces the histopathology and dysfunction
        of human familial HCM.
  - target: MYH6 Missense Variant in Alpha-Myosin Heavy Chain
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    description: >-
      The model does not represent the initiating lesion of this entry. It carries
      an MYH7-derived allele in the mouse ventricular myosin isoform, which is a
      different molecular claim from a human MYH6 missense allele in the human
      ventricle's minor isoform.
    limitations: >-
      The species substitution that makes this model good for human MYH7 disease
      is exactly what makes it inapplicable to human MYH6: mouse ventricular
      myosin is alpha-MHC, human ventricular myosin is beta-MHC, so putting a
      beta-MHC allele into mouse alpha-MHC preserves the ventricular context while
      changing the gene. Reading it as MYH6 evidence inverts the intent.
    evidence:
    - reference: PMID:8614836
      reference_title: "A mouse model of familial hypertrophic cardiomyopathy."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "A mouse model of familial hypertrophic cardiomyopathy (FHC) was generated by the introduction of an Arg 403 --> Gln mutation into the alpha cardiac myosin heavy chain (MHC) gene."
      explanation: >-
        The construction described is an R403Q allele in alpha-MHC. R403Q is a
        human MYH7 allele, so this establishes the gene/allele mismatch that makes
        the model inapplicable to human MYH6.
    - reference: CGGV:assertion_ee5380a4-0dee-49aa-b911-141502648144-2023-07-12T020000.000Z
      reference_title: "MYH6 / hypertrophic cardiomyopathy (Disputed)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Additional studies on mice models of HCM using pre-engineered heterozygous, pathogenic MYH7 variant orthologous to the human p.R403Q allele into the mouse MYH6 were reviewed, but not scored because these mice models are not analogous to human MYH6"
      explanation: >-
        ClinGen's expert panel states directly that these mouse models are not
        analogous to human MYH6 and were excluded from scoring on that basis.
discussions:
- discussion_id: myh6_hcm_allele_functional_effect_unknown
  kind: KNOWLEDGE_GAP
  prompt: >-
    Does any HCM-attributed human MYH6 missense allele alter alpha-myosin motor
    function, and if so is the effect large enough to matter in a ventricle where
    alpha-MHC is the minor isoform?
  attaches_to:
  - pathophysiology#Altered Sarcomere Motor Function
  - mechanistic_hypotheses#myh6_minor_ventricular_isoform_hcm
  rationale: >-
    This is the gap that keeps the gene-disease relationship Disputed rather than
    Limited or Moderate. ClinGen states that the mechanism for disease remains
    unknown, and the reason is that no functional characterisation of any
    HCM-attributed MYH6 allele has been published — the supporting functional
    literature it could find was about alpha-MHC's normal biochemistry, not about
    any patient allele. Because alpha-MHC is a minor ventricular isoform, a
    demonstrated functional effect would also need a dosage argument to explain a
    ventricular phenotype, so an assay showing a change is necessary but not
    sufficient. A patient-derived iPSC line carrying an MYH6 HCM allele already
    exists and has never been phenotyped as cardiomyocytes, which makes this an
    unusually tractable gap.
  evidence:
  - reference: CGGV:assertion_ee5380a4-0dee-49aa-b911-141502648144-2023-07-12T020000.000Z
    reference_title: "MYH6 / hypertrophic cardiomyopathy (Disputed)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The mechanism for disease remains unknown."
    explanation: >-
      The expert-panel statement that defines this gap.
  - reference: CGGV:assertion_ee5380a4-0dee-49aa-b911-141502648144-2023-07-12T020000.000Z
    reference_title: "MYH6 / hypertrophic cardiomyopathy (Disputed)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The gene-disease association is supported by expression studies in the human heart"
    explanation: >-
      Shows what the supporting functional literature actually consists of —
      normal-biology expression and biochemistry studies, not characterisation of
      any patient allele, which is precisely the gap.
  - reference: PMID:33385793
    reference_title: "Generation of an IPSC line from a patient with hypertrophic cardiomyopathy carrying a mutation in MYH6 gene."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The generated iPSC line expressed pluripotency markers, exhibited a normal karyotype, presented the specific mutation, and demonstrated differentiation potential into three germ layers in vitro."
    explanation: >-
      Establishes that a characterised patient-derived line carrying an MYH6 HCM
      allele already exists and is differentiation-competent, which is what makes
      this gap tractable.
  proposed_experiments:
  - experiment_id: exp_myh6_ipsc_cardiomyocyte_phenotyping
    name: Cardiomyocyte phenotyping of the MYH6 G3755A patient iPSC line
    description: >-
      Differentiate the existing patient-derived iPSC line and an isogenic
      variant-corrected control to ventricular cardiomyocytes and compare
      contractile and sarcomeric readouts. An isogenic control is essential: the
      line is from a single patient, so any uncorrected comparison confounds the
      allele with genetic background.
    would_support:
    - pathophysiology#Altered Sarcomere Motor Function
    would_refute:
    - pathophysiology#Altered Sarcomere Motor Function
    supporting_outcome:
    - >-
        Variant cardiomyocytes show altered contractile kinetics or sarcomere
        disorganisation relative to the isogenic control, with the effect
        abolished by correction of the allele.
    refuting_outcome:
    - >-
        Variant and isogenic-corrected cardiomyocytes are indistinguishable
        across contractile and sarcomeric readouts, indicating the allele has no
        measurable effect in a human ventricular-like cell.
    perturbations:
    - name: Isogenic correction of the MYH6 G3755A allele
      target: pathophysiology#MYH6 Missense Variant in Alpha-Myosin Heavy Chain
      effect: DECREASED
      gene:
        preferred_term: MYH6
        term:
          id: hgnc:7576
          label: MYH6
      description: >-
        CRISPR correction of the patient allele to wild type in the derived iPSC
        line, giving an isogenic control that differs only at the variant site.
    readouts:
    - name: Sarcomere organisation in differentiated cardiomyocytes
      target: pathophysiology#Altered Sarcomere Motor Function
      interpretation: >-
        Disorganisation in the variant line relative to its isogenic control would
        be the first functional evidence for any HCM-attributed MYH6 allele.
- discussion_id: myh6_mouse_myh6_r403q_is_myh7_disease
  kind: HUMAN_MODEL_MISMATCH
  prompt: >-
    The reference mouse models of hypertrophic cardiomyopathy carry their
    mutations in Myh6. Does that make them models of human MYH6 disease?
  attaches_to:
  - pathophysiology#MYH6 Missense Variant in Alpha-Myosin Heavy Chain
  - animal_models#alpha-MHC 403/+ mouse (Myh6 R403Q knock-in)
  rationale: >-
    No, and the mismatch is a species-level isoform switch that is easy to miss
    because the gene symbol matches. The human ventricle runs predominantly on
    beta-MHC (MYH7) with alpha-MHC as a minor component; the mouse ventricle runs
    on alpha-MHC. To model a human MYH7 ventricular allele faithfully in a mouse,
    the field therefore put the human MYH7-derived R403Q substitution into mouse
    Myh6 — preserving the ventricular context by changing the gene. The resulting
    alpha-MHC 403/+ mouse and its descendants, including allele-specific silencing
    work targeting mutant Myh6 transcripts, form a large and influential
    literature indexed under Myh6 and hypertrophic cardiomyopathy that is
    substantively about MYH7 biology.

    This matters concretely for curation. A text- or database-driven search for
    MYH6 model evidence returns these mice first, and they look like strong
    support: the phenotype is convincing, the gene symbol is right, and the
    disease term is right. ClinGen reviewed them and declined to score them for
    exactly this reason. Any future strengthening of the MYH6-HCM relationship has
    to come from human alleles or from a model built on a human MYH6 allele, not
    from this body of work.
  evidence:
  - reference: CGGV:assertion_ee5380a4-0dee-49aa-b911-141502648144-2023-07-12T020000.000Z
    reference_title: "MYH6 / hypertrophic cardiomyopathy (Disputed)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "these mice models are not analogous to human MYH6"
    explanation: >-
      ClinGen's explicit statement of the mismatch, and its stated ground for
      excluding the mouse literature from the MYH6 gene-disease evaluation.
  - reference: PMID:6234108
    reference_title: "Myosin types in the human heart. An immunofluorescence study of normal and hypertrophied atrial and ventricular myocardium."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "heavy chain beta was found to be a major component of ventricular myosin and a minor component of atrial myosin"
    explanation: >-
      Establishes the human side of the species isoform difference that creates
      the mismatch.
- discussion_id: myh6_late_onset_skew_allele_or_ascertainment
  kind: KNOWLEDGE_GAP
  prompt: >-
    Is the late-onset skew of MYH6-attributed hypertrophic cardiomyopathy a
    property of the allele, or an artefact of how elderly-onset HCM cohorts are
    ascertained?
  attaches_to:
  - phenotypes#Late-Onset Presentation
  rationale: >-
    The late-onset association is the most reproducible observation about this
    entity — it appears in the founding elderly-onset series and independently in
    a later cohort designed to contrast extreme ages at diagnosis. But the same
    cohorts show that elderly-onset HCM has a far lower genetic yield overall
    (23% versus 86% in the early-onset arm of the Italian series), which is the
    signature of a group enriched for phenocopies and for variants of small or
    absent effect. A weak-effect allele producing genuinely late disease and a
    benign variant surfacing in a low-yield cohort predict the same observation.
    Distinguishing them requires case-control allele-frequency comparison in
    age-stratified cohorts rather than more case series, and the answer bears
    directly on whether the Disputed classification should move in either
    direction.

