Hypertrophic Cardiomyopathy 15

Mendelian MONDO:0013200 Pathograph 13 Show in embeddings browser Hypertrophic Cardiomyopathy Cardiovascular Disease Genetic Disorder

Hypertrophic cardiomyopathy 15 (CMH15) is the VCL-attributed form of familial hypertrophic cardiomyopathy. VCL encodes two proteins from one gene: vinculin, expressed ubiquitously, and metavinculin, a splice isoform carrying a 68-residue insert in the C-terminal tail encoded by exon 19 and restricted to cardiac and smooth muscle. Both localize to the sites where the actin cytoskeleton is anchored to the membrane, so the proposed lesion is one of force transmission and cytoskeletal anchorage rather than of the contractile apparatus itself. The vinculin tail binds F-actin and dimerizes to bundle filaments into thick fibers; the metavinculin tail binds F-actin but cannot bundle it, severs filaments instead, and inhibits vinculin-mediated bundling, so metavinculin acts as a tuner of vinculin's actin-organizing activity. The cardiomyopathy-associated insert variants destabilize the conformational sub-domain that mediates that inhibition: they neither bundle normally nor restrain vinculin, and instead promote large, disordered actin assemblies. Myectomy tissue from the two reported probands showed vinculin and metavinculin markedly reduced at the intercalated disc with preserved Z-disc staining, and both had severely obstructive mid-ventricular hypertrophy, with apical involvement in one of the two. The gene-disease relationship is disputed, and this entry is curated on that footing rather than as an established cause. ClinGen's Hereditary Cardiovascular Disease Gene Curation Expert Panel reclassified VCL-hypertrophic cardiomyopathy from Limited to Disputed in May 2023: only two probands were ever reported, both in 2006 from one group, and the two missense variants carried by them are more common in gnomAD than the panel's pathogenicity cutoff allows. The intercalated-disc depletion seen in those probands was subsequently found in obstructive hypertrophic cardiomyopathy and aortic stenosis generally, so it tracks outflow obstruction rather than VCL genotype and cannot serve as VCL-specific corroboration. VCL's well-supported cardiac association is with dilated cardiomyopathy, which ClinGen rates Strong, and the best-characterized variant, p.Arg975Trp, has been reported in both hypertrophic and dilated presentations. CMH15 should therefore be read as a molecularly plausible but clinically unconfirmed entity: the metavinculin biochemistry is solid, the human genetic evidence that it causes hypertrophic cardiomyopathy is not.

Ask OpenScientist

Ask a research question about Hypertrophic Cardiomyopathy 15. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

1
Mappings
1
Inheritance
7
Pathophys.
1
Histopath.
4
Phenotypes
2
Gaps
13
Pathograph
1
Genes
1
Medical Actions
3
Differentials
2
Models
1
References
1
Deep Research
🏷

Classifications

Harrison's Part
CARDIOVASCULAR GENETICS ENVIRONMENT DISEASE
🔗

Mappings

MONDO
MONDO:0013200 hypertrophic cardiomyopathy 15
skos:exactMatch MONDO
Primary MONDO identifier for the CMH15 entity (OMIM:613255), the VCL-attributed locus of familial hypertrophic cardiomyopathy.
👪

Inheritance

1
Autosomal dominant inheritance HP:0000006
CMH15 is catalogued as an autosomal dominant trait, and ClinGen curated the VCL-hypertrophic cardiomyopathy relationship under an autosomal dominant mode of inheritance. The assignment rests on the catalogue classification and on the dominant pattern established for VCL in dilated cardiomyopathy rather than on segregation in hypertrophic cardiomyopathy families: both reported probands were ascertained as isolated cases from screening cohorts, and no multi-generation hypertrophic cardiomyopathy pedigree segregating a VCL variant has been published.
Autosomal dominant inheritance
Show evidence (1 reference)
CGGV:assertion_27365fd2-1203-4e2b-8830-3277e965d8bc-2023-05-10T160000.000Z SUPPORT Other
"| VCL | HGNC:12665 | hypertrophic cardiomyopathy | MONDO:0005045 | AD | Disputed | SOP9 | Hereditary Cardiovascular Disease Gene Curation Expert Panel | 2023-05-10T16:00:00.000Z |"
Records the mode of inheritance under which the relationship was curated (AD) together with the Disputed classification, which is why the inheritance claim is catalogue-derived rather than pedigree-derived.
?

Discussions and Knowledge Gaps

2
Does VCL cause hypertrophic cardiomyopathy at all, or is CMH15 an entity built on two 2006 case reports that later evidence has undercut?
KNOWLEDGE GAP OPEN cmh15_gene_disease_validity_disputed
Attached to
genetic#VCL pathophysiology#VCL Missense Variant in Vinculin or the Metavinculin Insert disease#Hypertrophic Cardiomyopathy 15
This is the entity's central open question and the reason every node upstream of the hypertrophy is marked HYPOTHETICAL or PROVISIONAL. The supporting case is two probands, both from one centre in 2006, both ascertained by sequencing a candidate gene in a myofilament-negative cohort, neither with segregation data. Three things have since worked against it. The two implicated variants are commoner in gnomAD than a rare dominant cardiomyopathy allele can be. The corroborating histology - vinculin depleted at the intercalated disc - was shown by the same group to occur in obstructive hypertrophic cardiomyopathy without a VCL variant and in aortic stenosis, so it marks obstruction rather than genotype. And the one variant carried forward as causal, p.Arg975Trp, had already been reported in dilated cardiomyopathy, which is the phenotype VCL is actually well supported for. ClinGen moved the classification from Limited to Disputed in 2023 and recorded that no new evidence had emerged since its own initial curation. Note that "initial curation" there is a ClinGen curation event, not the 2006 publications - the panel records an intervening HCM GCEP recuration on 04/06/21. Note what is not in dispute: metavinculin biochemistry. That the insert variants destabilize the inhibitory sub-domain and produce disordered actin assemblies is measured, reproducible, and structurally rationalized. The gap is between that biochemistry and the human hypertrophic phenotype, not within it. A mechanism can be real and still not be this disease's mechanism.
Proposed experiments
Metavinculin insert knock-in mouse carrying a CMH15 allele
cmh15_knockin_mouse
Generate a knock-in mouse carrying p.Arg975Trp or an equivalent exon-19 insert substitution at the endogenous Vcl locus, and phenotype it for wall thickness, outflow gradient, chamber dimensions and intercalated-disc ultrastructure, unstressed and after pressure loading. Every existing mouse model deletes vinculin, so none of them can test a gain-of-function missense hypothesis, and the two that exist both produce dilation rather than hypertrophy. Mouse hearts express proportionally less metavinculin than human hearts, so a negative result would need that caveat attached.
Decision criterion
Hypertrophy with outflow obstruction in the knock-in would supply the in vivo support the relationship has never had. A dilated or absent cardiac phenotype would align the allele with the loss-of-function models and further weaken the hypertrophic attribution.
Would support
pathophysiology#VCL Missense Variant in Vinculin or the Metavinculin Insert
Would refute
pathophysiology#VCL Missense Variant in Vinculin or the Metavinculin Insert
Rare-variant burden of VCL exon 19 in large hypertrophic cardiomyopathy cohorts
cmh15_case_control_burden
Test whether rare metavinculin-insert variants are enriched in sarcomere-negative hypertrophic cardiomyopathy probands relative to ancestry-matched population controls, in the large sequenced cohorts that did not exist in 2006. This is the direct answer to ClinGen's stated objection, which is a frequency argument, and burden analysis is the design that distinguishes a genuinely rare pathogenic allele class from a gene that is merely long and polymorphic.
Decision criterion
Significant case excess of rare exon-19 variants would move the relationship off Disputed. No excess would settle it as a non-cause.
Would refute
genetic#VCL
Show evidence (2 references)
CGGV:assertion_27365fd2-1203-4e2b-8830-3277e965d8bc-2023-05-10T160000.000Z SUPPORT Other
"More evidence is needed to either support or entirely refute the role VCL plays in this disease."
The expert panel leaves the question open rather than closed, which is why this is recorded as a knowledge gap and the entry is retained rather than argued out of scope.
CGGV:assertion_27365fd2-1203-4e2b-8830-3277e965d8bc-2023-05-10T160000.000Z SUPPORT Other
"This gene-disease pair was recurated by the HCM GCEP on 04/06/21 (SOP 8), and reevaluated by the Hereditary Cardiovascular Disease GCEP on 05/10/2023. As a result of this reevaluation, the classification changed from limited to disputed."
Documents the direction of travel: two successive expert reviews, each lowering the classification.
Can vinculin-deficiency models say anything about a disease proposed to act by gain of function?
HUMAN MODEL MISMATCH OPEN cmh15_model_allele_class_mismatch
Attached to
pathophysiology#Impaired Cardiomyocyte Force Transmission animal_models#Cardiomyocyte-specific vinculin knockout mouse (cVclKO) animal_models#Heterozygous vinculin knockout mouse (Vin+/-)
Every in vivo vinculin model in existence removes protein: a cardiomyocyte null, a heterozygous null. They agree with each other and with human loss-of-function VCL variants in producing dilation, arrhythmia and sudden death rather than hypertrophy. The mechanism proposed for CMH15 is the opposite in kind - mutant metavinculin that fails to restrain vinculin and actively drives disordered actin assembly, which ClinGen reads as gain of function. So the models are informative about what vinculin does and uninformative about what a CMH15 allele does, and their failure to produce hypertrophy is weak evidence against the hypothesis rather than strong evidence against it. There is a second, smaller mismatch stacked on the first: metavinculin makes up a much larger share of the combined vinculin pool in human than in mouse heart, so any insert-specific effect is attenuated in mouse regardless of allele.
Show evidence (3 references)
PMID:17785437 SUPPORT Model Organism
"we developed a mouse model with cardiac-myocyte-specific inactivation of the vinculin (Vcl) gene by using Cre-loxP technology"
Establishes the allele class of the principal in vivo model as an inactivation, which is the mismatch this discussion is about.
CGGV:assertion_27365fd2-1203-4e2b-8830-3277e965d8bc-2023-05-10T160000.000Z SUPPORT Other
"The mechanism for disease is believed to be gain-of-function, with mutants both failing to induce F-actin binding and promoting formation of large actin assemblies with linear bundles (PMID: 30844403)."
States the proposed human mechanism as gain of function, against which the loss-of-function models are mismatched.
PMID:17785437 SUPPORT Other
"The amount of metavinculin expressed in human cardiac tissue appears greater than that in mouse"
Sources the second, smaller mismatch stacked on the allele-class one: an insert-specific effect is attenuated in mouse heart because metavinculin is a smaller share of the combined pool there than in human heart. Graded OTHER because the sentence is a review statement in the paper's introduction citing prior work, not a result of the study it appears in.
⚙