    The nearest existing approach to that comparison is the ExAC-referenced
    burden analysis of 7,855 cardiomyopathy cases, which found MYH6 rare
    variation indistinguishable from background. It does not settle the question
    here, for a reason worth stating so it is not misread later: MYH6 appears
    only in that study's dilated cardiomyopathy panel and not in its hypertrophic
    panel, and the analysis was not age-stratified. So it constrains the gene's
    general credibility rather than answering the age question, which remains
    open.
  evidence:
  - reference: PMID:27483260
    reference_title: "A Next-Generation Sequencing Approach to Identify Gene Mutations in Early- and Late-Onset Hypertrophic Cardiomyopathy Patients of an Italian Cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The mutation detection rate was 85.7% (30/35) in the EO group and 22.9% (8/35) in the LO group."
    explanation: >-
      Quantifies the low genetic yield of the late-onset arm in which MYH6
      variants were exclusively found, which is the basis for the ascertainment
      alternative.
- discussion_id: myh6_cooccurring_established_gene_variants
  kind: KNOWLEDGE_GAP
  prompt: >-
    How much of the reported MYH6 hypertrophic cardiomyopathy signal survives once
    probands carrying a variant in an established HCM gene are excluded?
  attaches_to:
  - pathophysiology#MYH6 Missense Variant in Alpha-Myosin Heavy Chain
  - phenotypes#Sudden Cardiac Death
  rationale: >-
    Co-occurrence is the dominant confounder in this literature rather than an
    occasional complication. ClinGen excluded reported MYH6 variants from scoring
    on the grounds that the proband also carried a variant in another HCM gene, in
    three separate publications — a Japanese family with a MYH6 frameshift
    alongside an MYH7 missense variant, a multi-omics pedigree study in which the
    MYH6 carrier also carried a TNNT2 variant, and part of the Italian NGS series.
    In each case the severe phenotype is at least as attributable to the
    established gene. What remains after those exclusions is three probands, and
    that residue is the whole quantitative basis of the entity.
  evidence:
  - reference: CGGV:assertion_ee5380a4-0dee-49aa-b911-141502648144-2023-07-12T020000.000Z
    reference_title: "MYH6 / hypertrophic cardiomyopathy (Disputed)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "but were not scored because probands have variants in another HCM gene"
    explanation: >-
      States the exclusion criterion and, with the accompanying citation list, its
      scope across the reported literature.
  - reference: PMID:34087240
    reference_title: "Identification of three novel pathogenic mutations in sarcomere genes associated with familial hypertrophic cardiomyopathy based on multi-omics study."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "The proband of Family 1 and his father carried TNNT2-rs397516484 and MYH6-rs372446459 missense mutations"
    explanation: >-
      A worked instance of the confound: the MYH6 carriers in this pedigree also
      carry a TNNT2 variant, so the phenotype cannot be attributed to MYH6.
references:
- reference: PMID:20301725
  title: "Nonsyndromic Hypertrophic Cardiomyopathy Overview."
  tags:
  - GeneReviews

📚

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 (1)

Create: Hypertrophic Cardiomyopathy 14 (MYH6, ClinGen Disputed) · 2026-09-01T03:29:32Z · View source

Created the MYH6-attributed node of the HCM gene series as a disputed nosological entity. ClinGen's Hereditary Cardiovascular Disease GCEP classifies MYH6-HCM as Disputed (downgraded from Limited 2023-07-12); the entity rests on three probands in two publications with no known mechanism. The entry curates it as a real MONDO entity whose pathophysiology is an explicit hypothesis under dispute, following the precedent of Hypertrophic_Cardiomyopathy_25 (TCAP, likewise Disputed). All four pathophysiology edges are scoped to a single mechanistic_hypotheses group; the unestablished step carries a NO_EVIDENCE item rather than being asserted or silently omitted. Two named-entity hazards are curated explicitly rather than left as prose. First, MYH6's Definitive association is congenital heart defects, not HCM; dismech already curates MYH6 as causative in Atrial_Septal_Defect and Dilated_Cardiomyopathy_1EE and as susceptibility in Familial_Sick_Sinus_Syndrome and Hypoplastic_Left_Heart_Syndrome (verified against each file's genetic[] block — an initial draft wrongly listed Sick_Sinus_Syndrome_2 and Dilated_Cardiomyopathy_1Z, which are HCN4 and TNNC1). Second, the reference mouse HCM models carry an MYH7-derived R403Q allele knocked into mouse Myh6 because the mouse ventricle expresses alpha-MHC where the human ventricle expresses beta-MHC; ClinGen declined to score them as MYH6 evidence. That is recorded as a HUMAN_MODEL_MISMATCH discussion plus a FAILS_TO_RECAPITULATE model link, so a text search for Myh6 plus HCM does not silently become support. Deep research: requested falcon, which is not configured in this environment; ran with --fallback, which recorded fell_back: true and produced research/Hypertrophic_Cardiomyopathy_14-deep-research-claude_code.md. Report validation was clean (24/24 references resolved, confabulation_rate 0.0; 79/82 terms resolved, 0 named as a different term, the 3 flagged being benign paraphrases). The report converged independently on the Disputed framing and contributed PMID:39971408, the 2025 JACC ClinGen reappraisal, which supplied the clinical-reporting consequence and a diagnosis section. The reappraisal abstract gives the count of downgraded genes rather than naming them; the explanation says so and attributes MYH6's membership to the ClinGen assertion record instead. Primary literature came from the ClinGen evidence summary rather than the report: PMID:11815426 (Niimura 2002, founding elderly-onset variant), PMID:15998695 (Carniel 2005, Q1065H), PMID:27483260 (Rubattu 2016, MYH6 confined to the late-onset arm), PMID:6234108 (Gorza 1984, alpha-MHC is the minor ventricular isoform), PMID:8614836, PMID:10388558, PMID:33385793, PMID:34087240, PMID:35911064, plus CGGV assertions for MYH6-HCM (Disputed) and MYH6-CHD (Definitive). No datasets block: with three probands worldwide and a disputed relationship there is no disease-specific dataset, and a gene-level search would return the ASD/sick-sinus/DCM phenotypes this entry exists to distinguish itself from. Validation: just validate passes (schema + terms); count-verified-snippets 49/49; check-entity-refs, check-causal-targets, check-duplicate-keys, check-qualifier-terms, check-enum-values, check-snippet-grading, check-environmental-evidence all OK; weighted compliance 94.8%. HGNC REST confirmed hgnc:7576 and the MYH6/MYH7 14q11.2 tandem pair; OLS confirmed the MONDO:0013197 OMIM:613251 xref.

Claude Code ▸

1. Disease Information

claude-haiku-4-5-20251001, claude-opus-5[1m] 27 citations 2026-08-31T23:24:22.214256

1. Disease Information

Overview

Hypertrophic cardiomyopathy 14 (CMH14) is the MYH6-attributed member of the numbered OMIM hypertrophic cardiomyopathy series. It denotes hypertrophic cardiomyopathy — unexplained left ventricular hypertrophy, classically asymmetric and septal, not explained by loading conditions — in a person carrying a heterozygous missense variant in MYH6, encoding the α (alpha) heavy chain of cardiac myosin. It is not a clinically distinguishable entity: no CMH14-specific phenotype, imaging finding, natural history, or treatment exists. Its only definitional feature is the genotype, and that genotype–phenotype link is the disputed one.

The concept traces to exactly two publications:

Niimura et al., Circulation 2002 (PMID:11815426) — one MYH6 missense variant (R795Q) among 31 patients with elderly-onset HCM.
Carniel et al., Circulation 2005 (PMID:15998695) — one MYH6 missense variant (Q1065H) in 1 of 21 HCM probands.

ClinGen's tally: "It has been associated with HCM in 3 probands in 2 publications. Four unique heterozygous missense variants have been reported in humans with limited evidence to support their pathogenicity."

Key identifiers

Resource	Identifier
MONDO	MONDO:0013197 — "hypertrophic cardiomyopathy 14"
OMIM (phenotype)	613251 — CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 14; CMH14
OMIM (gene)	160710 — MYH6
HGNC	hgnc:7576 — MYH6 (note lowercase prefix per repo convention)
NCBI Gene	4624
Ensembl	ENSG00000197616
UniProt	P13533 (MYH6_HUMAN, myosin-6 / α-MHC)
Cytogenetic location	14q11.2
RefSeq transcript	NM_002471.4
Orphanet	No dedicated code. Closest is ORPHA:217569 (familial isolated hypertrophic cardiomyopathy). Orphanet does not maintain per-gene HCM numbers.
ICD-10	I42.1 (obstructive HCM), I42.2 (other HCM)
ICD-11	BC43.0 (hypertrophic cardiomyopathy)
MeSH	D002312 "Cardiomyopathy, Hypertrophic, Familial"
Parent MONDO	MONDO:0005045 (hypertrophic cardiomyopathy)

Synonyms

CMH14; cardiomyopathy, familial hypertrophic, 14; hypertrophic cardiomyopathy caused by mutation in MYH6; MYH6-related hypertrophic cardiomyopathy; α-myosin heavy chain hypertrophic cardiomyopathy. (The existing YAML synonym list is correct.)

Provenance of the underlying information

Aggregated disease-level resources plus a very small number of individual case reports. There is no EHR cohort, registry, or biobank study of CMH14 as such — the total human evidence base is 3 probands. The most informative sources are meta-level: the ClinGen curation record, the Walsh et al. case-vs-control burden analysis (PMID:27532257), and gnomAD population frequencies.

2. Etiology

Disease causal factors

Asserted: heterozygous missense variation in MYH6 (14q11.2), autosomal dominant, acting on the α-cardiac myosin heavy chain motor.

Actual evidentiary status: the causal claim does not survive contemporary gene-level burden analysis. Walsh et al. (PMID:27532257) compared variant burden in cardiomyopathy cases against ExAC and reported for MYH6 an excess-variant odds ratio of 1.06 (95% CI 0.34–3.34) with an etiological fraction of 0.06 (0.00–0.70) — i.e. indistinguishable from background. The paper names MYH6 explicitly as one of the offenders:

"For example, MYBPC3, MYH6, and SCN5A have all been reported to be major contributors to DCM but show little or no excess burden despite adequate numbers and power; instead, we see that these are in fact genes that have the highest background variation." — Walsh et al., Genet Med 2017 (PMID:27532257)

This is the mechanistic crux: MYH6 carries an unusually high rate of rare missense variation in unselected populations (gnomAD v4 pLI = 0, LOEUF ≈ 0.63; it is not LoF-constrained), so a rare MYH6 missense allele found in an HCM proband is a weak observation. The A1004S variant, reported in DCM, sits at ~1.1% in the general population (Anfinson et al. 2022, PMID:35621855) — far commoner than the disease.

ClinGen also discounted the Carniel proband on exactly this ground: "Additional missense variants have been reported in humans, but were not scored because probands have variants in another HCM gene (Rubattu et al. 2016… Liu et al. 2021… Suzuki et al. 2022), or high frequency in the population (Carniel et al. 2005)."

Genetic risk factors

Candidate causal variants (the entire reported set for HCM):

Variant	cDNA	Domain	Source	Current ClinVar status
p.Arg795Gln	c.2384G>A, rs267606907	head/converter region	Niimura 2002 (PMID:11815426)	Uncertain significance (VarID 14147; 5/6 submitters VUS; OMIM's 2002 "Pathogenic" no longer contributes). gnomAD exomes AF 0.00004; TOPMed 0.00002
p.Gln1065His	c.3195G>C, rs267606904	S2/tail	Carniel 2005 (PMID:15998695)	Conflicting (VarID 14149; 6 VUS + 3 likely benign). gnomAD overall AF ≈ 0.00015; ~0.1% in East Asian ancestry (ExAC)
MYH6-rs372446459	—	—	Liu 2021 (PMID:34087240)	Co-occurred with TNNT2-rs397516484 in the same proband — not scorable in isolation
p.Lys364fs (c.1091_1092insTGAA)	frameshift	head	Suzuki 2022 (PMID:35911064)	Co-occurred with MYH7 p.Pro731Thr — the MYH7 allele is the parsimonious explanation

Rubattu et al. (PMID:27483260) found MYH6 variants in 3/41 (7.5%) of identified variants in a 70-patient Italian NGS cohort, and noted a distribution signal worth recording:

"The distribution of the identified gene mutations was similar between the two groups with the exceptions of MYH6 and TNNT2. In fact, mutations in MYH6 were identified in the LO group only, whereas mutations in TNNT2 were identified in the EO group only." — Rubattu et al. 2016 (PMID:27483260), late-onset (≥65 y) vs early-onset (≤25 y)

This converges with Niimura's original elderly-onset finding and is the only replicated phenotypic association in the literature: to whatever extent MYH6 variants associate with HCM at all, they do so in late-onset, family-history-negative disease — the phenotype for which the causal prior is weakest and phenocopy risk highest.

Susceptibility / modifier loci: none established for CMH14. The general HCM modifier landscape (common-variant polygenic scores, hypertension, sarcomere-negative status) applies non-specifically and is not MYH6-informed.

Related MYH6 gene–disease relationships (ClinGen, HGNC:7576) — these are the important nosological neighbours and should be recorded in the entry, because they show the gene is real even where the HCM link is not:

Disease	MONDO	MOI	ClinGen classification	Date
MYH6-related congenital heart defects	MONDO:0800442	AD	Definitive	2023-05-09
Dilated cardiomyopathy 1EE	MONDO:0013198	AD	Limited	2026-03-04
Hypertrophic cardiomyopathy	MONDO:0005045	AD	Disputed	2023-07-12

MYH6 also carries a well-replicated arrhythmia association outside ClinGen's HCM curation — see §3.

Environmental risk factors

None specific to CMH14. Generic HCM modifiers of phenotype expression: age, systemic hypertension (HP:0000822), athletic conditioning (a diagnostic confounder rather than a cause), obesity, and male sex. None have been studied in MYH6 carriers.

Protective factors

Not established. No protective MYH6 allele is described. Guideline-era HCM care (ICD for primary prevention, septal reduction, myosin inhibitors) modifies outcome but is disease-level, not genotype-level.

Gene–environment interactions

Not applicable / not studied for CMH14. No GxE literature exists for MYH6 in HCM. Note one genuinely interesting environmental observation for the gene: Gorza et al. (PMID:6234108) showed that chronic haemodynamic overload shifts human atrial MHC composition toward β, i.e. the α-MHC content of the tissue where MYH6 actually dominates is itself load-dependent. That is a mechanism-relevant load–isoform interaction, but it has never been tested against MYH6 genotype.

3. Phenotypes

There is no CMH14-specific phenotype. The phenotype list below is the OMIM 613251 clinical synopsis and the HCM phenotype in general. Frequencies are HCM-level, not MYH6-level, and must be curated with that qualifier — the 3-proband evidence base cannot support any frequency claim.

Core cardiac phenotypes (all `category: Cardiovascular`)

Phenotype	HP term	Onset	Severity	Course	Frequency (HCM overall)
Hypertrophic cardiomyopathy	`HP:0001639` Hypertrophic cardiomyopathy	3rd–8th decade (per OMIM 613251)	Variable	Progressive	Definitional
Left ventricular hypertrophy	`HP:0001712` Left ventricular hypertrophy	as above	Max wall thickness 19.9 ± 3.8 mm in the Niimura elderly cohort	Progressive	Definitional
Asymmetric septal hypertrophy	`HP:0001670` Asymmetric septal hypertrophy	as above	Variable	Progressive	Majority
Systolic anterior motion of mitral valve / LVOT obstruction	(no clean HP term; use `preferred_term` + `HP:0001653` Mitral regurgitation for the consequence)	as above	SAM in 58% of Niimura cohort; LVOT gradient mean 63 ± 42.8 mmHg in 11 patients	Dynamic, load-dependent	~1/3 at rest in HCM broadly
Exertional dyspnea	`HP:0002875` Exertional dyspnea	Adult	Mild–severe	Progressive	Most common presenting symptom
Chest pain / angina	`HP:0100749` Chest pain; `HP:0001681` Angina pectoris	Adult	Variable	Episodic, exertional	Common
Syncope	`HP:0001279` Syncope; `HP:0031972` Presyncope	Adult	Variable	Episodic	~15–25% in HCM
Palpitations	`HP:0001962` Palpitations	Adult	Mild–moderate	Episodic	Common
Atrial fibrillation	`HP:0005110` Atrial fibrillation	Adult, rises with age	Moderate	Paroxysmal → persistent	~20% lifetime in HCM
Left atrial enlargement	`HP:0031295` Left atrial enlargement	Adult	—	Progressive	Common
Ventricular arrhythmia / VT	`HP:0004308` Ventricular arrhythmia; `HP:0004756` Ventricular tachycardia	Adult	Severe	Episodic	NSVT ~20–30% on monitoring
Sudden cardiac death	`HP:0001645` Sudden cardiac death	Any age	Fatal	Acute	~0.5%/yr contemporary HCM
Congestive heart failure	`HP:0001635` Congestive heart failure	Late	Severe	Progressive	Minority; end-stage
Myocardial fibrosis	`HP:0001685` Myocardial fibrosis	Adult	—	Progressive	LGE on CMR in ~60%
Cardiac arrest	`HP:0001695` Cardiac arrest	Any	Fatal/near-fatal	Acute	Minority

OMIM 613251 clinical synopsis phenotype set, per the entry: ventricular hypertrophy (often asymmetric, involving the interventricular septum); dyspnea; syncope; collapse; palpitations; chest pain — exercise-triggered. Age of onset third to eighth decade. Variability within and between families, "ranging from benign to malignant forms with a high risk of cardiac failure and sudden cardiac death."

The MYH6-specific phenotype signals that are real (and are not HCM)

These belong in the entry as differential/context, not as CMH14 phenotypes:

Sick sinus syndrome (HP:0011704) — the single best-supported MYH6 human phenotype association:

"A missense variant in this gene, c.2161C>T, results in the conceptual amino acid substitution p.Arg721Trp, has an allelic frequency of 0.38% in Icelanders and associates with sick sinus syndrome with an odds ratio = 12.53 and P = 1.5 × 10⁻²⁹. We show that the lifetime risk of being diagnosed with sick sinus syndrome is around 6% for non-carriers of c.2161C>T but is approximately 50% for carriers." — Holm et al., Nat Genet 2011 (PMID:21378987)

Also HP:0001688 Sinus bradycardia, HP:0012722 Heart block.

Atrial septal defect (HP:0001631) — the ClinGen Definitive MYH6 relationship:

"The underlying mutation is a missense substitution, I820N, in alpha-myosin heavy chain (MYH6), a structural protein expressed at high levels in the developing atria, which affects the binding of the heavy chain to its regulatory light chain." — Ching et al., Nat Genet 2005 (PMID:15735645)

Hypoplastic left heart syndrome with reduced RV EF — recessive/compound-heterozygous MYH6:

"Secondary family-based filtering for de novo and recessive variants revealed rare inherited missense mutations on both paternal and maternal alleles of MYH6… in 2 patients who developed right ventricular dysfunction 3 to 11 years postoperatively. Parents and siblings who were heterozygous carriers had normal echocardiograms." — Theis et al., Circ Cardiovasc Genet 2015 (PMID:26085007)

Dilated cardiomyopathy (HP:0001644) — Carniel's same paper that supplied the HCM proband found three DCM probands (P830L, A1004S, E1457K), and framed MYH6 as a pleiotropic locus:

"This study suggests that mutations in MYH6 may cause a spectrum of phenotypes ranging from DCM to HCM." — Carniel et al. 2005 (PMID:15998695)

That pleiotropy claim, read alongside the burden data, is better explained as non-specific rare variation than as a genuine allelic series.

Quality-of-life impact

No CMH14-specific QoL data. HCM-level: the disease-specific instrument is the Kansas City Cardiomyopathy Questionnaire (KCCQ-23/KCCQ-CSS), used as a primary or key secondary endpoint in EXPLORER-HCM and SEQUOIA-HCM; generic instruments are SF-36 and EQ-5D. Dominant QoL drivers in HCM are exertional limitation, ICD-related anxiety and shock burden, activity restriction, and reproductive/family-screening distress. Not available for CMH14 specifically — do not curate a per-phenotype QoL claim.

4. Genetic / Molecular Information

Causal gene

MYH6 (myosin heavy chain 6, cardiac muscle, alpha), hgnc:7576, OMIM 160710, 14q11.2, transcript NM_002471.4, protein NP_002462.2 / UniProt P13533 (1939 aa). It lies head-to-head with MYH7 (β-MHC) in a tandem gene cluster; the two proteins are ~93% identical, which is exactly why the MYH7 mechanistic literature has been borrowed to explain MYH6 and exactly why that borrowing is unsafe.