Pathophysiology

7
VCL Missense Variant in Vinculin or the Metavinculin Insert
Mechanism confidence: Hypothetical
The proposed initiating lesion is a heterozygous germline missense substitution in VCL. Two locations have been implicated and they are not equivalent. p.Leu277Met lies in a region present in both vinculin and metavinculin, so it would perturb the ubiquitous protein as well as the cardiac isoform. p.Ala934Val, p.Pro943Ala and p.Arg975Trp lie inside the 68-residue insert encoded by exon 19, which is present only in metavinculin, so their effect is restricted to cardiac and smooth muscle. Whether either class is pathogenic in hypertrophic cardiomyopathy is disputed, which is why this node and everything downstream of it are marked HYPOTHETICAL.
cardiac muscle cell CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
VCL hgnc:12665 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves VCL (hgnc:12665). hgnc:12665 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context allele_type: MISSENSE variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: GAIN_OF_FUNCTION
GAIN_OF_FUNCTION follows ClinGen's reading of the biochemical data: the mutant metavinculin tails do not simply lose their inhibitory function, they acquire the ability to drive formation of large disordered actin assemblies that neither wild-type isoform produces. Note that this is the mechanism proposed for the exon-19 insert variants; no functional characterization of p.Leu277Met has been published, so the category is extrapolated to that allele rather than measured for it.
Downstream
Loss of Metavinculin Restraint on Vinculin-Mediated Actin Bundling
Show evidence (1 reference)
CGGV:assertion_27365fd2-1203-4e2b-8830-3277e965d8bc-2023-05-10T160000.000Z SUPPORT Other
"The mechanism for disease is believed to be gain-of-function, with mutants both failing to induce F-actin binding and promoting formation of large actin assemblies with linear bundles (PMID: 30844403)."
Records the proposed mechanism class for this node, and the hedge ("believed to be") that justifies the HYPOTHETICAL confidence.
Loss of Metavinculin Restraint on Vinculin-Mediated Actin Bundling
Mechanism confidence: Provisional
In the normal heart the two VCL isoforms are co-expressed at sub-stoichiometric ratio and do opposite things to actin. The vinculin tail binds F-actin and dimerizes to bundle filaments into thick fibers; the metavinculin tail binds F-actin the same way but cannot bundle it, severs filaments instead, and inhibits vinculin-mediated bundling. That inhibition requires a protruding sub-domain formed by the 68-residue insert, which sterically blocks vinculin tail dimerization. The cardiomyopathy variants destabilize the sub-domain, so the brake is released and mutant metavinculin no longer restrains vinculin.
vinculin-mediated actin filament bundling GO:0051017 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves vinculin-mediated actin filament bundling, annotated with actin filament bundle assembly (GO:0051017), qualified as gain of function. GO:0051017 is a biological process from the Gene Ontology. ⇑ GAIN OF FUNCTION
metavinculin-mediated actin filament severing GO:0003789 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves metavinculin-mediated actin filament severing, annotated with actin filament severing activity (GO:0003789). GO:0003789 is a molecular function from the Gene Ontology.
Downstream
Disordered F-Actin Assembly at the Membrane Anchor
Show evidence (4 references)
PMID:30844403 SUPPORT In Vitro
"While MVt binds to F-actin in a similar manner to Vt, MVt is incapable of F-actin bundling and inhibits Vt-mediated F-actin bundling."
Establishes the wild-type inhibitory relationship between the two isoform tails, which is what the variants disrupt.
PMID:30844403 SUPPORT Computational
"Computational models of MVt bound to F-actin suggest that MVt undergoes a conformational change licensing the formation of a protruding sub-domain incorporating the insert, which sterically prevents dimerization and bundling of F-actin by Vt."
Supplies the structural mechanism for the inhibition, and is graded COMPUTATIONAL because it is a modelling result rather than a measurement.
PMID:22613835 SUPPORT In Vitro
"Unlike its splice variant, MVt did not bundle actin filaments. Instead, MVt promoted severing of actin filaments, most efficiently at substoichiometric concentrations."
Independent demonstration of the severing activity that distinguishes the metavinculin tail from the vinculin tail.
+ 1 more reference
Disordered F-Actin Assembly at the Membrane Anchor
Mechanism confidence: Provisional
With the inhibitory brake released, the mutant tails produce large actin assemblies embedded with linear bundles rather than the regular bundled architecture vinculin normally builds. The actin network that couples the contractile apparatus to the membrane is therefore built wrongly, not merely built less.
cardiac muscle cell CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
actin cytoskeleton organization GO:0030036 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal actin cytoskeleton organization (GO:0030036). GO:0030036 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Disrupted Intercalated Disc and Costamere Anchorage
Show evidence (1 reference)
PMID:30844403 SUPPORT In Vitro
"These findings provide new mechanistic insights into the ability of metavinculin to tune actin organization by vinculin and suggest that dysregulation of this process by CM mutants could underlie their malfunction in disease."
The authors' own statement of what the disordered assemblies are proposed to mean for disease, with the hedge preserved.
Disrupted Intercalated Disc and Costamere Anchorage
Mechanism confidence: Hypothetical
Vinculin and metavinculin are structural components of the junctions where cardiomyocyte actin is anchored: the intercalated disc, which couples adjacent myocytes end to end, and the costamere, which couples the myofibril laterally to the sarcolemma and extracellular matrix. Myectomy tissue from both reported probands showed vinculin and metavinculin markedly reduced at the intercalated disc with normal Z-disc staining, and the earlier metavinculin work had shown altered intercalated-disc organization in vivo. The specificity of that finding is the weak point of the chain rather than its existence; see the REFUTE evidence on this node.
cardiac muscle cell CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
adherens junction organization GO:0034332 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal adherens junction organization (GO:0034332). GO:0034332 is a biological process from the Gene Ontology. ⚠ ABNORMAL cell-matrix adhesion GO:0007160 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal cell-matrix adhesion (GO:0007160). GO:0007160 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Animal models
Cardiomyocyte-specific vinculin knockout mouse (cVclKO) Mouse recapitulates Establishes in vivo that removing cardiomyocyte vinculin dismantles exactly the junctions this node names, and that it does so before any contractile phenotype appears.
Heterozygous vinculin knockout mouse (Vin+/-) Mouse recapitulates Shows that a partial reduction in vinculin and metavinculin, closer in degree to a heterozygous human genotype than a complete null, is already enough to disorganize the intercalated disc and the Z-line register.
Downstream
Impaired Cardiomyocyte Force Transmission
Show evidence (3 references)
PMID:16712796 SUPPORT Human Clinical
"Immunohistochemical analysis of the proband's myectomy specimen demonstrated markedly reduced vinculin levels in the intercalated discs."
The human tissue observation in the vinculin proband on which this node rests.
PMID:16236538 SUPPORT Human Clinical
"Immunohistochemical analysis of the proband's myectomy specimen revealed a paucity of vinculin/metavinculin in the intercalated discs."
The matching observation in the metavinculin proband, from a different variant class.
PMID:16949038 REFUTE Human Clinical
"Tissue specimens derived from patients with obstructive HCM and aortic stenosis (AS) showed a universal defect of vinculin/metavinculin expression in the intercalated disc but preserved expression in the cardiac Z-disc"
Refutes the inference that intercalated-disc vinculin depletion is caused by the VCL variant. The same pattern occurs in obstructive hypertrophic cardiomyopathy without a VCL variant and in aortic stenosis, so it tracks outflow obstruction and cannot corroborate a VCL-specific lesion.
Impaired Cardiomyocyte Force Transmission
Mechanism confidence: Hypothetical
Consequence of a mis-built actin-membrane anchor: contractile force generated by the sarcomere is transmitted less efficiently to neighbouring myocytes and to the extracellular matrix. That vinculin loss impairs myocyte mechanics is measured rather than assumed - vinculin-deficient mouse myocytes have reduced membrane cortical stiffness, wider myofilament lattice spacing and reduced systolic transverse strain in vivo, all before global ventricular dysfunction appears. What is not measured is the same for a CMH15 allele: those experiments use vinculin deletion, whereas the human variants proposed here are missense changes acting by gain of function, so the mechanical consequence is transferred across allele classes. The node is marked HYPOTHETICAL for that reason rather than for lack of any evidence.
cardiac muscle cell CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
cardiac muscle contraction GO:0060048 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal cardiac muscle contraction (GO:0060048). GO:0060048 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Animal models
Heterozygous vinculin knockout mouse (Vin+/-) Mouse partially recapitulates Vin+/- hearts tolerate normal load but fail under acute pressure overload, which is the behaviour expected of a myocardium whose force-transmission apparatus has reduced reserve rather than reduced resting output.
Downstream
Maladaptive Left Ventricular Hypertrophy
Show evidence (3 references)
PMID:23561539 SUPPORT INDIRECT Model Organism
"MRI revealed significantly decreased systolic strains transverse to the myofiber axis in vivo, but no changes along the muscle fibers or in fiber tension in papillary muscles from heterozygous global Vcl null mice."
Measures a mechanical deficit attributable to reduced vinculin, and locates it transverse to the fibre axis rather than in fibre tension. INDIRECT because the allele is a null, not a CMH15 missense variant.
PMID:23561539 SUPPORT INDIRECT Model Organism
"AFM in Vcl heterozygous null mouse myocytes showed a significant decrease in membrane cortical stiffness."
Gives the cell-mechanical correlate of losing the actin-membrane anchor, which is the property this node claims is degraded.
PMID:37548861 SUPPORT INDIRECT Human Clinical
"Vinculin links the actin cytoskeleton to the cell membrane which is critical in force transmission and is needed to maintain cardiomyocyte function"
States the force-transmission role this node depends on. INDIRECT: it is a background statement in a dilated cardiomyopathy case series, not a measurement in hypertrophic disease.
Maladaptive Left Ventricular Hypertrophy
Mechanism confidence: Provisional
The tissue-level endpoint: left ventricular hypertrophy which in the two reported probands was severely obstructive and mid-ventricular or apical in distribution. A separate series from the same centre found that hypertrophic cardiomyopathy attributable to Z-disc genes, VCL among them, carries a sigmoidal septal contour in most cases, in contrast to the reverse-curvature morphology typical of myofilament disease.
Animal models
Cardiomyocyte-specific vinculin knockout mouse (cVclKO) Mouse fails to recapitulate The most informative negative result for this entity. Losing cardiomyocyte vinculin in vivo produces arrhythmic sudden death and then a dilated ventricle. It does not produce hypertrophy.
Downstream
Dynamic Outflow Obstruction
Hypertrophic cardiomyopathy The tissue lesion presenting as the clinical entity both probands were diagnosed with.
Apical hypertrophy Apical distribution of the hypertrophy, reported in the metavinculin proband.
Show evidence (2 references)
PMID:17097056 SUPPORT Human Clinical
"Thirteen of the 239 patients (5.4%) had one of 13 distinct HCM-associated Z-disc mutations involving residues highly conserved across species and absent in 600 reference alleles: LDB3 (6), ACTN2 (3), TCAP (1), CSRP3 (1), and VCL (2)."
Places VCL within the Z-disc class of hypertrophic cardiomyopathy and gives its share of that class in a myofilament-negative cohort.
PMID:17097056 SUPPORT INDIRECT Human Clinical
"For this subset with Z-disc-associated HCM, the septal contour was sigmoidal in 11 (85%) and apical in 2 (15%). While Z-disc-HCM is uncommon, it is equal in prevalence to thin filament-HCM. In contrast to myofilament-HCM, Z-disc-HCM is associated preferentially with sigmoidal morphology."
Characterizes the hypertrophy morphology of the Z-disc class as a whole. INDIRECT because the figures are for all thirteen Z-disc probands, of whom only two carried VCL variants, so the morphology is not resolved to VCL.
Dynamic Outflow Obstruction
Mechanism confidence: Provisional
Both reported probands had severely obstructive hypertrophy, mid-ventricular in one and mid-ventricular plus apical in the other. Obstruction is the point at which this chain rejoins ordinary hypertrophic cardiomyopathy physiology, and also the point at which the entity's key confound arises, since obstruction itself depletes intercalated-disc vinculin. Named for the haemodynamic mechanism rather than the finding, so that it stays distinct from the clinical phenotype of the same name: the pathograph matches target strings verbatim, and two nodes differing only in capitalization would render as two nodes for one concept.
Downstream
Left ventricular outflow tract obstruction The clinical finding this mechanism presents as.
Disrupted Intercalated Disc and Costamere Anchorage Feedback edge. Obstruction reduces intercalated-disc vinculin and metavinculin independently of genotype, which is the alternative explanation for the probands' histology.
Show evidence (1 reference)
PMID:16236538 SUPPORT Human Clinical
"One patient with severely obstructive, mid-ventricular and apical hypertrophy harbored the previously published DCM-associated mutation, R975W."
Documents obstruction and its distribution in the metavinculin proband.
✶

Histopathology

1
Reduced vinculin and metavinculin at the intercalated disc with preserved Z-disc staining
Immunohistochemistry on the surgical myectomy specimens from both probands showed vinculin and metavinculin markedly reduced at the intercalated disc while Z-disc staining was normal. The compartment specificity is the informative part of the finding. Its attribution is not: the same pattern was subsequently found in obstructive hypertrophic cardiomyopathy without a VCL variant and in aortic stenosis, and was absent in dilated, hypertensive and pulmonary-hypertensive hearts, so it segregates with outflow obstruction and not with genotype.
Show evidence (3 references)
PMID:16949038 SUPPORT Human Clinical
"Microscopic examination of both myectomy specimens from patients bearing genetic defects in metavinculin and vinculin showed a marked reduction of vinculin/metavinculin expression in the intercalated disc, but normal expression in the Z-disc."
The finding itself, stated for both probands together with its compartment specificity.
PMID:16949038 REFUTE Human Clinical
"Tissue specimens derived from patients with obstructive HCM and aortic stenosis (AS) showed a universal defect of vinculin/metavinculin expression in the intercalated disc but preserved expression in the cardiac Z-disc"
Refutes reading the finding as a marker of the VCL lesion. The identical pattern is universal in obstructive hypertrophic cardiomyopathy without a VCL variant, and in aortic stenosis, so it cannot corroborate a VCL-specific mechanism.
PMID:16949038 SUPPORT Human Clinical
"whereas tissue specimens derived from patients with either DCM, hypertensive heart disease (HTN), or pulmonary hypertension (PHTN) exhibited normal expression of vinculin/metavinculin in both the Z- and the intercalated disc despite being associated with hypertrophy."
Supports the narrower claim that the finding is real and specific to a compartment and an aetiology: it is absent in dilated, hypertensive and pulmonary-hypertensive hearts, so it is not a generic consequence of hypertrophy. It is that same specificity to obstruction which makes it uninformative about genotype.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Hypertrophic Cardiomyopathy 15 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

4
Hypertrophic cardiomyopathy Cardiovascular HP:0001639 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypertrophic cardiomyopathy (HP:0001639). HP:0001639 is a phenotype from the Human Phenotype Ontology.
Sequelae: Left ventricular outflow tract obstruction
Show evidence (1 reference)
PMID:16236538 SUPPORT Human Clinical
"mutational analysis of the metavinculin-specific exon of vinculin (VCL, exon 19) was performed in a cohort of 389 unrelated patients with clinical HCM, previously genotyped for the 8 most common HCM-associated myofilament-encoding genes."
Establishes that the ascertainment population, and therefore the phenotype attached to this entity, is clinically diagnosed hypertrophic cardiomyopathy.
Left ventricular outflow tract obstruction Cardiovascular HP:0032092 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Left ventricular outflow tract obstruction (HP:0032092), qualified as severity severe. HP:0032092 is a phenotype from the Human Phenotype Ontology.
Severity: SEVERE
Show evidence (2 references)
PMID:16712796 SUPPORT Human Clinical
"A novel missense mutation, L277M-VCL, involving a conserved residue was identified in a patient with severely obstructive, mid-ventricular hypertrophy."
Documents severe obstruction in the vinculin proband.
PMID:16236538 SUPPORT Human Clinical
"One patient with severely obstructive, mid-ventricular and apical hypertrophy harbored the previously published DCM-associated mutation, R975W."
Documents severe obstruction in the metavinculin proband.
Apical hypertrophy Cardiovascular HP:0031992 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Apical hypertrophic cardiomyopathy (HP:0031992). HP:0031992 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:16236538 SUPPORT Human Clinical
"One patient with severely obstructive, mid-ventricular and apical hypertrophy harbored the previously published DCM-associated mutation, R975W."
Names apical involvement in the one proband in whom it was reported.
Sigmoidal septal contour Cardiovascular HP:0001712 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Left ventricular hypertrophy with sigmoidal septal contour, annotated with Left ventricular hypertrophy (HP:0001712). HP:0001712 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:17097056 SUPPORT INDIRECT Human Clinical
"In contrast to myofilament-HCM, Z-disc-HCM is associated preferentially with sigmoidal morphology."
Supports sigmoidal contour for the Z-disc class that includes VCL. INDIRECT because the two VCL probands are pooled with eleven probands carrying variants in four other genes.
🧬

Genetic Associations

1
VCL
Gene: VCL hgnc:12665 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is VCL (hgnc:12665). hgnc:12665 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: DISPUTED variant_origin: GERMLINE
Show evidence (6 references)
PMID:16712796 SUPPORT Human Clinical
"A novel missense mutation, L277M-VCL, involving a conserved residue was identified in a patient with severely obstructive, mid-ventricular hypertrophy. This mutation was not detected in 400 reference alleles."
The primary report of the vinculin variant on which the entity's non-insert arm rests, with its contemporaneous control-allele screen.
PMID:16236538 SUPPORT Human Clinical
"Overall, 3 non-synonymous single nucleotide polymorphisms (A934V, P943A, and R975W) were detected in 4 patients. One patient with severely obstructive, mid-ventricular and apical hypertrophy harbored the previously published DCM-associated mutation, R975W."
Names the exon-19 variants found in the hypertrophic cohort and identifies the single proband whose variant was carried forward as causal.
PMID:16236538 SUPPORT Human Clinical
"However, this study demonstrates that the same fundamental mutation in humans can yield either cardiomyopathic phenotype, underscoring a critical role for modifier genes and/or environmental stressors in cardiac remodeling."
States the allelism directly: one VCL substitution has been reported with both hypertrophic and dilated remodelling, so genotype alone does not specify which entity results.
+ 3 more references
💊

Medical Actions

1
Septal myectomy for obstructive disease
Action: septal myectomyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is septal myectomy, annotated with Myectomy (NCIT:C51591). NCIT:C51591 is a clinical intervention from the NCI Thesaurus. Ontology label: Myectomy NCIT:C51591
Platform: Surgery
Both reported probands underwent surgical septal myectomy, which is how the tissue examined in the original studies was obtained. Management of CMH15 is the management of obstructive hypertrophic cardiomyopathy and is not genotype-directed: no VCL-specific therapy exists, none is in development, and the disputed status of the gene-disease relationship means the genotype should not influence treatment decisions at all.
Mechanism Target:
Dynamic Outflow Obstruction — Relieves the obstruction node directly by resecting the hypertrophied septum. It does not address anything upstream of it.
Target Phenotypes: Left ventricular outflow tract obstruction HP:0032092 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Left ventricular outflow tract obstruction (HP:0032092). HP:0032092 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:16949038 SUPPORT Human Clinical
"Microscopic examination of both myectomy specimens from patients bearing genetic defects in metavinculin and vinculin showed a marked reduction of vinculin/metavinculin expression in the intercalated disc, but normal expression in the Z-disc."
Records that both probands came to surgical myectomy - the tissue examined in that study is the myectomy specimen - which is the only treatment documented for either of them.
🔬