Weiss et al. sequenced the whole family and drew the relevant conclusion about how these isoforms differ:

"Results indicate that functional diversity among MyHCs is likely to be accomplished by having small pockets of sequence diversity in an otherwise highly conserved molecule." — Weiss et al., J Mol Biol 1999 (PMID:10388558) — cited by ClinGen as part of the (limited) experimental support

Pathogenic variants

Covered in §2. Key point for the KB: not one MYH6 variant is currently classified Pathogenic or Likely Pathogenic for HCM by any ClinVar submitter applying ACMG/AMP criteria. The two OMIM allelic variants are VUS (R795Q) and conflicting-VUS/likely-benign (Q1065H). Curate functional_impact_category as absent or UNKNOWN, not GAIN_OF_FUNCTION — the schema's FunctionalImpactEnum should not be used to assert a consequence nobody has demonstrated.

Variant type/class: missense throughout (one reported frameshift, p.Lys364fs, in a proband also carrying an MYH7 variant).
Somatic vs germline: germline only. No somatic role; MYH6 is not a COSMIC/cancer gene in this context.
Population frequency: see table in §2. The population-genetic signature is the diagnostic problem — MYH6 is not LoF-constrained (gnomAD v4 pLI 0, LOEUF ≈ 0.63) and carries high background missense variation.
Functional consequences: unknown for the HCM-reported alleles. The functional work that exists is on other MYH6 alleles from other phenotypes (see §6).

Modifier genes

None established. What the literature actually shows is oligogenic confounding rather than modification: two of the four HCM-reported MYH6 probands also carried a variant in a definitive HCM gene (TNNT2, MYH7). Suzuki et al. argued the double hit drives severity —

"Family members with the double variants demonstrated severe phenotypes, such as sudden cardiac-related death and heart failure. These double variants were well segregated and might be responsible for the severity of cardiovascular events in affected family members." — Suzuki et al., J Cardiol Cases 2022 (PMID:35911064)

— but ClinGen declined to score these, and the parsimonious reading is that the definitive-gene allele is causal and MYH6 is a passenger. If dismech curates this, relationship_type: MODIFIER on the MYH6 genetic: entry with an explicit notes: stating the alternative interpretation would be honest; asserting modification would not.

Epigenetic information

Not available for CMH14. No methylation, histone, or chromatin study addresses MYH6 variant carriers. The MYH6/MYH7 locus is under well-characterised developmental and hormonal (thyroid hormone) transcriptional control and is regulated by the Mir-208a intronic miRNA within Myh6, plus antisense/lncRNA regulation of the MYH7/MYH6 switch — but this is isoform-switch biology, not CMH14 epigenetics. Do not curate as disease mechanism.

Chromosomal abnormalities

Not applicable. No CNV, translocation, or aneuploidy mechanism; ClinGen records no dosage-sensitivity curation for MYH6 (0 classifications), so haploinsufficiency and triplosensitivity are both unassessed.

5. Environmental Information

Environmental factors: none identified. No toxicological, radiation, occupational, or pollutant association with CMH14 (CTD has no MYH6–HCM environmental interaction of note).
Lifestyle factors: high-intensity competitive athletics is relevant to HCM management (risk stratification, shared decision-making on participation per the 2024 AHA/ACC guideline) and to differential diagnosis (athlete's heart), but is not an aetiological factor. Hypertension and obesity influence LVH phenotype non-specifically.
Infectious agents: not applicable.

For the dismech environmental: block: I would leave it empty rather than manufacture entries. If the check-environmental-evidence gate ever needs an answer here, the waiver sentence form ("Left deliberately uncited." + ≥20 words of recorded search) is the right instrument.

6. Mechanism / Pathophysiology

Ordered causal chain

Read this whole section as inference. ClinGen's verdict — "The mechanism for disease remains unknown" — is the primary finding. Every arrow below is either (a) demonstrated for a different MYH6 allele in a different phenotype, or (b) demonstrated for MYH7 and transposed. I mark each step accordingly.

Branch A — the asserted (MYH7-analogy) chain, entirely INFERRED for MYH6:

A heterozygous MYH6 missense allele results in a single amino acid substitution in α-cardiac myosin heavy chain. [Demonstrated — this is just the variant.]
The substituted residue is predicted to perturb motor-domain, converter, lever-arm, or coiled-coil tail structure. [Computational only. Carniel: "All MYH6 mutations were distributed in highly conserved residues, were predicted to change the structure or chemical bonds of alphaMyHC." Note "predicted" — no biophysical assay was done on Q1065H or R795Q. The human α-MHC structure has never been solved; all structural inference is by homology to β-MHC (Anfinson 2022, PMID:35621855).]
Altered actomyosin cross-bridge kinetics lead to hypercontractility with impaired relaxation and inefficient ATP utilisation. [Transposed from MYH7. Never measured for any HCM-reported MYH6 allele.]
Sarcomeric energetic stress and altered Ca²⁺ handling lead to activation of hypertrophic signalling in ventricular cardiomyocytes (CL:0002131 regular ventricular cardiac myocyte). [Inferred.]
Hypertrophic signalling results in cardiomyocyte hypertrophy and myofibrillar disarray (GO:0014898 cardiac muscle hypertrophy in response to stress). [Inferred.]
Sustained hypertrophy plus microvascular ischaemia result in interstitial and replacement fibrosis via cardiac fibroblast (CL:0000057 fibroblast) activation → HP:0001685 Myocardial fibrosis. [Inferred; established for HCM generally.]
Asymmetric septal thickening (UBERON:0002094 interventricular septum) results in dynamic LVOT obstruction with systolic anterior motion of the mitral valve → HP:0001653 Mitral regurgitation and HP:0002875 Exertional dyspnea. [Established for HCM; not MYH6-attributed.]
Diastolic stiffening results in elevated filling pressures → HP:0031295 Left atrial enlargement → HP:0005110 Atrial fibrillation.
Fibrosis and disarray create a re-entrant substrate → HP:0004756 Ventricular tachycardia → HP:0001645 Sudden cardiac death.

Branch B — the alternative and arguably better-supported chain, "MYH6 is an atrial gene":

α-MHC is the atrial-predominant isoform in the adult human heart, a minor ventricular component. [Demonstrated.]

"Myosin heavy chain alpha was found to be a major component of atrial myosin and a minor component of ventricular myosin, while heavy chain beta was found to be a major component of ventricular myosin and a minor component of atrial myosin." — Gorza et al., Circ Res 1984 (PMID:6234108) — the expression evidence ClinGen scored

A MYH6 missense allele therefore acts principally on atrial cardiomyocytes (CL:0002129 regular atrial cardiac myocyte) and the developing atrium, not the adult LV. Anfinson et al. found exactly this pattern in patient tissue: "atrial sarcomeres were disrupted with the R443P, K849del, and E1503V variants, while the ventricular sarcomere structure remained intact… consistent with α-MHC being the predominant atrial MHC isoform postnatally." (PMID:35621855)
Atrial sarcomere disorganisation and contractile impairment lead to the phenotypes MYH6 is definitively or strongly associated with — atrial septal defect, sick sinus syndrome, HLHS — and do not straightforwardly lead to ventricular hypertrophy.
Where ventricular pathology is seen in MYH6 carriers, it may be secondary to atrial dysfunction: "Given the predominance of β-MHC in the postnatal ventricles, it is possible that ventricular fibrosis is, at the cellular level, a downstream response to atrial cardiomyocyte dysfunction caused by MYH6 variants in the patients studied." (PMID:35621855)

Branch B is the single most useful thing in this report for dismech. It explains why the MYH6–HCM link is weak on first principles — the gene's product is barely present in the tissue that hypertrophies — and it converts an "absence of evidence" curation into a positive mechanistic statement. It also has an elegant model-organism proof of the atrial→ventricular direction:

"We find that the zebrafish locus weak atrium encodes an atrium-specific myosin heavy chain that is required for atrial myofibrillar organization and contraction… However, the weak atrium mutant ventricle becomes unusually compact, exhibiting a thickened myocardial wall, a narrow lumen and changes in myocardial gene expression. As weak atrium/atrial myosin heavy chain is expressed only in the atrium, the ventricular phenotypes in weak atrium mutants represent a secondary response to atrial dysfunction." — Berdougo et al., Development 2003 (PMID:14573521)

A thickened ventricular myocardial wall arising secondarily to an atrium-restricted myosin defect is the closest thing in the whole literature to a mechanism by which MYH6 could produce ventricular hypertrophy — and it is a zebrafish nonsense allele, not a human HCM missense allele. Curate it as evidence_source: MODEL_ORGANISM, directness: INDIRECT, and say plainly in explanation what the inference step is.

Molecular pathways

Actomyosin cross-bridge cycling / thick-filament regulation. Reactome R-HSA-390522 (Striated Muscle Contraction); KEGG hsa04260 (Cardiac muscle contraction) and hsa05410 (Hypertrophic cardiomyopathy).
Downstream hypertrophic signalling implicated in HCM generally (calcineurin–NFAT, MAPK, PI3K–AKT–mTOR, TGF-β to fibroblasts) — none demonstrated for MYH6.

Cellular processes (GO — all CURIEs below verified against `cache/go/terms.csv`)

GO term	Label
`GO:0060048`	cardiac muscle contraction
`GO:0086003`	cardiac muscle cell contraction
`GO:0055117`	regulation of cardiac muscle contraction
`GO:0002026`	regulation of the force of heart contraction
`GO:0030049`	muscle filament sliding
`GO:0000146`	microfilament motor activity
`GO:0016887`	ATP hydrolysis activity
`GO:0051015`	actin filament binding
`GO:0003779`	actin binding
`GO:0030017`	sarcomere (CC)
`GO:0032982`	myosin filament (CC)
`GO:0014898`	cardiac muscle hypertrophy in response to stress
`GO:0055008`	cardiac muscle tissue morphogenesis
`GO:0002027`	regulation of heart rate
`GO:0086001`	cardiac muscle cell action potential

For a CMH14 node, GO:0000146 / GO:0016887 / GO:0051015 with modifier: UNKNOWN-equivalent (i.e. omit modifier) is more honest than tagging GAIN_OF_FUNCTION. Per the repo's GOF/LOF guidance, "the pathway is very active" would be INCREASED; here nobody has measured whether it is.

Protein dysfunction

α-MHC is an ATP-driven actin-based motor; ClinGen scored biochemical function evidence for "MHC-α interactions with ATP, actin and the light chains (Weiss et al. 1999)." The functional studies that exist target non-HCM alleles:

I820N (ASD): decreases α-MHC affinity for the regulatory light chain (Ching 2005, PMID:15735645).
E933del (SSS): enhances MyBP-C binding; slows electrical propagation in HL-1 atrial cardiomyocytes; disrupts sarcomere structure with perinuclear α-MHC aggregation in NRVCMs.
R721W (SSS): disrupted sarcomere structure and perinuclear aggregation in NRVCMs.
A230P, A1366D, E526K, R1822_E1823dup, R443P: decreased sarcomere organisation in cultured cardiomyocytes; H252Q increased myofibril striations; V700M no effect despite being predicted damaging.
A1004S (DCM): slower and reduced shortening in NRVCMs; P830L (DCM): no difference from WT — the opposite of what the structural prediction implied.

All from Anfinson et al. 2022 (PMID:35621855). The pattern is important: in vitro effect does not track with in silico prediction, and no HCM-reported allele has been assayed at all. Anfinson also notes: "At present, no such 'mutational hotspots' have been identified in MYH6" — unlike MYH7, where clustering informs ACMG/AMP classification.

Metabolic changes

Liu et al. (PMID:34087240) reported metabolomic disturbance in a pedigree carrying MYH6-rs372446459 together with TNNT2-rs397516484:

"They also showed disturbances of carbohydrate metabolism, including the citrate cycle (TCA cycle), glycolysis/gluconeogenesis, fructose and mannose metabolism, pentose and glucuronate interconversions and amino sugar and nucleotide sugar metabolism."

Do not attribute this to MYH6. The proband carried two sarcomere variants; the metabolomic signal cannot be assigned. If curated, it needs directness: INDIRECT and an explanation naming the confound.

Immune system involvement

Not applicable. No autoimmune or immunodeficiency component.

Tissue damage mechanisms

Myocardial fibrosis (HP:0001685), microvascular dysfunction/ischaemia, and myocyte disarray are the canonical HCM tissue lesions — established for HCM, unstudied in MYH6 carriers. Anfinson notes other groups have reported fibrosis in MYH6 carriers' conduction system, ventricular walls, and ventricular septum.

Biochemical abnormalities / epigenetic changes / molecular profiling

Transcriptomics: GTEx confirms MYH6 atrial-appendage-predominant expression. No CMH14 case–control transcriptomic dataset exists. One relevant in-vitro finding: MYH6-R443P iPSC-CMs showed "sarcomere disorganization and the upregulation of MYH7" — an isoform-compensation signal (PMID:35621855).
Proteomics, metabolomics, lipidomics, spatial transcriptomics, single-cell, multi-omics, CRISPR/RNAi screens: no CMH14-specific data. Do not populate a datasets: block by relaxing the search to "MYH6" or to "hypertrophic cardiomyopathy" — that is precisely the Named Entity Confusion trap the repo's dataset guidance warns about (searching a causal gene surfaces whatever disease the gene is famous for; here that would return ASD/HLHS/SSS datasets, and relaxing to the parent term collapses CMH14 into generic HCM). If datasets: is populated at all, every accession needs just verify-datasets plus manual relevance triage, and I would expect the honest answer to be an empty block.

7. Anatomical Structures Affected

Organ level

Primary: heart (UBERON:0000948); specifically the left ventricle (UBERON:0002084 heart left ventricle), left ventricular myocardium (UBERON:0006566), interventricular septum (UBERON:0002094), myocardium (UBERON:0002349).
On the Branch-B mechanism, the primary site is instead the cardiac atrium — right cardiac atrium (UBERON:0002078) and the atrial septum / cardiac septum (UBERON:0002099) — plus the sinoatrial node region.
Secondary: pulmonary circulation (post-capillary pulmonary hypertension from elevated filling pressures); systemic circulation and brain (cardioembolic stroke from AF).
Body system: cardiovascular, exclusively. CMH14 is a non-syndromic, heart-restricted phenotype — no skeletal, neurological, renal, or dermatological involvement, which is a useful negative for differential diagnosis against syndromic LVH mimics.

Tissue and cell level

Cell type	CL term	Role
cardiac muscle cell	`CL:0000746`	general
regular ventricular cardiac myocyte	`CL:0002131`	site of asserted hypertrophy/disarray
regular atrial cardiac myocyte	`CL:0002129`	site where α-MHC actually predominates
fibroblast	`CL:0000057`	interstitial fibrosis
cardiac endothelial cell	`CL:0010008`	microvascular dysfunction
Purkinje myocyte	`CL:0002068`	conduction-system involvement (relevant to the SSS/conduction phenotypes)

Tissue types: striated cardiac muscle; cardiac connective tissue/interstitium.

Subcellular level

Sarcomere (GO:0030017), thick/myosin filament (GO:0032982), A-band and M-band, contractile fibre. Mitochondrial energetic involvement is inferred from MYH7 biology, not shown for MYH6.

Localization and lateralization

Bilateral in the sense of being a whole-organ genetic disease, but the hypertrophy is characteristically asymmetric — septal-predominant, with the basal anteroseptum the classic site (HP:0001670). Apical, mid-cavity, and concentric variants occur. On Branch B the relevant asymmetry is chamber-level (atrial > ventricular), not wall-level.

8. Temporal Development

Onset

OMIM 613251: "variable age of onset from the third to eighth decade of life."
The replicated signal is late onset. Niimura's cohort: "Initial symptoms occurred at 59.3 (+/-12.3) years, and diagnosis was made at 62.8 (+/-10.8) years. None had family histories of cardiomyopathy." Carniel's HCM proband was diagnosed at 27 and died of congestive heart failure at 45 — the exception. Rubattu found MYH6 variants only in the late-onset (≥65 y) group.
Onset pattern: insidious and chronic. Hypertrophy develops subclinically; presentation is usually with exertional symptoms, an incidental murmur/ECG abnormality, or a family/screening echo.
HPO onset: Adult onset / Middle age onset / Late onset are the defensible categories. Do not curate childhood onset for CMH14.

Note the epistemic trap here. Elderly-onset, family-history-negative HCM is exactly the setting where a rare missense variant is least likely to be causal and a phenocopy (hypertensive LVH, cardiac amyloidosis, age-related sigmoid septum) is most likely — and it is the only setting where MYH6 variants have been replicated. Niimura's own framing acknowledged the distributional oddity: "The distribution of mutations in elderly-onset disease is strikingly different (P<0.00001) from that of familial, early onset hypertrophic cardiomyopathy."

Progression

Stages: the HCM natural-history stages apply — (i) subclinical/G+P− genotype-positive phenotype-negative; (ii) classic hypertrophic phase with or without obstruction; (iii) adverse remodelling; (iv) end-stage/"burnt-out" HCM with systolic dysfunction (EF <50%), affecting ~3–5% of HCM patients.
Rate: slow and variable over decades.
Course: chronic, progressive, lifelong; punctuated by episodic arrhythmic events.
The one CMH14-specific progression claim in the literature is Carniel's, and it is derived from a single proband: "the HCM phenotype was characterized by progression toward dilation, left ventricular dysfunction, and refractory heart failure." If curated as a progression: phase, it needs an explicit n=1 caveat in notes — a single patient cannot establish a phenotype's natural history.

Patterns

Remission: none spontaneous. Obstruction is relieved by septal reduction therapy or myosin inhibition, and symptoms remit; the myopathy does not.
Critical periods: adolescence/early adulthood is the window of maximal hypertrophy development in sarcomeric HCM and drives the paediatric screening schedule — but is likely irrelevant to a late-onset MYH6 phenotype. For the definitive MYH6 congenital phenotypes, the critical period is cardiac septation in embryogenesis.

9. Inheritance and Population

Epidemiology

HCM overall: phenotypic prevalence classically ~1 in 500 (0.2%; 200 per 100,000). The JACC reappraisal opens with exactly this figure: "Hypertrophic cardiomyopathy (HCM) is an inherited cardiac condition affecting ∼1 in 500 and exhibits marked genetic heterogeneity." (PMID:39971408). Genotypic prevalence including non-penetrant carriers may approach 1 in 200.
CMH14 specifically: no prevalence estimate exists and none can be constructed. With 3 probands worldwide and a disputed gene–disease relationship, the correct dismech prevalence record is measure_type: CASES_IN_LITERATURE with prevalence_class: NOT_YET_DOCUMENTED (or UNKNOWN) and notes recording the 3-proband count. Do not compute a rate_per_100000.
Incidence: not available.

For genetic etiology

Inheritance pattern: autosomal dominant as asserted (ClinGen MOI: AD). HPO HP:0000006 Autosomal dominant inheritance.
Penetrance: unknown and, on the burden data, likely very low or zero for the reported alleles. Note the instructive contrast: for the sick sinus syndrome association, penetrance is quantified and high (lifetime risk ~50% for R721W carriers vs ~6% non-carriers, Holm 2011). Nothing comparable exists for HCM.
Expressivity: OMIM describes "variability within and between families, ranging from benign to malignant forms." With n=3, this is HCM-general language, not a CMH14 observation.
Genetic anticipation: not applicable (not a repeat-expansion disorder).
Germline mosaicism: not reported.
Founder effects: none for HCM alleles. There is a MYH6 founder-like signal for a different phenotype — R721W at 0.38% allele frequency in Icelanders (Holm 2011) — worth recording as context but not as CMH14 epidemiology.
Consanguinity: not relevant to the dominant HCM claim. It is relevant to the recessive MYH6–HLHS mechanism (compound heterozygosity; Theis 2015).
Carrier frequency: not applicable to a dominant condition. The relevant population figure is the allele frequency of the reported variants (§2) — and their commonness relative to the disease is the argument against pathogenicity.

Population demographics

Affected populations: no ethnic enrichment for CMH14. Q1065H is notably commoner in East Asian ancestry (~0.1% in ExAC), which further undercuts pathogenicity rather than indicating a founder disease population.
Geographic distribution: reported probands are from US (Niimura), US/Italy (Carniel), Italy (Rubattu), China (Liu; Wang iPSC line), and Japan (Suzuki). This is publication geography, not disease geography.
Sex ratio: not established for CMH14. HCM overall is diagnosed more often in men (roughly 3:2), though this partly reflects ascertainment; women present later and with worse outcomes. Niimura's late-onset cohort was 18 women / 13 men.
Age distribution: skewed late — see §8.