Diagnosis

2
Clinical diagnosis of hypertrophic cardiomyopathy by echocardiography
The diagnosis in both reported cases was a clinical one, made on imaging, with the VCL variant found afterwards by research sequencing of an already phenotyped cohort. Nothing about CMH15 changes how hypertrophic cardiomyopathy is recognized: wall thickness, the distribution of hypertrophy, and the presence and level of outflow obstruction are assessed exactly as in any other form. Where this entity does bear on imaging is in what to expect - both probands had severe obstruction at mid-ventricular level, one with apical involvement, and the wider Z-disc series was preferentially sigmoidal in septal contour rather than reverse-curvature.
Echocardiography NCIT:C16525 NCI Thesaurus (NCIT)
Results: Left ventricular hypertrophy with severe outflow obstruction, mid-ventricular and in one case apical; sigmoidal septal contour reported for the Z-disc class that includes VCL.
Show evidence (1 reference)
PMID:17097056 SUPPORT INDIRECT Human Clinical
"Blinded to the Z-disc genotype status, the septal contour was graded qualitatively using standard transthoracic echocardiography."
Establishes the modality and the blinded grading behind the morphology claim. INDIRECT because the two VCL probands are pooled with eleven others.
Genetic testing, and why VCL should not be reported for hypertrophic cardiomyopathy
This is the practically important entry on the whole record. VCL appears on many commercial cardiomyopathy panels, so a rare VCL missense variant will be found in hypertrophic cardiomyopathy probands and can be reported against OMIM's CMH15 entry. ClinGen's expert panel has classified that relationship as Disputed, having found that the two originally reported variants exceed the panel's gnomAD frequency ceiling for pathogenicity and that no new evidence has emerged since ClinGen's initial curation. A VCL variant is therefore not a molecular diagnosis of hypertrophic cardiomyopathy, must not be used for predictive testing or cascade screening in a hypertrophic family, and should not end the diagnostic search. The same variant found in a dilated presentation is a different matter, since ClinGen rates VCL-dilated cardiomyopathy Strong.
Genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Results: A VCL variant in a hypertrophic cardiomyopathy proband is uninformative and should be treated as such; the finding does not establish a molecular diagnosis or support cascade testing.
Show evidence (3 references)
CGGV:assertion_27365fd2-1203-4e2b-8830-3277e965d8bc-2023-05-10T160000.000Z SUPPORT Other
"This gene was noted to be a potential rare cause of HCM; however, no new evidence has emerged since the initial curation."
The state of the evidence base, which is what makes a VCL finding uninterpretable in this setting.
PMID:30681346 SUPPORT INDIRECT Human Clinical
"The majority of genes previously reported as causative of HCM and commonly included in diagnostic tests have limited or no evidence of disease association."
Sets the general problem this entry is an instance of. INDIRECT because the abstract states the aggregate result without naming VCL; the gene-specific verdict is carried by the ClinGen record cited alongside it.
PMID:30681346 SUPPORT INDIRECT Human Clinical
"Of 4191 HCM variants in ClinVar, 31% were in genes with limited or no evidence of disease association."
Quantifies how often variants in genes of this evidential class reach a public variant database, which is the reporting risk this entry warns about.
📊

Prevalence

1
Worldwide published cases
Cases In Literature Ultra Rare
No population prevalence estimate exists, and none can be derived, because the gene-disease relationship is disputed. The entire published case base is two unrelated probands, both reported by one group in 2006 from Mayo Clinic hypertrophic cardiomyopathy cohorts that had already been screened negative for the common myofilament genes. The denominators are informative even though the numerator is not: one novel VCL missense variant in 228 genotype-negative probands, and three non-synonymous exon-19 variants across four patients among 389 clinically diagnosed probands, of which one (R975W) was carried forward as causal. A separate Z-disc series from the same centre found VCL variants in 2 of 239 myofilament-negative probands; whether those are the same two probands is not stated, and the cohorts overlap.
Show evidence (1 reference)
CGGV:assertion_27365fd2-1203-4e2b-8830-3277e965d8bc-2023-05-10T160000.000Z SUPPORT Other
"Although variants in this gene have been reported in only two probands with hypertrophic cardiomyopathy, an association with dilated cardiomyopathy (DCM) has been assessed separately with a higher number or reported probands."
ClinGen's own count of the published hypertrophic cardiomyopathy case base for VCL, which is what fixes this entity at the case-report tier.
🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Hypertrophic Cardiomyopathy 15:

Sarcomeric (myofilament) hypertrophic cardiomyopathy MONDO:0005045
Overlapping Features The overwhelmingly more likely explanation for hypertrophic cardiomyopathy in any given proband, and the diagnosis that should be pursued before a VCL variant is entertained. Only eight genes have definitive evidence for hypertrophic cardiomyopathy, all encoding sarcomeric proteins. Both CMH15 probands were drawn from cohorts already screened negative for these, which is the only reason a VCL variant was looked for at all.
Distinguishing Features
  • A pathogenic variant in MYBPC3, MYH7, TNNT2, TNNI3, TPM1, ACTC1, MYL2 or MYL3
  • Reverse-curvature septal morphology rather than the sigmoidal contour reported for the Z-disc class
  • Myocyte disarray on histology
Show evidence (1 reference)
PMID:30681346 SUPPORT Human Clinical
"Of 33 HCM genes, only 8 (24%) were categorized as definitive ( MYBPC3, MYH7, TNNT2, TNNI3, TPM1, ACTC1, MYL2, and MYL3); 3 had moderate evidence ( CSRP3, TNNC1, and JPH2; 33%); and 22 (66%) had limited (n=16) or no evidence (n=6)."
Names the genes that do have definitive evidence, and by omission places VCL outside them.
Obstructive hypertrophy of other cause, including aortic stenosis
Overlapping Features Included because of the specific trap this entity sets. Intercalated-disc depletion of vinculin and metavinculin was the histological finding used to corroborate the VCL attribution in both probands, and it turns out to be a feature of outflow obstruction rather than of VCL genotype: the same pattern appears in obstructive hypertrophic cardiomyopathy generally and in aortic stenosis, and is absent in dilated, hypertensive and pulmonary-hypertensive hearts. The finding therefore cannot be used to distinguish CMH15 from any other obstructive lesion, and should not be treated as a diagnostic marker.
Distinguishing Features
  • None histologically - the intercalated-disc vinculin pattern is shared, which is the point of this entry
  • Aortic stenosis is distinguished by valve morphology and the level of the gradient on imaging, not by vinculin staining
Show evidence (1 reference)
PMID:16949038 SUPPORT Human Clinical
"Tissue specimens derived from patients with obstructive HCM and aortic stenosis (AS) showed a universal defect of vinculin/metavinculin expression in the intercalated disc but preserved expression in the cardiac Z-disc"
Supports the claim this differential rests on: the staining pattern is shared between CMH15, obstructive hypertrophic cardiomyopathy without a VCL variant, and aortic stenosis, so it cannot distinguish them.
🐁

Animal Models

2
Cardiomyocyte-specific vinculin knockout mouse (cVclKO)
Cre-loxP deletion of Vcl in cardiomyocytes. Half the animals died suddenly before three months from ventricular tachycardia with preserved contractile function; survivors developed dilated cardiomyopathy and died before six months. Ultrastructure before dysfunction showed dissolution of the intercalated disc, reduced cadherin and beta-1D integrin, and connexin-43 mislocalized to the lateral border.
Species
Mouse
Genotype
Vcl conditional null, cardiomyocyte-restricted Cre-loxP excision
Publication
PMID:17785437
Pathograph links
Disrupted Intercalated Disc and Costamere Anchorage recapitulates fidelity: moderate observes: cellular Establishes in vivo that removing cardiomyocyte vinculin dismantles exactly the junctions this node names, and that it does so before any contractile phenotype appears.
Limitations: A complete tissue-specific null, not a missense allele: it models absence of vinculin, whereas the CMH15 variants are proposed to act by gain of function through mutant metavinculin. Mouse hearts also express less metavinculin relative to vinculin than human hearts do, so an insert-specific effect is under-represented in this system.
Show evidence (1 reference)
PMID:17785437 SUPPORT Model Organism
"ultrastructural analysis of cVclKO heart tissue showed abnormal adherens junctions with dissolution of the intercalated disc structure, expression of the junctional proteins cadherin and beta1D integrin were reduced, and the gap junction protein connexin 43 was mislocalized to the lateral myocyte border"
The junctional lesion this link claims the model reproduces, observed directly.
Maladaptive Left Ventricular Hypertrophy fails to recapitulate fidelity: low observes: organism The most informative negative result for this entity. Losing cardiomyocyte vinculin in vivo produces arrhythmic sudden death and then a dilated ventricle. It does not produce hypertrophy.
Limitations: The failure is not decisive against a hypertrophic mechanism, because the allele is wrong for the question: a null cannot test a gain-of-function missense hypothesis, and the opposite remodelling direction is what loss-of-function VCL alleles produce in humans too. The result constrains what can be inferred from vinculin-deficiency models about hypertrophy, and no CMH15 knock-in mouse exists to answer the question properly.
Show evidence (1 reference)
PMID:17785437 REFUTE Model Organism
"cVclKO mice that survived through the vulnerable period of sudden death developed dilated cardiomyopathy and died before 6 months of age."
The model's cardiac endpoint is dilation, not hypertrophy, so it does not reproduce the phenotype this entity is defined by.
Show evidence (1 reference)
PMID:17785437 SUPPORT Model Organism
"This is the first report of tissue-specific inactivation of the Vcl gene and shows that it is required for preservation of normal cell-cell and cell-matrix adhesive structures."
Supports treating this model as informative for cardiomyocyte junctional biology, which is the ground on which it is linked to this entry's anchorage node.
Heterozygous vinculin knockout mouse (Vin+/-)
Global heterozygous Vcl inactivation, giving roughly 58% less vinculin and 63% less metavinculin. These animals are grossly normal with normal baseline cardiac function, but carry abnormal electrocardiograms, abnormal intercalated discs, misaligned Z-lines, and decompensate when pressure-loaded by transverse aortic constriction.
Species
Mouse
Genotype
Vcl heterozygous null
Publication
PMID:15331426
Pathograph links
Disrupted Intercalated Disc and Costamere Anchorage recapitulates fidelity: moderate observes: cellular Shows that a partial reduction in vinculin and metavinculin, closer in degree to a heterozygous human genotype than a complete null, is already enough to disorganize the intercalated disc and the Z-line register.
Limitations: Reduced dosage of normal protein, whereas the CMH15 hypothesis is that mutant metavinculin is actively mis-functional; a 58% reduction does not test that. The phenotype is also latent until haemodynamic stress is applied.
Show evidence (1 reference)
PMID:15331426 SUPPORT Model Organism
"normal basal cardiac function and histology but abnormal electrocardiograms, intercalated disks, and ICD-related protein distribution"
Junctional disorganization at partial vinculin dosage, with function still normal, which is the node's claim.
Impaired Cardiomyocyte Force Transmission partially recapitulates fidelity: moderate observes: organism Vin+/- hearts tolerate normal load but fail under acute pressure overload, which is the behaviour expected of a myocardium whose force-transmission apparatus has reduced reserve rather than reduced resting output.
Limitations: The readout is organ-level decompensation after aortic constriction, not a measurement of force transmission, so the mechanism is inferred from the stress response. PARTIALLY_RECAPITULATES because baseline function is normal: the model reproduces the vulnerability, not a resting deficit.
Show evidence (1 reference)
PMID:15331426 SUPPORT Model Organism
"increased mortality following acute hemodynamic stress imposed by transverse aortic constriction (TAC); 4) cardiac dysfunction by 6 weeks post-TAC"
Documents the load-dependent failure that this link reads as reduced force-transmission reserve.
Show evidence (1 reference)
PMID:15331426 SUPPORT Model Organism
"Decreased expression of vinculin/metavinculin leads to abnormal myocyte structure without baseline physiological evidence of cardiac dysfunction. These structural changes predispose to stress-induced cardiomyopathy."
Supports treating this model as informative for the structural consequences of reduced vinculin and metavinculin dosage, which is why it is linked here.
{ }

Source YAML

click to show 
name: Hypertrophic Cardiomyopathy 15
creation_date: "2026-09-08T00:00:00Z"
synonyms:
- CMH15
- cardiomyopathy, familial hypertrophic, 15
- VCL-related hypertrophic cardiomyopathy
- metavinculin hypertrophic cardiomyopathy
description: >-
  Hypertrophic cardiomyopathy 15 (CMH15) is the VCL-attributed form of familial
  hypertrophic cardiomyopathy. VCL encodes two proteins from one gene: vinculin,
  expressed ubiquitously, and metavinculin, a splice isoform carrying a
  68-residue insert in the C-terminal tail encoded by exon 19 and restricted to
  cardiac and smooth muscle. Both localize to the sites where the actin
  cytoskeleton is anchored to the membrane, so the proposed lesion is one of
  force transmission and cytoskeletal anchorage rather than of the contractile
  apparatus itself. The vinculin tail binds F-actin and dimerizes to bundle
  filaments into thick fibers; the metavinculin tail binds F-actin but cannot
  bundle it, severs filaments instead, and inhibits vinculin-mediated bundling,
  so metavinculin acts as a tuner of vinculin's actin-organizing activity. The
  cardiomyopathy-associated insert variants destabilize the conformational
  sub-domain that mediates that inhibition: they neither bundle normally nor
  restrain vinculin, and instead promote large, disordered actin assemblies.
  Myectomy tissue from the two reported probands showed vinculin and
  metavinculin markedly reduced at the intercalated disc with preserved Z-disc
  staining, and both had severely obstructive mid-ventricular hypertrophy, with
  apical involvement in one of the two.

  The gene-disease relationship is disputed, and this entry is curated on that
  footing rather than as an established cause. ClinGen's Hereditary
  Cardiovascular Disease Gene Curation Expert Panel reclassified VCL-hypertrophic
  cardiomyopathy from Limited to Disputed in May 2023: only two probands were
  ever reported, both in 2006 from one group, and the two missense variants
  carried by them are more common in gnomAD than the panel's pathogenicity
  cutoff allows. The intercalated-disc depletion seen in those probands was
  subsequently found in obstructive hypertrophic cardiomyopathy and aortic
  stenosis generally, so it tracks outflow obstruction rather than VCL genotype
  and cannot serve as VCL-specific corroboration. VCL's well-supported cardiac
  association is with dilated cardiomyopathy, which ClinGen rates Strong, and the
  best-characterized variant, p.Arg975Trp, has been reported in both hypertrophic
  and dilated presentations. CMH15 should therefore be read as a molecularly
  plausible but clinically unconfirmed entity: the metavinculin biochemistry is
  solid, the human genetic evidence that it causes hypertrophic cardiomyopathy is
  not.
category: Mendelian
classifications:
  harrisons_chapter:
  - classification_value: CARDIOVASCULAR
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
disease_term:
  preferred_term: hypertrophic cardiomyopathy 15
  term:
    id: MONDO:0013200
    label: hypertrophic cardiomyopathy 15
parents:
- Hypertrophic Cardiomyopathy
- Cardiovascular Disease
- Genetic Disorder
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0013200
      label: hypertrophic cardiomyopathy 15
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >-
      Primary MONDO identifier for the CMH15 entity (OMIM:613255), the
      VCL-attributed locus of familial hypertrophic cardiomyopathy.
prevalence:
- population: Worldwide published cases
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    No population prevalence estimate exists, and none can be derived, because
    the gene-disease relationship is disputed. The entire published case base is
    two unrelated probands, both reported by one group in 2006 from Mayo Clinic
    hypertrophic cardiomyopathy cohorts that had already been screened negative
    for the common myofilament genes. The denominators are informative even though
    the numerator is not: one novel VCL missense variant in 228 genotype-negative
    probands, and three non-synonymous exon-19 variants across four patients among
    389 clinically diagnosed probands, of which one (R975W) was carried forward as
    causal. A separate Z-disc series from the same centre found VCL variants in 2
    of 239 myofilament-negative probands; whether those are the same two probands
    is not stated, and the cohorts overlap.
  evidence:
  - reference: CGGV:assertion_27365fd2-1203-4e2b-8830-3277e965d8bc-2023-05-10T160000.000Z
    reference_title: VCL / hypertrophic cardiomyopathy (Disputed)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Although variants in this gene have been reported in only two probands with
      hypertrophic cardiomyopathy, an association with dilated cardiomyopathy
      (DCM) has been assessed separately with a higher number or reported
      probands.
    explanation: >-
      ClinGen's own count of the published hypertrophic cardiomyopathy case base
      for VCL, which is what fixes this entity at the case-report tier.
inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    CMH15 is catalogued as an autosomal dominant trait, and ClinGen curated the
    VCL-hypertrophic cardiomyopathy relationship under an autosomal dominant mode
    of inheritance. The assignment rests on the catalogue classification and on
    the dominant pattern established for VCL in dilated cardiomyopathy rather
    than on segregation in hypertrophic cardiomyopathy families: both reported
    probands were ascertained as isolated cases from screening cohorts, and no
    multi-generation hypertrophic cardiomyopathy pedigree segregating a VCL
    variant has been published.
  evidence:
  - reference: CGGV:assertion_27365fd2-1203-4e2b-8830-3277e965d8bc-2023-05-10T160000.000Z
    reference_title: VCL / hypertrophic cardiomyopathy (Disputed)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "| VCL | HGNC:12665 | hypertrophic cardiomyopathy | MONDO:0005045 | AD | Disputed | SOP9 | Hereditary Cardiovascular Disease Gene Curation Expert Panel | 2023-05-10T16:00:00.000Z |"
    explanation: >-
      Records the mode of inheritance under which the relationship was curated
      (AD) together with the Disputed classification, which is why the inheritance
      claim is catalogue-derived rather than pedigree-derived.
genetic:
- name: VCL
  presence: PRESENT
  relationship_type: DISPUTED
  variant_origin: GERMLINE
  gene_term:
    preferred_term: VCL
    term:
      id: hgnc:12665
      label: VCL
  notes: >-
    VCL encodes vinculin and, through inclusion of the alternatively spliced exon
    19, the muscle-restricted isoform metavinculin. Two classes of variant have
    been attributed to hypertrophic cardiomyopathy, in different parts of the
    protein: p.Leu277Met in a region shared by both isoforms, and exon-19
    substitutions (p.Ala934Val, p.Pro943Ala, p.Arg975Trp) falling inside the
    68-residue metavinculin-specific insert. p.Arg975Trp is the best characterized
    and had already been reported in dilated cardiomyopathy, so one substitution
    has been assigned to both remodelling directions.