10. Diagnostics

CMH14 is diagnosed as HCM plus a genotype. There is no CMH14-specific test.

Clinical tests

Modality	Findings	Notes
Transthoracic echocardiography	LV wall thickness ≥15 mm (≥13 mm with family history), asymmetric septal hypertrophy, SAM of the mitral valve, dynamic LVOT gradient (rest + Valsalva + exercise provocation), diastolic dysfunction, LA enlargement	First-line. Niimura cohort: max wall thickness 19.9 ± 3.8 mm, SAM in 58%, LVOT gradient mean 63 ± 42.8 mmHg in 11 patients
Cardiac MRI with LGE	Confirms wall thickness where echo windows are poor; quantifies late gadolinium enhancement (fibrosis); detects apical/anterolateral hypertrophy and apical aneurysm	Extensive LGE (≥15% LV mass) is an SCD risk modifier in the 2024 AHA/ACC guideline
12-lead ECG	LVH voltage, repolarisation abnormality, deep narrow Q waves, giant negative T waves (apical HCM). Abnormal in >90% of HCM	Also the modality that would detect the MYH6-associated conduction phenotypes: sinus bradycardia, sinus pauses, AV block
Ambulatory ECG (24–48 h Holter / extended)	NSVT detection for SCD risk stratification; AF detection	Guideline-recommended at diagnosis and periodically
Exercise stress testing	Provokable LVOT gradient; abnormal blood-pressure response; functional capacity
Laboratory	NT-proBNP / BNP; high-sensitivity troponin. Critically, the amyloid rule-out panel: serum/urine immunofixation, serum free light chains, and ⁹⁹ᵐTc-PYP/DPD bone scintigraphy	In a 60–80-year-old with new LVH — the CMH14 demographic — transthyretin cardiac amyloidosis is the single most important phenocopy to exclude
Endomyocardial biopsy	Myocyte hypertrophy, myofibrillar disarray, interstitial fibrosis, small-vessel disease	Rarely indicated; used to exclude infiltrative disease

Note that no biomarker distinguishes CMH14 from any other HCM, and none is MYH6-informed.

Genetic testing

Recommended approach: a targeted HCM gene panel on the proband, per the 2024 AHA/ACC guideline. The panel should be narrow. This is the operational consequence of the ClinGen work, and it is stated bluntly in the reappraisal: "Nine (29%) genes were downgraded to disputed, further discouraging clinical reporting of variants in these genes." (PMID:39971408). MYH6 is one of those nine.
Practical implication: a MYH6 variant found on a legacy broad panel should not be reported as causative of HCM, and should not be used for cascade testing. A laboratory still returning MYH6 for HCM is using a stale gene list. Rubattu reached the same conclusion empirically in 2016: "Our findings support the choice of a limited, well-selected panel of HCM genes as the best tool for diagnostic purposes."
The genes that should be on the panel (ClinGen Definitive/Strong/Moderate, per PMID:39971408 — 29 genes): the sarcomere core MYBPC3, MYH7, TNNT2, TNNI3, TPM1, ACTC1, MYL2, MYL3 plus TNNC1 (newly upgraded, "a 9th sarcomere gene with definitive HCM association"); sarcomere-associated ACTN2, CSRP3, FHOD3, FLNC (missense), PLN, DES, ALPK3, TRIM63 (AR), PRKAG2; syndromic/phenocopy GLA, LAMP2, TTR, FHL1, CACNA1C, PTPN11, RAF1, RIT1; and MT-TI, KLHL24 (moderate).
WES / WGS: reasonable when the phenotype is syndromic or panel-negative with strong family history. WGS was the discovery modality for the recessive MYH6–HLHS finding (Theis 2015).
Single-gene testing: appropriate only for cascade testing of a known familial variant. Not applicable to MYH6/HCM, since no MYH6 variant meets the P/LP bar.
CMA, karyotyping, FISH, mtDNA testing, repeat-expansion testing: not indicated for CMH14. CMA has a role in syndromic congenital heart disease, and mtDNA testing is relevant for the MT-TI phenocopy — neither is a CMH14 test.

Clinical criteria

Diagnosis (2024 AHA/ACC, PMID:38718139; 2023 ESC cardiomyopathy guideline, PMID:37622657): LV wall thickness ≥15 mm in any segment by any imaging modality, not solely explained by abnormal loading conditions; ≥13 mm in first-degree relatives of an affected proband or in genotype-positive individuals. Paediatric criteria use z-scores (≥2 SD, or ≥2.5 SD in relatives).

Differential diagnosis — and this is where CMH14's late-onset skew matters most:

Mimic	Distinguishing features
Transthyretin cardiac amyloidosis (ATTR)	Low voltage relative to wall thickness, apical sparing on strain, positive PYP scan, biventricular thickening, older age. The top consideration in a 70-year-old with new "HCM."
Hypertensive LVH / age-related basal septal bulge	Concentric, hypertension history, typically <15 mm
Athlete's heart	Wall <15 mm, dilated LV cavity, normal diastolic function, regression on detraining
Fabry disease (GLA)	X-linked, angiokeratoma, neuropathy, renal involvement, low α-Gal A
Danon disease (LAMP2)	Massive LVH, WPW pre-excitation, myopathy, intellectual disability
PRKAG2 glycogen storage cardiomyopathy	Marked pre-excitation and conduction disease
RASopathies (PTPN11, RAF1, RIT1 — Noonan spectrum)	Dysmorphology, pulmonary valve stenosis, short stature
Aortic stenosis / subaortic membrane	Fixed rather than dynamic gradient
Mitochondrial cardiomyopathy (incl. MT-TI)	Maternal inheritance, multisystem

Screening

Cascade clinical screening of first-degree relatives — ECG + echo, repeating every 1–2 years in adolescence and every 3–5 years in adults — is the guideline standard and remains appropriate for CMH14 families, because the phenotype is real even where the genotype attribution is not.
Cascade genetic testing is not appropriate for a MYH6 variant, since no such variant is P/LP. This distinction (clinical screening yes, genetic screening no) is the key practical point for the entry.
Newborn screening: not applicable.
Preparticipation athletic screening: ECG-based programmes detect HCM but are population-level and not CMH14-specific.

11. Outcome / Prognosis

All figures below are HCM-level. There is no CMH14 survival, mortality, or morbidity dataset.

Survival / mortality: contemporary HCM cohorts show near-normal life expectancy with modern management; HCM-related mortality ~0.5%/yr, down from historical tertiary-referral estimates of 2–4%/yr. Sudden cardiac death, heart failure, and stroke are the three modes.
Life expectancy: approaching that of the general population in guideline-managed cohorts; substantially reduced in the minority progressing to end-stage disease.
Morbidity / disability: exertional limitation, AF-related stroke, ICD-related complications, restriction from competitive sport. Disease-specific instrument: KCCQ. No ICF-coded disability data for CMH14.
Complications: LVOT obstruction; atrial fibrillation with thromboembolism; ventricular arrhythmia and SCD; progressive heart failure; infective endocarditis (rare); end-stage systolic dysfunction requiring transplant.
Recovery potential: none — the myopathy is not reversible. Symptomatic and haemodynamic improvement with obstruction relief is excellent.
Prognostic factors (HCM SCD risk, per 2024 AHA/ACC / HCM Risk-SCD): prior cardiac arrest or sustained VT; family history of SCD; unexplained syncope; maximal LV wall thickness ≥30 mm; NSVT; LV apical aneurysm; LV systolic dysfunction (EF <50%); extensive LGE on CMR.
Genotype as a prognostic factor: sarcomere-positive HCM is associated with earlier onset and worse outcomes than sarcomere-negative HCM in general. This does not transfer to MYH6. A MYH6 VUS should not be entered into risk stratification, and I would flag any clinical use of it as an error.
Prognostic biomarkers: NT-proBNP and hs-troponin correlate with adverse outcome in HCM; LGE burden is the strongest imaging prognosticator. None MYH6-specific.

12. Treatment

There is no MYH6-directed therapy, and no evidence that MYH6 genotype should alter management. Management is standard HCM care. NCIT bindings below are verified against cache/ncit/terms.csv where marked ✓.

Pharmacotherapy

Treatment	`treatment_term`	`therapeutic_agent`	`therapeutic_modality`
Beta blockade (first-line for obstructive and symptomatic HCM)	`NCIT:C15986` Pharmacotherapy ✓	`CHEBI:6904` metoprolol ✓	`SMALL_MOLECULE`
Non-dihydropyridine calcium channel blockade (beta-blocker intolerant)	`NCIT:C15986` ✓	`CHEBI:9948` verapamil ✓; `CHEBI:101278` diltiazem ✓	`SMALL_MOLECULE`
Disopyramide (added for refractory obstruction)	`NCIT:C15986` ✓	`NCIT:C61730` Disopyramide ✓	`SMALL_MOLECULE`
Cardiac myosin inhibition — mavacamten	`NCIT:C15986` ✓	`CHEBI:756998` mavacamten ✓ / `NCIT:C174901` Mavacamten ✓	`SMALL_MOLECULE`
Cardiac myosin inhibition — aficamten	`NCIT:C15986` ✓	`CHEBI:747213` aficamten ✓	`SMALL_MOLECULE`
Anticoagulation for AF (DOAC preferred; CHA₂DS₂-VASc not used — any AF in HCM warrants anticoagulation)	`NCIT:C15986` ✓	—	`SMALL_MOLECULE`
Antiarrhythmic therapy for AF/VT	`NCIT:C15986` ✓	`CHEBI:2663` amiodarone ✓	`SMALL_MOLECULE`

The mechanistic irony worth curating. Mavacamten and aficamten are allosteric inhibitors of cardiac β-myosin (MYH7) ATPase, reducing the number of force-generating cross-bridges. They target the ventricular isoform. If CMH14 were genuinely an α-MHC (MYH6) disease, the pharmacological rationale for these agents in it would be indirect at best. Anfinson et al. raise the corresponding therapeutic question for MYH6 carriers and note it cuts both ways:

"However, choosing to use a cardiac MHC-specific activator vs. inhibitor requires the understanding of whether a specific variant will cause systolic or diastolic dysfunction." — Anfinson et al. 2022 (PMID:35621855)

Their evidence_source for that passage is a review, and the drug-approval detail in it is dated (mavacamten approval was pending at writing; it has since been approved) — quote it for the mechanistic point, not the regulatory status.