    relationship_type is DISPUTED, the enum value corresponding to ClinGen
    "Disputed" or "Refuted". CAUSATIVE would be wrong: it is defined as ClinGen
    Definitive or Strong, and a prose caveat under a CAUSATIVE value would not
    survive export, query, or any consumer that reads the structured field rather
    than this note. MONDO and OMIM do assert the entity; that assertion is carried
    by the entry existing and by disease_term, not by overstating this slot.
    ClinGen classifies VCL-hypertrophic cardiomyopathy as Disputed (Hereditary
    Cardiovascular Disease GCEP, 2023-05-10, changed from Limited) while rating
    VCL-dilated cardiomyopathy Strong (Dilated Cardiomyopathy GCEP, 2024-08-09).
    A VCL variant found in a cardiomyopathy proband is therefore interpretable for
    dilated cardiomyopathy and not for hypertrophic cardiomyopathy. See the REFUTE
    evidence below and the discussions section; do not cite this block as support
    for clinical reporting of a VCL variant in a hypertrophic cardiomyopathy case.
  evidence:
  - reference: PMID:16712796
    reference_title: A missense mutation in a ubiquitously expressed protein, vinculin, confers susceptibility to hypertrophic cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A novel missense mutation, L277M-VCL, involving a conserved residue was
      identified in a patient with severely obstructive, mid-ventricular
      hypertrophy. This mutation was not detected in 400 reference alleles.
    explanation: >-
      The primary report of the vinculin variant on which the entity's non-insert
      arm rests, with its contemporaneous control-allele screen.
  - reference: PMID:16236538
    reference_title: Identification of a metavinculin missense mutation, R975W, associated with both hypertrophic and dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Overall, 3 non-synonymous single nucleotide polymorphisms (A934V, P943A, and
      R975W) were detected in 4 patients. One patient with severely obstructive,
      mid-ventricular and apical hypertrophy harbored the previously published
      DCM-associated mutation, R975W.
    explanation: >-
      Names the exon-19 variants found in the hypertrophic cohort and identifies
      the single proband whose variant was carried forward as causal.
  - reference: PMID:16236538
    reference_title: Identification of a metavinculin missense mutation, R975W, associated with both hypertrophic and dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, this study demonstrates that the same fundamental mutation in
      humans can yield either cardiomyopathic phenotype, underscoring a critical
      role for modifier genes and/or environmental stressors in cardiac
      remodeling.
    explanation: >-
      States the allelism directly: one VCL substitution has been reported with
      both hypertrophic and dilated remodelling, so genotype alone does not
      specify which entity results.
  - reference: CGGV:assertion_2d46699a-5f8c-460d-9233-bec4e2ecf560-2024-08-09T160000.000Z
    reference_title: VCL / dilated cardiomyopathy (Strong)
    supports: NO_EVIDENCE
    evidence_source: OTHER
    snippet: "VCL | HGNC:12665 | dilated cardiomyopathy | MONDO:0005021 | AD | Strong"
    explanation: >-
      NO_EVIDENCE because this record is about a different disease. It establishes
      the contrasting, well-supported VCL cardiac association against which this
      entity's disputed status should be read, and bears on this entry's claim only
      by contrast; it is not evidence that VCL causes hypertrophic cardiomyopathy.
  - reference: CGGV:assertion_27365fd2-1203-4e2b-8830-3277e965d8bc-2023-05-10T160000.000Z
    reference_title: VCL / hypertrophic cardiomyopathy (Disputed)
    supports: REFUTE
    evidence_source: OTHER
    snippet: >-
      Two missense variants from these initial publications have been reported in
      humans, but the frequency in gnomAD is above the cutoff for pathogenicity in
      this GCEP.
    explanation: >-
      Contradicts the causal claim directly: population frequency of the two
      reported variants is incompatible with them causing a rare dominant
      cardiomyopathy. This is the specific finding that moved the classification
      to Disputed.
  - reference: CGGV:assertion_27365fd2-1203-4e2b-8830-3277e965d8bc-2023-05-10T160000.000Z
    reference_title: VCL / hypertrophic cardiomyopathy (Disputed)
    supports: REFUTE
    evidence_source: OTHER
    snippet: >-
      In summary, the evidence supporting the relationship between VCL and
      autosomal dominant hypertrophic cardiomyopathy has been disputed and no
      valid evidence remains to support the claim.
    explanation: >-
      The expert panel's summary verdict on the gene-disease relationship that
      defines this entity.
pathophysiology:
- name: VCL Missense Variant in Vinculin or the Metavinculin Insert
  biological_scale: MOLECULAR
  mechanism_confidence: HYPOTHETICAL
  description: >-
    The proposed initiating lesion is a heterozygous germline missense
    substitution in VCL. Two locations have been implicated and they are not
    equivalent. p.Leu277Met lies in a region present in both vinculin and
    metavinculin, so it would perturb the ubiquitous protein as well as the
    cardiac isoform. p.Ala934Val, p.Pro943Ala and p.Arg975Trp lie inside the
    68-residue insert encoded by exon 19, which is present only in metavinculin,
    so their effect is restricted to cardiac and smooth muscle. Whether either
    class is pathogenic in hypertrophic cardiomyopathy is disputed, which is why
    this node and everything downstream of it are marked HYPOTHETICAL.
  genetic_context:
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    allele_type: MISSENSE
    functional_impact_category: GAIN_OF_FUNCTION
    notes: >-
      GAIN_OF_FUNCTION follows ClinGen's reading of the biochemical data: the
      mutant metavinculin tails do not simply lose their inhibitory function, they
      acquire the ability to drive formation of large disordered actin assemblies
      that neither wild-type isoform produces. Note that this is the mechanism
      proposed for the exon-19 insert variants; no functional characterization of
      p.Leu277Met has been published, so the category is extrapolated to that
      allele rather than measured for it.
  genes:
  - preferred_term: VCL
    term:
      id: hgnc:12665
      label: VCL
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  downstream:
  - target: Loss of Metavinculin Restraint on Vinculin-Mediated Actin Bundling
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30844403
      reference_title: Cardiomyopathy Mutations in Metavinculin Disrupt Regulation of Vinculin-Induced F-Actin Assemblies.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Sub-domain formation is destabilized by CM mutations, disrupting this
        inhibitory mechanism.
      explanation: >-
        States the causal step from the variant to loss of the inhibitory
        mechanism, which is the edge drawn here.
  evidence:
  - reference: CGGV:assertion_27365fd2-1203-4e2b-8830-3277e965d8bc-2023-05-10T160000.000Z
    reference_title: VCL / hypertrophic cardiomyopathy (Disputed)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The mechanism for disease is believed to be gain-of-function, with mutants
      both failing to induce F-actin binding and promoting formation of large
      actin assemblies with linear bundles (PMID: 30844403).
    explanation: >-
      Records the proposed mechanism class for this node, and the hedge
      ("believed to be") that justifies the HYPOTHETICAL confidence.
- name: Loss of Metavinculin Restraint on Vinculin-Mediated Actin Bundling
  biological_scale: MOLECULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    In the normal heart the two VCL isoforms are co-expressed at
    sub-stoichiometric ratio and do opposite things to actin. The vinculin tail
    binds F-actin and dimerizes to bundle filaments into thick fibers; the
    metavinculin tail binds F-actin the same way but cannot bundle it, severs
    filaments instead, and inhibits vinculin-mediated bundling. That inhibition
    requires a protruding sub-domain formed by the 68-residue insert, which
    sterically blocks vinculin tail dimerization. The cardiomyopathy variants
    destabilize the sub-domain, so the brake is released and mutant metavinculin
    no longer restrains vinculin.
  molecular_functions:
  - preferred_term: metavinculin-mediated actin filament severing
    term:
      id: GO:0003789
      label: actin filament severing activity
  biological_processes:
  - preferred_term: vinculin-mediated actin filament bundling
    term:
      id: GO:0051017
      label: actin filament bundle assembly
    modifier: GAIN_OF_FUNCTION
  downstream:
  - target: Disordered F-Actin Assembly at the Membrane Anchor
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30844403
      reference_title: Cardiomyopathy Mutations in Metavinculin Disrupt Regulation of Vinculin-Induced F-Actin Assemblies.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        These CM mutants were found to weakly induce the formation of disordered
        F-actin assemblies. Notably, they fail to inhibit Vt-mediated F-actin
        bundling and instead promote formation of large assemblies embedded with
        linear bundles.
      explanation: >-
        Directly links the loss of inhibition to the disordered assemblies that
        the downstream node names.
  evidence:
  - reference: PMID:30844403
    reference_title: Cardiomyopathy Mutations in Metavinculin Disrupt Regulation of Vinculin-Induced F-Actin Assemblies.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      While MVt binds to F-actin in a similar manner to Vt, MVt is incapable of
      F-actin bundling and inhibits Vt-mediated F-actin bundling.
    explanation: >-
      Establishes the wild-type inhibitory relationship between the two isoform
      tails, which is what the variants disrupt.
  - reference: PMID:30844403
    reference_title: Cardiomyopathy Mutations in Metavinculin Disrupt Regulation of Vinculin-Induced F-Actin Assemblies.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      Computational models of MVt bound to F-actin suggest that MVt undergoes a
      conformational change licensing the formation of a protruding sub-domain
      incorporating the insert, which sterically prevents dimerization and
      bundling of F-actin by Vt.
    explanation: >-
      Supplies the structural mechanism for the inhibition, and is graded
      COMPUTATIONAL because it is a modelling result rather than a measurement.
  - reference: PMID:22613835
    reference_title: The C-terminal tail domain of metavinculin, vinculin's splice variant, severs actin filaments.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Unlike its splice variant, MVt did not bundle actin filaments. Instead, MVt
      promoted severing of actin filaments, most efficiently at substoichiometric
      concentrations.
    explanation: >-
      Independent demonstration of the severing activity that distinguishes the
      metavinculin tail from the vinculin tail.
  - reference: PMID:3129429
    reference_title: Diversity of vinculin/meta-vinculin in human tissues and cultivated cells. Expression of muscle specific variants of vinculin in human aorta smooth muscle cells.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      gamma-Isoform of vinculin and both alpha- and beta-isoforms of meta-vinculin
      were found in smooth (aorta wall and myometrium) and cardiac muscle, rather
      than in skeletal muscle, liver, foreskin fibroblasts, and macrophages.
    explanation: >-
      Establishes that metavinculin expression is restricted to cardiac and smooth
      muscle, which is why a variant confined to the metavinculin insert can yield
      a cardiac-specific phenotype from a ubiquitously transcribed gene.
- name: Disordered F-Actin Assembly at the Membrane Anchor
  biological_scale: MOLECULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    With the inhibitory brake released, the mutant tails produce large actin
    assemblies embedded with linear bundles rather than the regular bundled
    architecture vinculin normally builds. The actin network that couples the
    contractile apparatus to the membrane is therefore built wrongly, not merely
    built less.
  biological_processes:
  - preferred_term: actin cytoskeleton organization
    term:
      id: GO:0030036
      label: actin cytoskeleton organization
    modifier: ABNORMAL
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  downstream:
  - target: Disrupted Intercalated Disc and Costamere Anchorage
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:30844403
    reference_title: Cardiomyopathy Mutations in Metavinculin Disrupt Regulation of Vinculin-Induced F-Actin Assemblies.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      These findings provide new mechanistic insights into the ability of
      metavinculin to tune actin organization by vinculin and suggest that
      dysregulation of this process by CM mutants could underlie their malfunction
      in disease.
    explanation: >-
      The authors' own statement of what the disordered assemblies are proposed to
      mean for disease, with the hedge preserved.
- name: Disrupted Intercalated Disc and Costamere Anchorage
  biological_scale: CELLULAR
  mechanism_confidence: HYPOTHETICAL
  description: >-
    Vinculin and metavinculin are structural components of the junctions where
    cardiomyocyte actin is anchored: the intercalated disc, which couples adjacent
    myocytes end to end, and the costamere, which couples the myofibril laterally
    to the sarcolemma and extracellular matrix. Myectomy tissue from both reported
    probands showed vinculin and metavinculin markedly reduced at the intercalated
    disc with normal Z-disc staining, and the earlier metavinculin work had shown
    altered intercalated-disc organization in vivo. The specificity of that
    finding is the weak point of the chain rather than its existence; see the
    REFUTE evidence on this node.
  biological_processes:
  - preferred_term: adherens junction organization
    term:
      id: GO:0034332
      label: adherens junction organization
    modifier: ABNORMAL
  - preferred_term: cell-matrix adhesion
    term:
      id: GO:0007160
      label: cell-matrix adhesion
    modifier: ABNORMAL
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  downstream:
  - target: Impaired Cardiomyocyte Force Transmission
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:16712796
    reference_title: A missense mutation in a ubiquitously expressed protein, vinculin, confers susceptibility to hypertrophic cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Immunohistochemical analysis of the proband's myectomy specimen demonstrated
      markedly reduced vinculin levels in the intercalated discs.
    explanation: >-
      The human tissue observation in the vinculin proband on which this node
      rests.
  - reference: PMID:16236538
    reference_title: Identification of a metavinculin missense mutation, R975W, associated with both hypertrophic and dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Immunohistochemical analysis of the proband's myectomy specimen revealed a
      paucity of vinculin/metavinculin in the intercalated discs.
    explanation: >-
      The matching observation in the metavinculin proband, from a different
      variant class.
  - reference: PMID:16949038
    reference_title: Obstructive hypertrophic cardiomyopathy is associated with reduced expression of vinculin in the intercalated disc.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Tissue specimens derived from patients with obstructive HCM and aortic
      stenosis (AS) showed a universal defect of vinculin/metavinculin expression
      in the intercalated disc but preserved expression in the cardiac Z-disc
    explanation: >-
      Refutes the inference that intercalated-disc vinculin depletion is caused by
      the VCL variant. The same pattern occurs in obstructive hypertrophic
      cardiomyopathy without a VCL variant and in aortic stenosis, so it tracks
      outflow obstruction and cannot corroborate a VCL-specific lesion.
- name: Impaired Cardiomyocyte Force Transmission
  biological_scale: CELLULAR
  mechanism_confidence: HYPOTHETICAL
  description: >-
    Consequence of a mis-built actin-membrane anchor: contractile force generated
    by the sarcomere is transmitted less efficiently to neighbouring myocytes and
    to the extracellular matrix. That vinculin loss impairs myocyte mechanics is
    measured rather than assumed - vinculin-deficient mouse myocytes have reduced
    membrane cortical stiffness, wider myofilament lattice spacing and reduced
    systolic transverse strain in vivo, all before global ventricular dysfunction
    appears. What is not measured is the same for a CMH15 allele: those
    experiments use vinculin deletion, whereas the human variants proposed here
    are missense changes acting by gain of function, so the mechanical consequence
    is transferred across allele classes. The node is marked HYPOTHETICAL for that
    reason rather than for lack of any evidence.
  biological_processes:
  - preferred_term: cardiac muscle contraction
    term:
      id: GO:0060048
      label: cardiac muscle contraction
    modifier: ABNORMAL
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  downstream:
  - target: Maladaptive Left Ventricular Hypertrophy
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:23561539
    reference_title: Novel role for vinculin in ventricular myocyte mechanics and dysfunction.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      MRI revealed significantly decreased systolic strains transverse to the
      myofiber axis in vivo, but no changes along the muscle fibers or in fiber
      tension in papillary muscles from heterozygous global Vcl null mice.
    explanation: >-
      Measures a mechanical deficit attributable to reduced vinculin, and locates
      it transverse to the fibre axis rather than in fibre tension. INDIRECT
      because the allele is a null, not a CMH15 missense variant.
  - reference: PMID:23561539
    reference_title: Novel role for vinculin in ventricular myocyte mechanics and dysfunction.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      AFM in Vcl heterozygous null mouse myocytes showed a significant decrease in
      membrane cortical stiffness.
    explanation: >-
      Gives the cell-mechanical correlate of losing the actin-membrane anchor,
      which is the property this node claims is degraded.
  - reference: PMID:37548861
    reference_title: Heart Failure with Recovered Ejection Fraction in Patients with Vinculin Loss-of-function Variants.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Vinculin links the actin cytoskeleton to the cell membrane which is critical
      in force transmission and is needed to maintain cardiomyocyte function
    explanation: >-
      States the force-transmission role this node depends on. INDIRECT: it is a
      background statement in a dilated cardiomyopathy case series, not a
      measurement in hypertrophic disease.
- name: Maladaptive Left Ventricular Hypertrophy
  biological_scale: TISSUE
  mechanism_confidence: PROVISIONAL
  description: >-
    The tissue-level endpoint: left ventricular hypertrophy which in the two
    reported probands was severely obstructive and mid-ventricular or apical in
    distribution. A separate series from the same centre found that hypertrophic
    cardiomyopathy attributable to Z-disc genes, VCL among them, carries a
    sigmoidal septal contour in most cases, in contrast to the reverse-curvature
    morphology typical of myofilament disease.
  downstream:
  - target: Dynamic Outflow Obstruction
    causal_link_type: DIRECT
  - target: Hypertrophic cardiomyopathy
    causal_link_type: DIRECT
    description: >-
      The tissue lesion presenting as the clinical entity both probands were
      diagnosed with.
  - target: Apical hypertrophy
    causal_link_type: DIRECT
    description: >-
      Apical distribution of the hypertrophy, reported in the metavinculin proband.
  evidence:
  - reference: PMID:17097056
    reference_title: Echocardiographic-determined septal morphology in Z-disc hypertrophic cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Thirteen of the 239 patients (5.4%) had one of 13 distinct HCM-associated
      Z-disc mutations involving residues highly conserved across species and
      absent in 600 reference alleles: LDB3 (6), ACTN2 (3), TCAP (1), CSRP3 (1),
      and VCL (2).
    explanation: >-
      Places VCL within the Z-disc class of hypertrophic cardiomyopathy and gives
      its share of that class in a myofilament-negative cohort.
  - reference: PMID:17097056
    reference_title: Echocardiographic-determined septal morphology in Z-disc hypertrophic cardiomyopathy.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      For this subset with Z-disc-associated HCM, the septal contour was sigmoidal
      in 11 (85%) and apical in 2 (15%). While Z-disc-HCM is uncommon, it is equal
      in prevalence to thin filament-HCM. In contrast to myofilament-HCM, Z-disc-HCM
      is associated preferentially with sigmoidal morphology.
    explanation: >-
      Characterizes the hypertrophy morphology of the Z-disc class as a whole.
      INDIRECT because the figures are for all thirteen Z-disc probands, of whom
      only two carried VCL variants, so the morphology is not resolved to VCL.
- name: Dynamic Outflow Obstruction
  biological_scale: ORGANISM
  mechanism_confidence: PROVISIONAL
  description: >-
    Both reported probands had severely obstructive hypertrophy, mid-ventricular
    in one and mid-ventricular plus apical in the other. Obstruction is the point
    at which this chain rejoins ordinary hypertrophic cardiomyopathy physiology,
    and also the point at which the entity's key confound arises, since
    obstruction itself depletes intercalated-disc vinculin. Named for the
    haemodynamic mechanism rather than the finding, so that it stays distinct from
    the clinical phenotype of the same name: the pathograph matches target strings
    verbatim, and two nodes differing only in capitalization would render as two
    nodes for one concept.
  downstream:
  - target: Left ventricular outflow tract obstruction
    causal_link_type: DIRECT
    description: >-
      The clinical finding this mechanism presents as.
  - target: Disrupted Intercalated Disc and Costamere Anchorage
    causal_link_type: DIRECT
    description: >-
      Feedback edge. Obstruction reduces intercalated-disc vinculin and
      metavinculin independently of genotype, which is the alternative explanation
      for the probands' histology.
    evidence:
    - reference: PMID:16949038
      reference_title: Obstructive hypertrophic cardiomyopathy is associated with reduced expression of vinculin in the intercalated disc.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        obstructive disease substantially reduces the expression of vinculin
        preferentially in the intercalated disc.
      explanation: >-
        Supports drawing obstruction as a cause of the anchorage abnormality, which
        is the reverse of the direction the original reports assumed.
  evidence:
  - reference: PMID:16236538
    reference_title: Identification of a metavinculin missense mutation, R975W, associated with both hypertrophic and dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      One patient with severely obstructive, mid-ventricular and apical hypertrophy
      harbored the previously published DCM-associated mutation, R975W.
    explanation: >-
      Documents obstruction and its distribution in the metavinculin proband.
phenotypes:
- category: Cardiovascular
  name: Hypertrophic cardiomyopathy
  phenotype_term:
    preferred_term: Hypertrophic cardiomyopathy
    term:
      id: HP:0001639
      label: Hypertrophic cardiomyopathy
  description: >-
    The defining phenotype. Both reported probands were ascertained from clinical
    hypertrophic cardiomyopathy cohorts at a single referral centre, having
    already been screened negative for the common myofilament genes.
  sequelae:
  - target: Left ventricular outflow tract obstruction
    description: >-
      Both reported probands had severely obstructive disease, and obstruction is
      what brought each of them to the myectomy that produced the tissue examined
      in these studies.
  evidence:
  - reference: PMID:16236538
    reference_title: Identification of a metavinculin missense mutation, R975W, associated with both hypertrophic and dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      mutational analysis of the metavinculin-specific exon of vinculin (VCL, exon
      19) was performed in a cohort of 389 unrelated patients with clinical HCM,
      previously genotyped for the 8 most common HCM-associated myofilament-encoding
      genes.
    explanation: >-
      Establishes that the ascertainment population, and therefore the phenotype
      attached to this entity, is clinically diagnosed hypertrophic cardiomyopathy.
- category: Cardiovascular
  name: Left ventricular outflow tract obstruction
  phenotype_term:
    preferred_term: Left ventricular outflow tract obstruction
    term:
      id: HP:0032092
      label: Left ventricular outflow tract obstruction
    severity: SEVERE
  description: >-
    Both reported probands had severely obstructive disease and both came to
    surgical myectomy, which is how the tissue examined in these studies was
    obtained. Obstruction is the most consistent clinical feature of the two-case
    series, and it is also the feature that generates the entity's principal
    confound, since obstruction independently depletes intercalated-disc vinculin.
  evidence:
  - reference: PMID:16712796
    reference_title: A missense mutation in a ubiquitously expressed protein, vinculin, confers susceptibility to hypertrophic cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A novel missense mutation, L277M-VCL, involving a conserved residue was
      identified in a patient with severely obstructive, mid-ventricular
      hypertrophy.
    explanation: >-
      Documents severe obstruction in the vinculin proband.
  - reference: PMID:16236538
    reference_title: Identification of a metavinculin missense mutation, R975W, associated with both hypertrophic and dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      One patient with severely obstructive, mid-ventricular and apical hypertrophy
      harbored the previously published DCM-associated mutation, R975W.
    explanation: >-
      Documents severe obstruction in the metavinculin proband.
- category: Cardiovascular
  name: Apical hypertrophy
  phenotype_term:
    preferred_term: Apical hypertrophic cardiomyopathy
    term:
      id: HP:0031992
      label: Apical hypertrophic cardiomyopathy
  description: >-
    Reported in the metavinculin proband, whose hypertrophy was mid-ventricular
    and apical. Apical contour was also the minority morphology in the wider
    Z-disc hypertrophic cardiomyopathy series, in 2 of 13 probands. Recorded as a
    reported feature of the individual cases, not as a characteristic of the
    entity, which has too few cases to have one.
  evidence:
  - reference: PMID:16236538
    reference_title: Identification of a metavinculin missense mutation, R975W, associated with both hypertrophic and dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      One patient with severely obstructive, mid-ventricular and apical hypertrophy
      harbored the previously published DCM-associated mutation, R975W.
    explanation: >-
      Names apical involvement in the one proband in whom it was reported.
- category: Cardiovascular
  name: Sigmoidal septal contour
  phenotype_term:
    preferred_term: Left ventricular hypertrophy with sigmoidal septal contour
    term:
      id: HP:0001712
      label: Left ventricular hypertrophy
  description: >-
    Hypertrophic cardiomyopathy attributed to Z-disc genes, VCL among them, was
    preferentially sigmoidal in septal contour rather than showing the reverse
    curvature typical of myofilament disease. The finding is a property of the
    Z-disc class in that series and is not resolved to the two VCL probands within
    it, so it is recorded here as class-level context.