Pivotal trials (for a clinical_trials: block): - EXPLORER-HCM, NCT03470545, PHASE_III, COMPLETED — mavacamten in symptomatic obstructive HCM (Olivotto et al., Lancet 2020, PMID:32871100). - SEQUOIA-HCM, NCT05186818, PHASE_III, COMPLETED — aficamten in obstructive HCM (Maron et al., NEJM 2024, PMID:38739079).

Use the enum values PHASE_III / COMPLETED, not the prose spellings.

Pharmacogenomics

No CPIC or PharmGKB guideline is keyed to MYH6. Mavacamten dosing is pharmacogenomically guided — by CYP2C19 metabolizer status (poor metabolizers require reduced starting dose and altered titration; this is in the US label and in the 2024 guideline). That is a drug-metabolism interaction, not a MYH6 interaction, and should be curated on the treatment, not the gene.

Advanced therapeutics

Gene therapy / gene editing: none for CMH14. AAV-based approaches (e.g. MYBPC3 replacement, allele-specific editing for MYH7) are in early development for other HCM genotypes. Nothing MYH6-directed.
RNA-based therapy (ASO/siRNA): none for CMH14. Leave aso_details absent.
Cell therapy, immunotherapy: not applicable.

Surgical and interventional

Intervention	NCIT
Septal myectomy (surgical, for drug-refractory obstruction)	`NCIT:C15329` Surgical Procedure ✓
Alcohol septal ablation (catheter-based alternative)	`NCIT:C49236` Therapeutic Procedure ✓
ICD implantation for primary or secondary SCD prevention	`NCIT:C15329` ✓ with `qualifiers` predicate `NCIT:C16830` Medical Device ✓ carrying the ICD device term; `therapeutic_modality: DEVICE`
Permanent pacemaker (for the MYH6-associated bradyarrhythmia phenotypes, not for HCM per se)	as above, `DEVICE`
Catheter ablation for AF	`NCIT:C49236` ✓
Heart transplantation (end-stage)	`NCIT:C15289` Organ Transplantation ✓

Per the repo's device rule: bind the clinical action (NCIT:C15329) and carry the device in a qualifiers predicate–value pair with NCIT:C16830 as the predicate. Do not put a device term in the treatment_term.term slot.

Supportive, rehabilitative, and counselling

Supportive care NCIT:C15747 ✓ — heart-failure management, volume optimisation, avoidance of dehydration and high-dose vasodilators/diuretics in obstructive physiology.
Exercise counselling — the 2024 guideline liberalised recommendations toward shared decision-making on vigorous and competitive activity; therapeutic_modality: BEHAVIORAL.
Cardiac rehabilitation NCIT:C15302 Physical Therapy ✓ / NCIT:C15315 Rehabilitation — moderate-intensity exercise is now considered beneficial.
Genetic counselling NCIT:C15240 ✓ — and this is the one place where CMH14's disputed status changes clinical practice directly. The counselling content is: this MYH6 variant does not explain the HCM, cascade genetic testing on it is not indicated, and relatives need clinical (ECG/echo) screening regardless. therapeutic_modality: BEHAVIORAL.

Treatment strategy

Guideline algorithms (2024 AHA/ACC PMID:38718139; 2023 ESC PMID:37622657) branch on obstructive vs non-obstructive physiology and on SCD risk — not on genotype. Beta blocker → add/switch verapamil or disopyramide → myosin inhibitor → septal reduction therapy for refractory obstruction; parallel SCD risk assessment for ICD; parallel AF management. Personalised-medicine approaches in HCM are genotype-informed for family screening and for phenocopy-specific therapy (e.g. agalsidase for Fabry, tafamidis for ATTR) — neither pathway is available for MYH6.

13. Prevention

Primary prevention (preventing the disease): not possible — a germline dominant condition. Reproductive options (PGT-M, prenatal diagnosis) exist in principle for definitively pathogenic HCM variants; they are not offered for a VUS, which is what every MYH6 HCM allele currently is.
Secondary prevention (early detection):
Cascade clinical screening of first-degree relatives — ECG and echo, every 1–2 years in adolescence, every 3–5 years in adults. Appropriate and recommended.
Cascade genetic screening — not indicated for MYH6, as above.
Preparticipation athletic screening — population-level, not CMH14-specific.
Tertiary prevention (preventing complications in affected people): this is where nearly all real preventive value sits.
ICD for primary SCD prevention in high-risk patients (the largest single mortality intervention in HCM).
Anticoagulation for any documented AF, to prevent cardioembolic stroke.
Relief of LVOT obstruction to prevent progressive symptoms and remodelling.
Blood-pressure control, weight management, sleep-apnoea treatment, endocarditis awareness.
Immunization: not applicable as disease prevention; influenza/COVID/pneumococcal vaccination is standard for patients with structural heart disease.
Risk stratification: HCM Risk-SCD (ESC) and the 2024 AHA/ACC major-risk-marker approach. Note both are validated on HCM cohorts and neither incorporates MYH6 genotype.
Genetic counselling: see §12. The counselling message is dominated by the disputed-gene finding.
Public health / environmental interventions: not applicable. No environmental exposure to modify.

14. Other Species / Natural Disease

Taxonomy: Homo sapiens, NCBITaxon:9606. Species used experimentally: Mus musculus NCBITaxon:10090; Danio rerio NCBITaxon:7955; Rattus norvegicus NCBITaxon:10116; Gallus gallus NCBITaxon:9031 (Ching's chick morpholino).
Orthologous genes: mouse Myh6 (MGI:97255, NCBI Gene 17888); rat Myh6 (NCBI Gene 29556); zebrafish myh6 / amhc (ZFIN ZDB-GENE-031112-1); chick MYH6. The α/β MHC pair is deeply conserved across gnathostomes.

The single most important comparative fact — and it is a trap for anyone extrapolating from mouse: the α/β ventricular isoform ratio is inverted between human and rodent. Adult human ventricle is β-MHC (MYH7)-dominant with α-MHC a minor component; adult mouse and rat ventricle is α-MHC (Myh6)-dominant. A mouse Myh6 ventricular phenotype therefore has no straightforward human counterpart. ClinGen made this exact call when refusing to score the classic mouse HCM models:

"Additional studies on mice models of HCM using pre-engineered heterozygous, pathogenic MYH7 variant orthologous to the human p.R403Q allele into the mouse MYH6 were reviewed, but not scored because these mice models are not analogous to human MYH6." — ClinGen CGGV:assertion_ee5380a4…

This should be curated in dismech as a discussions: entry with kind: HUMAN_MODEL_MISMATCH, not KNOWLEDGE_GAP — evidence exists in the model, and it is the translational validity that is the open question. That is precisely the distinction the repo's guidance draws.

Natural disease in other species: hypertrophic cardiomyopathy is the commonest feline heart disease (~15% of cats; higher in Maine Coon and Ragdoll breeds), and it is a genuine spontaneous animal model. But it is not MYH6. The identified feline causal variants are in MYBPC3 — Maine Coon p.A31P and Ragdoll p.R820W (OMIA 000515-9685). No MYH6 variant causes naturally occurring HCM in any species. Curate this as a negative comparative finding; it is informative, and the VBO breed terms (Maine Coon, Ragdoll) belong on the feline MYBPC3 concept, not here.
Comparative pathology: myocyte hypertrophy, disarray, and interstitial fibrosis are conserved lesions across human and feline HCM.
Evolutionary conservation of mechanism: the sarcomere and the α/β MHC duplication are ancient and conserved; the chamber-specific deployment of the two isoforms differs by species, which is exactly what breaks the translational chain here.
Zoonotic potential / cross-species transmission: not applicable.

15. Model Organisms

No model organism carries a human CMH14-associated MYH6 allele. This is the experimental gap, and it is stark: of the four MYH6 variants reported in HCM probands, zero have been functionally assayed in any system.

Available models and what they actually show

Model	Type	Allele	What it recapitulates	`ModelMechanismLink` guidance
αMHC-403 knock-in mouse (Geisterfer-Lowrance 1996, PMID:8614836)	`animal_models:`, Mus musculus	mouse Myh6 R403Q — an MYH7-derived human allele placed in the mouse α-MHC gene	"Cardiac histopathology and dysfunction in the alpha MHC 403/+ mice resembled human FHC… myocyte disarray, hypertrophy, and fibrosis increased with age." Homozygotes die at 7 days; sedentary heterozygotes survive 1 year; young males more affected than females	`relationship: FAILS_TO_RECAPITULATE` for CMH14 specifically — it models human MYH7 HCM, not MYH6 HCM. `fidelity: LOW`. `limitations:` the allele is orthologous to human MYH7 R403Q, and mouse ventricle is α-MHC-dominant whereas human ventricle is β-MHC-dominant, so the model is a mouse-genetics convenience, not an MYH6 model. Requires `limitations` + `evidence` per `test_failure_to_recapitulate_links_are_substantiated`. ClinGen explicitly declined to score it.
zebrafish weak atrium (wea) / myh6 (Berdougo 2003, PMID:14573521)	`animal_models:`, Danio rerio	nonsense allele truncating Amhc C-terminus	Atrial myofibrillar disorganisation and loss of atrial contraction; secondary ventricular compaction with a thickened myocardial wall and narrow lumen	`relationship: PARTIALLY_RECAPITULATES` against a "ventricular wall thickening secondary to atrial contractile failure" node. `fidelity: LOW–MODERATE`. `limitations:` null allele vs human missense; two-chambered heart; the ventricular change is compaction, not the sarcomeric disarray of human HCM. The most mechanistically informative model available.
*zebrafish myh6* knockdown + human variant rescue** (reviewed in PMID:35621855)	`animal_models:`	rescue with human MYH6-WT, -E933del, -R1252Q	Bradycardia in knockdowns (137.7 ± 2.2 bpm vs 150.2 ± 1.6 uninjected); WT and R1252Q rescue heart rate, E933del fails to	Models the conduction phenotype, not HCM. `relationship: MEASURES` against a rate/conduction node; do not link to a hypertrophy node.
Patient-derived iPSC line, MYH6 c.3755G>A (Wang et al. 2021, PMID:33385793)	`experimental_models:` (NAM), `experimental_model_type` iPSC-derived	"a G3755A heterozygote mutation in the MYH6 gene" from an HCM patient	A resource paper — line generation and characterisation only. No disease phenotype demonstrated.	Curate as an available model with no `modeled_mechanisms` link, or a link with `relationship: MEASURES` and `fidelity: UNKNOWN`. Do not let a resource paper carry a mechanistic claim.
MYH6-R443P patient iPSC-CMs (HLHS; PMID:35621855)	`experimental_models:`	R443P	"decreased the shortening rate, relaxation rate, extent of shortening, percent shortening, and calcium transient amplitude at the single CM level… without affecting action potentials"; sarcomere disorganisation and MYH7 upregulation	The best-characterised MYH6 human cellular model — but the allele is an HLHS allele. Relevant as mechanism-of-the-gene context, `evidence_source: IN_VITRO`, `directness: INDIRECT`.
NRVCM / HL-1 transfection systems (PMID:35621855)	`experimental_models:`, in vitro	A230P, A1004S, P830L, E526K, E933del, R721W, H252Q, V700M, A1366D, R1822_E1823dup	Variable and prediction-discordant sarcomere and contractility effects (see §6)	Useful negative-result material. `V700M` (no effect despite "likely damaging" predictions) and `P830L` (no shortening deficit) are worth curating as `supports: REFUTE` items against a naive structure→function claim.
Myh6 null / haploinsufficient mouse	`animal_models:`	targeted ablation	Gene-dosage effects and functional deficits in the heart; homozygous null is embryonic lethal	Models loss of function. Since no HCM-reported MYH6 allele has a demonstrated LoF mechanism, this cannot be linked to a CMH14 node without an inference step.