    It should be read against the primary reports rather than instead of them, and
    the two do not agree. That series graded 11 of 13 Z-disc probands sigmoidal and
    2 apical, while both VCL probands are described in their own reports as
    mid-ventricular, one with apical involvement. Same group, overlapping Mayo
    cohorts, so the two apical cases in the pooled series may well be the two VCL
    cases - in which case the sigmoidal majority is carried by the other four genes
    and does not describe VCL at all. Neither paper resolves this, and it is not
    resolvable from the published data.
  evidence:
  - reference: PMID:17097056
    reference_title: Echocardiographic-determined septal morphology in Z-disc hypertrophic cardiomyopathy.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In contrast to myofilament-HCM, Z-disc-HCM is associated preferentially with
      sigmoidal morphology.
    explanation: >-
      Supports sigmoidal contour for the Z-disc class that includes VCL. INDIRECT
      because the two VCL probands are pooled with eleven probands carrying
      variants in four other genes.
histopathology:
- name: Reduced vinculin and metavinculin at the intercalated disc with preserved Z-disc staining
  description: >-
    Immunohistochemistry on the surgical myectomy specimens from both probands
    showed vinculin and metavinculin markedly reduced at the intercalated disc
    while Z-disc staining was normal. The compartment specificity is the
    informative part of the finding. Its attribution is not: the same pattern was
    subsequently found in obstructive hypertrophic cardiomyopathy without a VCL
    variant and in aortic stenosis, and was absent in dilated, hypertensive and
    pulmonary-hypertensive hearts, so it segregates with outflow obstruction and
    not with genotype.
  evidence:
  - reference: PMID:16949038
    reference_title: Obstructive hypertrophic cardiomyopathy is associated with reduced expression of vinculin in the intercalated disc.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Microscopic examination of both myectomy specimens from patients bearing
      genetic defects in metavinculin and vinculin showed a marked reduction of
      vinculin/metavinculin expression in the intercalated disc, but normal
      expression in the Z-disc.
    explanation: >-
      The finding itself, stated for both probands together with its compartment
      specificity.
  - reference: PMID:16949038
    reference_title: Obstructive hypertrophic cardiomyopathy is associated with reduced expression of vinculin in the intercalated disc.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Tissue specimens derived from patients with obstructive HCM and aortic
      stenosis (AS) showed a universal defect of vinculin/metavinculin expression
      in the intercalated disc but preserved expression in the cardiac Z-disc
    explanation: >-
      Refutes reading the finding as a marker of the VCL lesion. The identical
      pattern is universal in obstructive hypertrophic cardiomyopathy without a VCL
      variant, and in aortic stenosis, so it cannot corroborate a VCL-specific
      mechanism.
  - reference: PMID:16949038
    reference_title: Obstructive hypertrophic cardiomyopathy is associated with reduced expression of vinculin in the intercalated disc.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      whereas tissue specimens derived from patients with either DCM, hypertensive
      heart disease (HTN), or pulmonary hypertension (PHTN) exhibited normal
      expression of vinculin/metavinculin in both the Z- and the intercalated disc
      despite being associated with hypertrophy.
    explanation: >-
      Supports the narrower claim that the finding is real and specific to a
      compartment and an aetiology: it is absent in dilated, hypertensive and
      pulmonary-hypertensive hearts, so it is not a generic consequence of
      hypertrophy. It is that same specificity to obstruction which makes it
      uninformative about genotype.
animal_models:
- name: Cardiomyocyte-specific vinculin knockout mouse (cVclKO)
  species: Mouse
  genotype: Vcl conditional null, cardiomyocyte-restricted Cre-loxP excision
  publication: PMID:17785437
  description: >-
    Cre-loxP deletion of Vcl in cardiomyocytes. Half the animals died suddenly
    before three months from ventricular tachycardia with preserved contractile
    function; survivors developed dilated cardiomyopathy and died before six
    months. Ultrastructure before dysfunction showed dissolution of the
    intercalated disc, reduced cadherin and beta-1D integrin, and connexin-43
    mislocalized to the lateral border.
  evidence:
  - reference: PMID:17785437
    reference_title: Cardiac-myocyte-specific excision of the vinculin gene disrupts cellular junctions, causing sudden death or dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      This is the first report of tissue-specific inactivation of the Vcl gene and
      shows that it is required for preservation of normal cell-cell and cell-matrix
      adhesive structures.
    explanation: >-
      Supports treating this model as informative for cardiomyocyte junctional
      biology, which is the ground on which it is linked to this entry's anchorage
      node.
  modeled_mechanisms:
  - target: Disrupted Intercalated Disc and Costamere Anchorage
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Establishes in vivo that removing cardiomyocyte vinculin dismantles exactly
      the junctions this node names, and that it does so before any contractile
      phenotype appears.
    limitations: >-
      A complete tissue-specific null, not a missense allele: it models absence of
      vinculin, whereas the CMH15 variants are proposed to act by gain of function
      through mutant metavinculin. Mouse hearts also express less metavinculin
      relative to vinculin than human hearts do, so an insert-specific effect is
      under-represented in this system.
    evidence:
    - reference: PMID:17785437
      reference_title: Cardiac-myocyte-specific excision of the vinculin gene disrupts cellular junctions, causing sudden death or dilated cardiomyopathy.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        ultrastructural analysis of cVclKO heart tissue showed abnormal adherens
        junctions with dissolution of the intercalated disc structure, expression
        of the junctional proteins cadherin and beta1D integrin were reduced, and
        the gap junction protein connexin 43 was mislocalized to the lateral
        myocyte border
      explanation: >-
        The junctional lesion this link claims the model reproduces, observed
        directly.
  - target: Maladaptive Left Ventricular Hypertrophy
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    model_scale: ORGANISM
    description: >-
      The most informative negative result for this entity. Losing cardiomyocyte
      vinculin in vivo produces arrhythmic sudden death and then a dilated
      ventricle. It does not produce hypertrophy.
    limitations: >-
      The failure is not decisive against a hypertrophic mechanism, because the
      allele is wrong for the question: a null cannot test a gain-of-function
      missense hypothesis, and the opposite remodelling direction is what
      loss-of-function VCL alleles produce in humans too. The result constrains
      what can be inferred from vinculin-deficiency models about hypertrophy, and
      no CMH15 knock-in mouse exists to answer the question properly.
    evidence:
    - reference: PMID:17785437
      reference_title: Cardiac-myocyte-specific excision of the vinculin gene disrupts cellular junctions, causing sudden death or dilated cardiomyopathy.
      supports: REFUTE
      evidence_source: MODEL_ORGANISM
      snippet: >-
        cVclKO mice that survived through the vulnerable period of sudden death
        developed dilated cardiomyopathy and died before 6 months of age.
      explanation: >-
        The model's cardiac endpoint is dilation, not hypertrophy, so it does not
        reproduce the phenotype this entity is defined by.
- name: Heterozygous vinculin knockout mouse (Vin+/-)
  species: Mouse
  genotype: Vcl heterozygous null
  publication: PMID:15331426
  description: >-
    Global heterozygous Vcl inactivation, giving roughly 58% less vinculin and 63%
    less metavinculin. These animals are grossly normal with normal baseline
    cardiac function, but carry abnormal electrocardiograms, abnormal intercalated
    discs, misaligned Z-lines, and decompensate when pressure-loaded by transverse
    aortic constriction.
  evidence:
  - reference: PMID:15331426
    reference_title: Heterozygous inactivation of the vinculin gene predisposes to stress-induced cardiomyopathy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Decreased expression of vinculin/metavinculin leads to abnormal myocyte
      structure without baseline physiological evidence of cardiac dysfunction.
      These structural changes predispose to stress-induced cardiomyopathy.
    explanation: >-
      Supports treating this model as informative for the structural consequences of
      reduced vinculin and metavinculin dosage, which is why it is linked here.
  modeled_mechanisms:
  - target: Disrupted Intercalated Disc and Costamere Anchorage
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Shows that a partial reduction in vinculin and metavinculin, closer in degree
      to a heterozygous human genotype than a complete null, is already enough to
      disorganize the intercalated disc and the Z-line register.
    limitations: >-
      Reduced dosage of normal protein, whereas the CMH15 hypothesis is that mutant
      metavinculin is actively mis-functional; a 58% reduction does not test that.
      The phenotype is also latent until haemodynamic stress is applied.
    evidence:
    - reference: PMID:15331426
      reference_title: Heterozygous inactivation of the vinculin gene predisposes to stress-induced cardiomyopathy.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        normal basal cardiac function and histology but abnormal electrocardiograms,
        intercalated disks, and ICD-related protein distribution
      explanation: >-
        Junctional disorganization at partial vinculin dosage, with function still
        normal, which is the node's claim.
  - target: Impaired Cardiomyocyte Force Transmission
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Vin+/- hearts tolerate normal load but fail under acute pressure overload,
      which is the behaviour expected of a myocardium whose force-transmission
      apparatus has reduced reserve rather than reduced resting output.
    limitations: >-
      The readout is organ-level decompensation after aortic constriction, not a
      measurement of force transmission, so the mechanism is inferred from the
      stress response. PARTIALLY_RECAPITULATES because baseline function is normal:
      the model reproduces the vulnerability, not a resting deficit.
    evidence:
    - reference: PMID:15331426
      reference_title: Heterozygous inactivation of the vinculin gene predisposes to stress-induced cardiomyopathy.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        increased mortality following acute hemodynamic stress imposed by transverse
        aortic constriction (TAC); 4) cardiac dysfunction by 6 weeks post-TAC
      explanation: >-
        Documents the load-dependent failure that this link reads as reduced
        force-transmission reserve.
diagnosis:
- name: Clinical diagnosis of hypertrophic cardiomyopathy by echocardiography
  diagnosis_term:
    preferred_term: Echocardiography
    term:
      id: NCIT:C16525
      label: Echocardiography Test
  description: >-
    The diagnosis in both reported cases was a clinical one, made on imaging, with
    the VCL variant found afterwards by research sequencing of an already
    phenotyped cohort. Nothing about CMH15 changes how hypertrophic cardiomyopathy
    is recognized: wall thickness, the distribution of hypertrophy, and the
    presence and level of outflow obstruction are assessed exactly as in any other
    form. Where this entity does bear on imaging is in what to expect - both
    probands had severe obstruction at mid-ventricular level, one with apical
    involvement, and the wider Z-disc series was preferentially sigmoidal in septal
    contour rather than reverse-curvature.
  results: >-
    Left ventricular hypertrophy with severe outflow obstruction, mid-ventricular
    and in one case apical; sigmoidal septal contour reported for the Z-disc class
    that includes VCL.
  evidence:
  - reference: PMID:17097056
    reference_title: Echocardiographic-determined septal morphology in Z-disc hypertrophic cardiomyopathy.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Blinded to the Z-disc genotype status, the septal contour was graded
      qualitatively using standard transthoracic echocardiography.
    explanation: >-
      Establishes the modality and the blinded grading behind the morphology claim.
      INDIRECT because the two VCL probands are pooled with eleven others.
- name: Genetic testing, and why VCL should not be reported for hypertrophic cardiomyopathy
  diagnosis_term:
    preferred_term: Genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  description: >-
    This is the practically important entry on the whole record. VCL appears on
    many commercial cardiomyopathy panels, so a rare VCL missense variant will be
    found in hypertrophic cardiomyopathy probands and can be reported against
    OMIM's CMH15 entry. ClinGen's expert panel has classified that relationship as
    Disputed, having found that the two originally reported variants exceed the
    panel's gnomAD frequency ceiling for pathogenicity and that no new evidence has
    emerged since ClinGen's initial curation. A VCL variant is therefore not a molecular
    diagnosis of hypertrophic cardiomyopathy, must not be used for predictive
    testing or cascade screening in a hypertrophic family, and should not end the
    diagnostic search. The same variant found in a dilated presentation is a
    different matter, since ClinGen rates VCL-dilated cardiomyopathy Strong.
  results: >-
    A VCL variant in a hypertrophic cardiomyopathy proband is uninformative and
    should be treated as such; the finding does not establish a molecular
    diagnosis or support cascade testing.
  evidence:
  - reference: CGGV:assertion_27365fd2-1203-4e2b-8830-3277e965d8bc-2023-05-10T160000.000Z
    reference_title: VCL / hypertrophic cardiomyopathy (Disputed)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      This gene was noted to be a potential rare cause of HCM; however, no new
      evidence has emerged since the initial curation.
    explanation: >-
      The state of the evidence base, which is what makes a VCL finding
      uninterpretable in this setting.
  - reference: PMID:30681346
    reference_title: Evaluating the Clinical Validity of Hypertrophic Cardiomyopathy Genes.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The majority of genes previously reported as causative of HCM and commonly
      included in diagnostic tests have limited or no evidence of disease
      association.
    explanation: >-
      Sets the general problem this entry is an instance of. INDIRECT because the
      abstract states the aggregate result without naming VCL; the gene-specific
      verdict is carried by the ClinGen record cited alongside it.
  - reference: PMID:30681346
    reference_title: Evaluating the Clinical Validity of Hypertrophic Cardiomyopathy Genes.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of 4191 HCM variants in ClinVar, 31% were in genes with limited or no
      evidence of disease association.
    explanation: >-
      Quantifies how often variants in genes of this evidential class reach a
      public variant database, which is the reporting risk this entry warns about.
treatments:
- name: Septal myectomy for obstructive disease
  description: >-
    Both reported probands underwent surgical septal myectomy, which is how the
    tissue examined in the original studies was obtained. Management of CMH15 is
    the management of obstructive hypertrophic cardiomyopathy and is not
    genotype-directed: no VCL-specific therapy exists, none is in development, and
    the disputed status of the gene-disease relationship means the genotype should
    not influence treatment decisions at all.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: septal myectomy
    term:
      id: NCIT:C51591
      label: Myectomy
  target_phenotypes:
  - preferred_term: Left ventricular outflow tract obstruction
    term:
      id: HP:0032092
      label: Left ventricular outflow tract obstruction
  target_mechanisms:
  - target: Dynamic Outflow Obstruction
    description: >-
      Relieves the obstruction node directly by resecting the hypertrophied septum.
      It does not address anything upstream of it.
  evidence:
  - reference: PMID:16949038
    reference_title: Obstructive hypertrophic cardiomyopathy is associated with reduced expression of vinculin in the intercalated disc.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Microscopic examination of both myectomy specimens from patients bearing
      genetic defects in metavinculin and vinculin showed a marked reduction of
      vinculin/metavinculin expression in the intercalated disc, but normal
      expression in the Z-disc.
    explanation: >-
      Records that both probands came to surgical myectomy - the tissue examined in
      that study is the myectomy specimen - which is the only treatment documented
      for either of them.
  notes: >-
    Sourced from the fact that both probands underwent the procedure, not from a
    trial or guideline recommendation for this entity, of which there are none.
    Indications, alternatives (alcohol septal ablation), and the medical therapy
    that precedes septal reduction are those of obstructive hypertrophic
    cardiomyopathy generally and are curated on the parent entry.
discussions:
- discussion_id: cmh15_gene_disease_validity_disputed
  prompt: >-
    Does VCL cause hypertrophic cardiomyopathy at all, or is CMH15 an entity built
    on two 2006 case reports that later evidence has undercut?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - genetic#VCL
  - pathophysiology#VCL Missense Variant in Vinculin or the Metavinculin Insert
  - disease#Hypertrophic Cardiomyopathy 15
  rationale: >-
    This is the entity's central open question and the reason every node upstream
    of the hypertrophy is marked HYPOTHETICAL or PROVISIONAL. The supporting case
    is two probands, both from one centre in 2006, both ascertained by sequencing
    a candidate gene in a myofilament-negative cohort, neither with segregation
    data. Three things have since worked against it. The two implicated variants
    are commoner in gnomAD than a rare dominant cardiomyopathy allele can be. The
    corroborating histology - vinculin depleted at the intercalated disc - was
    shown by the same group to occur in obstructive hypertrophic cardiomyopathy
    without a VCL variant and in aortic stenosis, so it marks obstruction rather
    than genotype. And the one variant carried forward as causal, p.Arg975Trp, had
    already been reported in dilated cardiomyopathy, which is the phenotype VCL is
    actually well supported for. ClinGen moved the classification from Limited to
    Disputed in 2023 and recorded that no new evidence had emerged since its own
    initial curation. Note that "initial curation" there is a ClinGen curation
    event, not the 2006 publications - the panel records an intervening HCM GCEP
    recuration on 04/06/21.

    Note what is not in dispute: metavinculin biochemistry. That the insert
    variants destabilize the inhibitory sub-domain and produce disordered actin
    assemblies is measured, reproducible, and structurally rationalized. The gap is
    between that biochemistry and the human hypertrophic phenotype, not within it.
    A mechanism can be real and still not be this disease's mechanism.
  proposed_experiments:
  - experiment_id: cmh15_knockin_mouse
    name: Metavinculin insert knock-in mouse carrying a CMH15 allele
    description: >-
      Generate a knock-in mouse carrying p.Arg975Trp or an equivalent exon-19
      insert substitution at the endogenous Vcl locus, and phenotype it for wall
      thickness, outflow gradient, chamber dimensions and intercalated-disc
      ultrastructure, unstressed and after pressure loading. Every existing mouse
      model deletes vinculin, so none of them can test a gain-of-function missense
      hypothesis, and the two that exist both produce dilation rather than
      hypertrophy. Mouse hearts express proportionally less metavinculin than human
      hearts, so a negative result would need that caveat attached.
    decision_criterion: >-
      Hypertrophy with outflow obstruction in the knock-in would supply the in vivo
      support the relationship has never had. A dilated or absent cardiac phenotype
      would align the allele with the loss-of-function models and further weaken
      the hypertrophic attribution.
    would_support:
    - pathophysiology#VCL Missense Variant in Vinculin or the Metavinculin Insert
    would_refute:
    - pathophysiology#VCL Missense Variant in Vinculin or the Metavinculin Insert
  - experiment_id: cmh15_case_control_burden
    name: Rare-variant burden of VCL exon 19 in large hypertrophic cardiomyopathy cohorts
    description: >-
      Test whether rare metavinculin-insert variants are enriched in
      sarcomere-negative hypertrophic cardiomyopathy probands relative to
      ancestry-matched population controls, in the large sequenced cohorts that did
      not exist in 2006. This is the direct answer to ClinGen's stated objection,
      which is a frequency argument, and burden analysis is the design that
      distinguishes a genuinely rare pathogenic allele class from a gene that is
      merely long and polymorphic.
    decision_criterion: >-
      Significant case excess of rare exon-19 variants would move the relationship
      off Disputed. No excess would settle it as a non-cause.
    would_refute:
    - genetic#VCL
  evidence:
  - reference: CGGV:assertion_27365fd2-1203-4e2b-8830-3277e965d8bc-2023-05-10T160000.000Z
    reference_title: VCL / hypertrophic cardiomyopathy (Disputed)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      More evidence is needed to either support or entirely refute the role VCL
      plays in this disease.
    explanation: >-
      The expert panel leaves the question open rather than closed, which is why
      this is recorded as a knowledge gap and the entry is retained rather than
      argued out of scope.
  - reference: CGGV:assertion_27365fd2-1203-4e2b-8830-3277e965d8bc-2023-05-10T160000.000Z
    reference_title: VCL / hypertrophic cardiomyopathy (Disputed)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      This gene-disease pair was recurated by the HCM GCEP on 04/06/21 (SOP 8), and
      reevaluated by the Hereditary Cardiovascular Disease GCEP on 05/10/2023. As a
      result of this reevaluation, the classification changed from limited to
      disputed.
    explanation: >-
      Documents the direction of travel: two successive expert reviews, each
      lowering the classification.
- discussion_id: cmh15_model_allele_class_mismatch
  prompt: >-
    Can vinculin-deficiency models say anything about a disease proposed to act by
    gain of function?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Impaired Cardiomyocyte Force Transmission
  - animal_models#Cardiomyocyte-specific vinculin knockout mouse (cVclKO)
  - animal_models#Heterozygous vinculin knockout mouse (Vin+/-)
  rationale: >-
    Every in vivo vinculin model in existence removes protein: a cardiomyocyte
    null, a heterozygous null. They agree with each other and with human
    loss-of-function VCL variants in producing dilation, arrhythmia and sudden
    death rather than hypertrophy. The mechanism proposed for CMH15 is the
    opposite in kind - mutant metavinculin that fails to restrain vinculin and
    actively drives disordered actin assembly, which ClinGen reads as gain of
    function. So the models are informative about what vinculin does and
    uninformative about what a CMH15 allele does, and their failure to produce
    hypertrophy is weak evidence against the hypothesis rather than strong
    evidence against it. There is a second, smaller mismatch stacked on the first:
    metavinculin makes up a much larger share of the combined vinculin pool in
    human than in mouse heart, so any insert-specific effect is attenuated in
    mouse regardless of allele.
  evidence:
  - reference: PMID:17785437
    reference_title: Cardiac-myocyte-specific excision of the vinculin gene disrupts cellular junctions, causing sudden death or dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      we developed a mouse model with cardiac-myocyte-specific inactivation of the
      vinculin (Vcl) gene by using Cre-loxP technology
    explanation: >-
      Establishes the allele class of the principal in vivo model as an
      inactivation, which is the mismatch this discussion is about.
  - reference: CGGV:assertion_27365fd2-1203-4e2b-8830-3277e965d8bc-2023-05-10T160000.000Z
    reference_title: VCL / hypertrophic cardiomyopathy (Disputed)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The mechanism for disease is believed to be gain-of-function, with mutants
      both failing to induce F-actin binding and promoting formation of large actin
      assemblies with linear bundles (PMID: 30844403).
    explanation: >-
      States the proposed human mechanism as gain of function, against which the
      loss-of-function models are mismatched.
  - reference: PMID:17785437
    reference_title: Cardiac-myocyte-specific excision of the vinculin gene disrupts cellular junctions, causing sudden death or dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The amount of metavinculin expressed in human cardiac tissue appears greater
      than that in mouse
    explanation: >-
      Sources the second, smaller mismatch stacked on the allele-class one: an
      insert-specific effect is attenuated in mouse heart because metavinculin is a
      smaller share of the combined pool there than in human heart. Graded OTHER
      because the sentence is a review statement in the paper's introduction citing
      prior work, not a result of the study it appears in.
differential_diagnoses:
- name: VCL-related dilated cardiomyopathy
  disease_term:
    preferred_term: dilated cardiomyopathy
    term:
      id: MONDO:0005021
      label: dilated cardiomyopathy
  description: >-
    The same gene, and in the case of p.Arg975Trp the same substitution, with the
    opposite remodelling direction and a far stronger evidence base. Loss-of-function
    VCL variants are the well-supported class here, presenting in infancy with
    severe systolic dysfunction and dilation. This is the first alternative to
    consider when a VCL variant is found, because it is the interpretation the
    evidence supports.
  distinguishing_features:
  - Dilated, thin-walled left ventricle with reduced ejection fraction rather than hypertrophy with outflow obstruction
  - Typically truncating or frameshift VCL alleles rather than missense
  - Frequently infantile onset, with recovery of ventricular function by early childhood in most of a paediatric series - no counterpart in hypertrophic disease
  - ClinGen rates the gene-disease relationship Strong rather than Disputed
  evidence:
  - reference: PMID:37548861
    reference_title: Heart Failure with Recovered Ejection Fraction in Patients with Vinculin Loss-of-function Variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This case series identified a unique phenotype of HF with reduced ejection
      fraction at presentation that evolved to HF with recovered EF in over 80% of
      infant DCM cases with LOF VCL variants.
    explanation: >-
      Characterizes the VCL phenotype that is actually well supported, and its
      distinctive natural history, against which a hypertrophic attribution should
      be weighed.
- name: Sarcomeric (myofilament) hypertrophic cardiomyopathy
  disease_term:
    preferred_term: hypertrophic cardiomyopathy
    term:
      id: MONDO:0005045
      label: hypertrophic cardiomyopathy
  description: >-
    The overwhelmingly more likely explanation for hypertrophic cardiomyopathy in
    any given proband, and the diagnosis that should be pursued before a VCL
    variant is entertained. Only eight genes have definitive evidence for
    hypertrophic cardiomyopathy, all encoding sarcomeric proteins. Both CMH15
    probands were drawn from cohorts already screened negative for these, which is
    the only reason a VCL variant was looked for at all.
  distinguishing_features:
  - A pathogenic variant in MYBPC3, MYH7, TNNT2, TNNI3, TPM1, ACTC1, MYL2 or MYL3
  - Reverse-curvature septal morphology rather than the sigmoidal contour reported for the Z-disc class
  - Myocyte disarray on histology
  evidence:
  - reference: PMID:30681346
    reference_title: Evaluating the Clinical Validity of Hypertrophic Cardiomyopathy Genes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of 33 HCM genes, only 8 (24%) were categorized as definitive ( MYBPC3, MYH7,
      TNNT2, TNNI3, TPM1, ACTC1, MYL2, and MYL3); 3 had moderate evidence ( CSRP3,
      TNNC1, and JPH2; 33%); and 22 (66%) had limited (n=16) or no evidence (n=6).
    explanation: >-
      Names the genes that do have definitive evidence, and by omission places VCL
      outside them.
- name: Obstructive hypertrophy of other cause, including aortic stenosis
  description: >-
    Included because of the specific trap this entity sets. Intercalated-disc
    depletion of vinculin and metavinculin was the histological finding used to
    corroborate the VCL attribution in both probands, and it turns out to be a
    feature of outflow obstruction rather than of VCL genotype: the same pattern
    appears in obstructive hypertrophic cardiomyopathy generally and in aortic
    stenosis, and is absent in dilated, hypertensive and pulmonary-hypertensive
    hearts. The finding therefore cannot be used to distinguish CMH15 from any
    other obstructive lesion, and should not be treated as a diagnostic marker.
  distinguishing_features:
  - None histologically - the intercalated-disc vinculin pattern is shared, which is the point of this entry
  - Aortic stenosis is distinguished by valve morphology and the level of the gradient on imaging, not by vinculin staining
  evidence:
  - reference: PMID:16949038
    reference_title: Obstructive hypertrophic cardiomyopathy is associated with reduced expression of vinculin in the intercalated disc.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Tissue specimens derived from patients with obstructive HCM and aortic
      stenosis (AS) showed a universal defect of vinculin/metavinculin expression
      in the intercalated disc but preserved expression in the cardiac Z-disc
    explanation: >-
      Supports the claim this differential rests on: the staining pattern is shared
      between CMH15, obstructive hypertrophic cardiomyopathy without a VCL variant,
      and aortic stenosis, so it cannot distinguish them.
references:
- reference: PMID:20301725
  title: Nonsyndromic Hypertrophic Cardiomyopathy Overview.
  tags:
  - GeneReviews
notes: >-
  Curated deliberately as a disputed entity rather than as an established disease,
  and the shape of the record follows from that. The `genetic` block carries
  REFUTE evidence alongside its SUPPORT; the pathophysiology nodes upstream of the
  hypertrophy are HYPOTHETICAL or PROVISIONAL rather than ESTABLISHED; and the
  histopathology finding is recorded together with the paper that showed it is
  non-specific. Nothing here should be read as asserting that VCL causes
  hypertrophic cardiomyopathy.

  Why the entry exists at all, given the dispute. MONDO carries the term, OMIM
  carries the entity (613255), and VCL sits on commercial cardiomyopathy panels,
  so the attribution will keep being encountered whether or not it is curated.
  Recording it with its counter-evidence attached is more useful than leaving the
  concept to be met without any. ClinGen's own verdict is that more evidence is
  needed to support or entirely refute the relationship, so the honest state is
  open rather than closed. Should a future recuration move VCL to Refuted, the
  right response is to record that and keep the entry, not to delete it.

  Two evidential distinctions worth preserving through later edits. First, the
  metavinculin biochemistry and the human genetic attribution are separate claims
  with different support: the actin-bundling and severing work is solid in vitro
  and structurally rationalized, and none of the dispute touches it. Second, the
  intercalated-disc depletion is cited twice from PMID:16949038, once SUPPORT and
  once REFUTE, because that paper establishes the finding and destroys its
  specificity in the same study. Do not consolidate those into one item.

  On GeneReviews: PMID:20301725 (Nonsyndromic Hypertrophic Cardiomyopathy
  Overview) is the applicable chapter and is tagged in `references`, but its
  cached PubMed record contains only the chapter's purpose statement with no
  clinical-characteristics text, so no phenotype in this entry is sourced from it
  and no snippet is claimed against it. There is no VCL-specific GeneReviews
  chapter.

  No `datasets` block, and this is a decision rather than an omission. No GEO
  series names VCL, vinculin or metavinculin; what a dataset search surfaces is
  generic hypertrophic cardiomyopathy material, which resolves perfectly and is
  about a different population. Attaching that to an entity defined by a disputed
  VCL attribution would be the Named Entity Confusion the dataset-curation guidance
  warns about. If a VCL-specific series appears later, it is welcome here.