Model types not available

Rat, Drosophila, C. elegans, yeast, organ-chip, and engineered heart tissue models of MYH6-HCM: none exist. No humanized MYH6 mouse, no conditional MYH6 knock-in of a human HCM allele, no CRISPR-corrected isogenic iPSC pair for any CMH14 variant.

Anfinson et al. state the scope of the whole field plainly:

"To date, zebrafish embryos are the only animal model that has been used to study human MYH6 variants." — PMID:35621855

and

"Relative to the large body of literature assessing MYH7 variants, few studies have sought to understand MYH6 variant pathology at the molecular level."

Resources

MGI (Myh6, MGI:97255) and IMPC/KOMP for mouse alleles; ZFIN for myh6/wea; Alliance of Genome Resources for orthology; Cellosaurus/hPSCreg for the patient iPSC line from PMID:33385793; IMSR/MMRRC for mouse strain distribution.

Curation summary for the dismech entry

The placeholder file currently asserts a pathophysiology node "MYH6 Missense Variant in Alpha-Myosin Heavy Chain" and a Left Ventricular Hypertrophy phenotype. Both are defensible, but the entry's substance should be the epistemic situation, not a borrowed MYH7 causal chain. Concretely:

Rewrite description to state that MYH6–HCM is ClinGen-Disputed and that the mechanism is unknown.
Keep the pathophysiology graph short and honest. One or two nodes, with biological_scale: MOLECULAR on the variant node. Do not build a 7-node MYH7-style chain; the check-causal-targets gate will happily accept a fabricated chain, and nothing else will catch it.
Lead evidence with CGGV:assertion_ee5380a4-0dee-49aa-b911-141502648144-2023-07-12T020000.000Z (already cached, quotable by row: MYH6 | HGNC:7576 | hypertrophic cardiomyopathy | MONDO:0005045 | AD | Disputed | SOP9 | Hereditary Cardiovascular Disease Gene Curation Expert Panel | 2023-07-12T02:00:00.000Z) and PMID:39971408.
Add a discussions: entry, kind: HUMAN_MODEL_MISMATCH, for the mouse αMHC-403 problem — the model exists and is famous, and its inapplicability to MYH6 is the substantive point.
Add a discussions: entry, kind: KNOWLEDGE_GAP, attaches_to: pathophysiology#…, for the unmeasured biophysics of R795Q and Q1065H.
Leave datasets: empty unless a genuinely CMH14-relevant accession survives manual relevance triage. I found none.
Record the atrial-isoform argument (Branch B) — Gorza 1984 + Berdougo 2003 + Anfinson 2022 — as the positive mechanistic content of the entry. It is the one thing here that is both well-evidenced and explanatory.
conforms_to candidates: check just list-modules for a cardiomyopathy remodeling module before conforming. cardiomyopathy_maladaptive_remodeling is the likely target for a fibrosis/remodeling node — but conform only if the entry ends up carrying such a node, which on the evidence it may not.

References fetched into references_cache/ during this work: PMID:11815426, 15998695, 27483260, 33385793, 34087240, 35911064, 21378987, 10388558, 6234108, 8614836, 24092743, 15735645, 26085007, 35621855, 14573521, 39971408, 30681346, 38718139, 37622657, 32871100, 38739079, 27532257, 23074333. Two mis-targeted fetches (PMID:14568893, PMID:35544178) are stale and should be deleted before committing; I did not remove them, as the deletion command needed approval this session.

Sources: - OMIM #613251 — CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 14 - OMIM #160710 — MYH6 - ClinGen MYH6 curation results (HGNC:7576) - ClinGen gene-validity assertion — MYH6 / hypertrophic cardiomyopathy (Disputed) - Hespe et al., JACC 2025 — Genes Associated With HCM: A Reappraisal (PMID:39971408) · PMC preprint - Ingles et al. 2019 — Evaluating the Clinical Validity of HCM Genes (PMID:30681346) - Niimura et al., Circulation 2002 (PMID:11815426) - Carniel et al., Circulation 2005 (PMID:15998695) - Rubattu et al. 2016 (PMID:27483260) - Walsh et al., Genet Med 2017 (PMID:27532257) - Holm et al., Nat Genet 2011 (PMID:21378987) - Ching et al., Nat Genet 2005 (PMID:15735645) - Theis et al., Circ Cardiovasc Genet 2015 (PMID:26085007) - Anfinson et al., J Cardiovasc Dev Dis 2022 (PMID:35621855) - Berdougo et al., Development 2003 (PMID:14573521) - Gorza et al., Circ Res 1984 (PMID:6234108) - Geisterfer-Lowrance et al., Science 1996 (PMID:8614836) - Weiss et al., J Mol Biol 1999 (PMID:10388558) - Liu et al., Clin Chim Acta 2021 (PMID:34087240) - Suzuki et al., J Cardiol Cases 2022 (PMID:35911064) - Wang et al. 2021 iPSC line (PMID:33385793) - Ommen et al., 2024 AHA/ACC HCM Guideline (PMID:38718139) - Arbelo et al., 2023 ESC Cardiomyopathy Guideline (PMID:37622657) - ClinVar VCV000014147 — MYH6 p.Arg795Gln - ClinVar VCV000014149 — MYH6 p.Gln1065His - gnomAD v4.0 gene constraint

Next step: tell me whether you want the entry curated as a disputed-entity Disease file (my recommendation, and I'd write it against the evidence above), or whether the lump/split call should go the other way — a SUBTYPE/OUT_OF_SCOPE disposition on Hypertrophic_Cardiomyopathy with the stub deleted and the reasoning recorded in notes.

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	24
Resolved	24
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	24
On topic	14
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	82
Resolved	79
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	3
Terms whose name was checked	25
Terms named correctly	22
Terms named as a different term	0
Terms whose name is worth a second look	3

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:

MONDO:0013197 (2 mentions) - the report calls it "Any hypertrophic cardiomyopathy in which the cause of the disease is a mutation in the MYH6 gene"; MONDO calls it hypertrophic cardiomyopathy 14, and lists "hypertrophic cardiomyopathy caused by mutation in MYH6" among its other names
GO:0030017 (2 mentions) - the report calls it "sarcomere (CC)"; GO calls it sarcomere
GO:0032982 (2 mentions) - the report calls it "myosin filament (CC)"; GO calls it myosin filament

Terms named inconsistently

The report gives these identifiers more than one name of its own:

MONDO:0005045 - called "hypertrophic cardiomyopathy", "Hypertrophic cardiomyopathy"

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA, MGI.

79 of 82 terms resolved to a current term; the rest could not be looked up either way.

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OpenScientist Report

Classifications

Inheritance

Mechanistic Hypotheses

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Diagnosis

Prevalence

Clinical Trials

Experimental Models

Animal Models

Source YAML

References & Deep Research

References

Deep Research

1. Disease Information

Overview

Key identifiers

Synonyms

Provenance of the underlying information

2. Etiology

Disease causal factors

Genetic risk factors

Environmental risk factors

Protective factors

Gene–environment interactions

3. Phenotypes

Core cardiac phenotypes (all category: Cardiovascular)

The MYH6-specific phenotype signals that are real (and are not HCM)

Quality-of-life impact

4. Genetic / Molecular Information

Causal gene

Pathogenic variants

Modifier genes

Epigenetic information

Chromosomal abnormalities

5. Environmental Information

6. Mechanism / Pathophysiology

Ordered causal chain

Molecular pathways

Cellular processes (GO — all CURIEs below verified against cache/go/terms.csv)

Protein dysfunction

Metabolic changes

Immune system involvement

Tissue damage mechanisms

Biochemical abnormalities / epigenetic changes / molecular profiling

7. Anatomical Structures Affected

Organ level

Tissue and cell level

Subcellular level

Localization and lateralization

8. Temporal Development

Onset

Progression

Patterns

9. Inheritance and Population

Epidemiology

For genetic etiology

Population demographics

10. Diagnostics

Clinical tests

Genetic testing

Clinical criteria

Screening

11. Outcome / Prognosis

12. Treatment

Pharmacotherapy

Pharmacogenomics

Advanced therapeutics

Surgical and interventional

Supportive, rehabilitative, and counselling

Treatment strategy

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Core cardiac phenotypes (all `category: Cardiovascular`)

Cellular processes (GO — all CURIEs below verified against `cache/go/terms.csv`)