  Coverage gaps that are real rather than editorial. No prevalence figure can be
  given, and none should be invented. No treatment is genotype-directed, so the
  treatments block is deliberately thin and defers to the parent entry. No
  penetrance, age of onset, or progression data exist, because there is no
  pedigree - both probands were isolated cases from screening cohorts. No CMH15
  knock-in animal model exists; the two mouse models curated here both delete
  vinculin and are recorded with that mismatch made explicit.
📚

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 15 (VCL, ClinGen-disputed) · 2026-09-08T10:24:50Z · View source

Created kb/disorders/Hypertrophic_Cardiomyopathy_15.yaml for MONDO:0013200 (OMIM:613255), the VCL/metavinculin locus of familial hypertrophic cardiomyopathy, claimed via issue #11449. Curated deliberately as a DISPUTED gene-disease relationship rather than as an established disease. ClinGen's Hereditary Cardiovascular Disease Gene Curation Expert Panel reclassified VCL-hypertrophic cardiomyopathy from Limited to Disputed on 2023-05-10 (CGGV:assertion_27365fd2-...), while the Dilated Cardiomyopathy GCEP rates VCL-dilated cardiomyopathy Strong. The entry carries REFUTE evidence in the genetic block and on the histopathology finding, HYPOTHETICAL/PROVISIONAL mechanism_confidence throughout the chain, and an OPEN KNOWLEDGE_GAP discussion with two proposed experiments (a metavinculin-insert knock-in mouse, and a rare-variant burden test that directly answers ClinGen's frequency objection). The diagnosis block states explicitly that a VCL variant is not a molecular diagnosis of hypertrophic cardiomyopathy and must not drive cascade testing. Three specific things the curation establishes that a summary would lose. The corroborating histology in both 2006 probands - vinculin depleted at the intercalated disc - was shown by the same group (PMID:16949038) to occur in obstructive HCM without a VCL variant and in aortic stenosis, so it tracks outflow obstruction, not genotype; that paper is therefore cited twice on the same node, once SUPPORT and once REFUTE, and the entry's notes ask that those not be consolidated. The metavinculin biochemistry (PMID:30844403, PMID:22613835) is solid and is NOT part of the dispute; the gap is between that biochemistry and the human phenotype. And every in vivo model deletes vinculin (PMID:17785437, PMID:15331426) while the proposed human mechanism is gain of function, so the models' failure to produce hypertrophy is recorded as a HUMAN_MODEL_MISMATCH discussion and a FAILS_TO_RECAPITULATE link with explicit limitations, not as decisive evidence against. DEEP RESEARCH: falcon (Edison Scientific Literature), 981s, 30 citations, research/Hypertrophic_Cardiomyopathy_15-deep-research-falcon.md plus its citations sidecar and one non-image artifact. The report independently reached the same framing (sparse subtype evidence; do not encode general-HCM prevalence, prognosis or mavacamten response as VCL-specific; the Vcl-null mouse models loss of function and evolves to DCM). It did NOT surface the ClinGen Disputed classification, nor PMID:16236538, PMID:16949038, PMID:30844403, PMID:17097056, PMID:15331426 or PMID:23561539, all of which were found by direct PubMed/ClinGen work and carry most of this entry's content. DEEP RESEARCH CITATION DEFECT, reported rather than silently dropped. The report's executive summary and section 4 attribute five PMIDs to Open Targets as human genetic literature supporting the VCL-HCM association: 16712796, 20052757, 21779496, 22826437, 24937142. Only the first is about VCL. The other four are RAF1/BRAF Noonan-syndrome papers (RAF1 dephosphorylation of Ser259; Raf family kinases review; BRAF heterodimerization in Noonan RAF1 mutants; a Raf/Mek/Erk interactome review) - wrong gene, wrong disease. All four resolve in PubMed, so an identifier-resolution check scores them clean; the retro-fitted `just validate-research-reference` section reports 6/6 resolved and 0 off topic because its extractor does not parse the comma-separated list they appear in. None of the four was used. Flagged here because the failure mode - resolvable identifiers naming an unrelated disease - is invisible to the report's own validation. VALIDATION RUN: `just validate` passes (54/54 snippets verified against cached references); `just validate-terms` passes; `just compliance` 90.5% global / 91.1% weighted. Offline gates run and clean: check-duplicate-keys, check-enum-values, check-qualifier-terms, check-entity-refs, check-causal-targets (no new dangling targets). `just validate-disorders` run as the final batched gate. The falcon report had no validation frontmatter, so both sections were retro-fitted with one `just validate-research-reference` run, which wrote a `## Reference Validation` section (6 references checked, 6 resolved, 0 unresolved, 0 off topic) and a `## Term Validation` section (48 terms checked, 48 resolved, 0 unresolved). A subsequent `just validate-research-terms` re-run failed on an OLS read timeout resolving HP:0031640 and changed nothing; the section from the first run is what is committed. The single term flagged as "named as a different term" is MONDO:0013200, which the report renders as "MONDO:0013200 (if available)" straight from the template - a parsing artifact, not a mis-binding. Note that the reference section's clean result is the reason the RAF1 defect above is recorded by hand. DELIBERATE OMISSIONS. No `datasets` block: `just discover-datasets` returns only generic hypertrophic cardiomyopathy series (myosin-inhibitor mouse studies, sarcomeric iPSC lines, HCM lncRNA networks) and none mentions VCL, vinculin or metavinculin, so attaching them would be Named Entity Confusion reached through dataset search. No prevalence figure, penetrance, onset or progression data: the published case base is two isolated probands from screening cohorts, with no pedigree. Treatments are deliberately thin and defer to the parent entry, since nothing here is genotype-directed. GeneReviews PMID:20301725 (Nonsyndromic Hypertrophic Cardiomyopathy Overview) is the applicable chapter and is tagged in `references`, but its cached PubMed record contains only the chapter's purpose statement with no clinical-characteristics text, so no phenotype is sourced from it and no snippet is claimed against it; there is no VCL-specific chapter. PRE-PR RED-TEAM REVIEW (dismech-pr-review skill, fresh-context subagent) found 21 findings, all of which were taken. The two that mattered: (1) relationship_type was CAUSATIVE with a ten-line note retracting it. The enum has a DISPUTED value defined as ClinGen "Disputed" or "Refuted", and CAUSATIVE is defined as ClinGen Definitive or Strong. The structured field is what an export or query reads; the prose caveat does not survive either. Changed to DISPUTED. This was the one field in the entry that contradicted its own framing. (2) The description said both probands had apical hypertrophy. Only the R975W proband did; the L277M proband's report says mid-ventricular only. With a two-patient case base that is not cosmetic. Corrected. Also taken: the pathophysiology chain terminated at obstruction and never reached the phenotype layer, and a pathophysiology node differed from a phenotype only in capitalization, which the verbatim-matching pathograph would have rendered as two nodes for one concept - the node is now "Dynamic Outflow Obstruction" and edges run into three phenotypes (orphan_targets is now empty, 17 edges). A `Dilated cardiomyopathy` phenotype whose own description opened "Not a feature of this entity" was deleted, since a phenotypes[] entry asserts the opposite of what it said; the boundary is carried by the differential diagnosis and the allelism evidence. The ClinGen DCM-Strong record was regraded SUPPORT -> NO_EVIDENCE, being true, worth citing, and about a different disease. Two evidence items had quotes that did not carry their explanations: the histopathology REFUTE quoted the DCM/HTN/PHTN comparator arm, which if anything makes the marker look more specific, and the differential quoted a sentence saying the marker discriminates between pathophysiologies; both now quote the obstructive-HCM/aortic-stenosis sentence that actually destroys VCL-specificity, and the comparator sentence is retained as a SUPPORT item for compartment and aetiology specificity. An unevidenced `modifier: LOSS_OF_FUNCTION` on GO:0003789 was dropped - the cited work shows mutants fail to inhibit bundling, not that they lose severing. "No new evidence since 2006" / "the intervening seventeen years" over-read ClinGen, whose phrase is "since the initial curation", a curation event with an intervening 2021 recuration; both were corrected. The mouse-versus-human metavinculin share, asserted three times without a citation, is now evidenced from PMID:17785437's full text. The sigmoidal-contour phenotype now records that the class-level finding is in tension with both VCL probands' described morphology and that the series' two apical cases may be the VCL pair. `attaches_to: animal_models#Mouse` bound only the first of two same-species models and now names both by model name. A prevalence record that was really a diagnostic yield was removed and its content folded into the remaining record's notes, where the 389-proband denominator was also corrected (three variants across four patients, one carried forward, not "one variant"). The treatment term moved from NCIT:C15329 Surgical Procedure to NCIT:C51591 Myectomy, already an enum-validated member. A `would_refute` pointing at the hypertrophy node now points at the variant node, since the probands demonstrably had hypertrophy. Prose describing one `discover-datasets` run was trimmed to the durable claim. Compliance moved 90.5% -> 87.4% across this revision. That is the placeholder prevalence record and the Dilated cardiomyopathy phenotype being removed; both scored full marks on evidence coverage and neither should have existed. UNRELATED PRE-EXISTING CHURN, surfaced not fixed. Eight references_cache/DOI_*.md files show as modified in a freshly created worktree off origin/main - a tool in the validation path lowercases the DOI in `reference_id` and `doi` (e.g. DOI:10.7554/eLife.74270 -> DOI:10.7554/elife.74270). This predates and is unrelated to this curation and has been left unstaged.

Falcon ▸
Hypertrophic Cardiomyopathy 15 (HCM15): Comprehensive Disease-Characteristics Report
Edison Scientific Literature 30 citations 2026-09-08T11:22:37.042774

Hypertrophic Cardiomyopathy 15 (HCM15): Comprehensive Disease-Characteristics Report

Executive summary and evidence boundary

Hypertrophic cardiomyopathy 15 (HCM15) is a historically catalogued, extremely rare Mendelian hypertrophic-cardiomyopathy subtype attributed to heterozygous germline variants in VCL, which encodes vinculin and its muscle-specific splice isoform metavinculin. The supplied disease identifier is MONDO:0013200. Because disease numbering and gene–disease assertions can change between ontology releases, this identifier and the HCM15–VCL relationship should be checked against the current MONDO, OMIM, ClinGen, and ClinVar releases before production use. Open Targets supports a VCL–HCM association and points to human literature including PMIDs 16712796, 20052757, 21779496, 22826437, and 24937142, but this is gene-level evidence rather than proof that every rare VCL variant causes HCM15. (OpenTargets Search: hypertrophic cardiomyopathy-VCL)

The central limitation is that published HCM15-specific human data are too sparse to estimate penetrance, age-specific onset, phenotype frequencies, incidence, prognosis, or treatment response. Consequently, this report distinguishes:

  • Subtype-specific evidence: human VCL association and experimental Vcl biology.
  • Parent-disease evidence: contemporary phenotype-defined HCM criteria, surveillance, prognosis, and treatment, which guide management but must not be encoded as VCL-specific outcomes.
Domain HCM15/VCL-specific evidence General HCM evidence used for clinical context Confidence / knowledge-base handling
Identity/genetics HCM15 is catalogued as a rare Mendelian HCM subtype associated with heterozygous germline VCL variants; Open Targets links VCL to HCM using human genetic literature including PMIDs 16712796, 20052757, 21779496, 22826437, and 24937142. The submitted identifier is MONDO:0013200, but identifier/version consistency should be checked against the live MONDO and OMIM releases. (OpenTargets Search: hypertrophic cardiomyopathy-VCL) Monogenic HCM is usually autosomal dominant, with variable penetrance and expressivity; identifiable pathogenic variants occur in roughly 30–60% of unselected HCM, predominantly in established sarcomeric genes. (verheyen2024austrianconsensusstatement pages 11-12, verheyen2024austrianconsensusstatement pages 9-11) Low–moderate subtype confidence. Record VCL as the reported causal gene and inheritance as autosomal dominant, but retain provenance and current ClinGen/ClinVar classification. Do not infer penetrance, pathogenicity, or phenotype from gene-level association alone; distinguish P/LP variants from VUS explicitly.
Phenotype Published VCL-associated human observations support a cardiomyopathy spectrum, but available evidence is too sparse to estimate HCM15-specific frequencies, typical onset, severity, obstruction rate, or extracardiac manifestations. (OpenTargets Search: hypertrophic cardiomyopathy-VCL) HCM ranges from asymptomatic hypertrophy to dyspnea, chest pain, syncope, atrial or ventricular arrhythmia, heart failure, and sudden cardiac death. LV hypertrophy may be asymmetric, reverse-curvature, sigmoid, concentric, or apical; LVOTO/SAM can occur at rest or with provocation. (verheyen2024austrianconsensusstatement pages 11-12, verheyen2024austrianconsensusstatement pages 6-7) Low subtype confidence; high general-HCM confidence. Encode observed features patient by patient when primary VCL case data are available. General HCM manifestations may define the diagnostic phenotype but must not be stored as VCL-specific frequencies, onset distributions, or obligate features.
Mechanism Vinculin localizes to cardiomyocyte costameres and intercalated discs, linking actin to cell–matrix and cell–cell adhesion systems. Direct human variant-specific mechanisms remain incompletely established; disruption of force transmission, junctional stability, and mechanosensing is biologically plausible. (zemljicharpf2007cardiacmyocytespecificexcisionof pages 1-2, zemljicharpf2007cardiacmyocytespecificexcisionof pages 2-3) Focal-adhesion mechanotransduction involves integrins, vinculin, FAK/Src, PI3K–AKT, and Wnt/β-catenin signaling; mechanical-load responses can promote hypertrophic growth. These pathways provide context, not proof of the causal route in HCM15. Moderate protein-function, low variant-mechanism confidence. Annotate adhesion/mechanotransduction as supported VCL biology; label the route from a particular VCL allele to human hypertrophy as inferred unless demonstrated by segregation and variant-specific functional assays.
Epidemiology No reliable HCM15-specific prevalence, incidence, carrier-frequency, founder-effect, sex-ratio, or geographic-distribution estimate was identified. Phenotype-defined unexplained LV thickening affects approximately 0.16–0.23% of adults; including genotype-positive/phenotype-negative individuals may raise estimated HCM prevalence to about 0.6%. (verheyen2024austrianconsensusstatement pages 1-2) HCM15 epidemiology unavailable. Store general HCM prevalence only at the parent-disease level. Never attribute the 0.16–0.23% or 0.6% estimates to VCL-associated HCM15.
Diagnosis Molecular confirmation requires a VCL variant classified as pathogenic/likely pathogenic with appropriate phenotype, inheritance, segregation, and exclusion of alternative causes; a VCL VUS does not establish HCM15. HCM is generally diagnosed by otherwise unexplained maximal LV wall thickness ≥15 mm, or ≥13 mm in a relative of an affected person or a carrier of a confirmed disease-causing variant. Evaluation uses pedigree, ECG, echocardiography, ambulatory ECG, CMR, exercise testing, and exclusion of hypertension, valvular disease, athlete’s heart, amyloidosis, and metabolic/storage phenocopies. (verheyen2024austrianconsensusstatement pages 11-12, verheyen2024austrianconsensusstatement pages 6-7, verheyen2024austrianconsensusstatement pages 1-2) High general diagnostic confidence; moderate subtype confidence. Encode HCM phenotype and molecular diagnosis as separate assertions. Reassess VCL variants periodically; panel, exome, or genome findings require ACMG/AMP interpretation and phenotype correlation.
Treatment No VCL-specific drug, gene therapy, RNA therapy, editing strategy, or genotype-guided treatment has demonstrated clinical efficacy. Phenotype-directed HCM care includes β-blockers or non-dihydropyridine calcium-channel blockers, disopyramide in selected obstructive disease, myosin inhibition, septal reduction for refractory obstruction, AF anticoagulation, ICD-based SCD prevention, and advanced-heart-failure therapy. In EXPLORER-HCM, mavacamten achieved the primary endpoint in 37% versus 17% with placebo; in VALOR-HCM, 17.9% versus 76.8% met criteria for or underwent septal reduction at 16 weeks. (pagel2025advancesincardiovascular pages 5-6, seferovic2023stateoftheartdocumenton pages 11-12) High general-HCM, no subtype-specific efficacy evidence. Treatments should be attached to the patient’s obstruction, arrhythmia, SCD-risk, or heart-failure phenotype—not to VCL genotype. Do not encode mavacamten response or procedural outcomes as HCM15-specific.
Prognosis HCM15-specific survival, SCD rate, heart-failure progression, transplant risk, and quality-of-life trajectories are unknown; limited VCL reports cannot define penetrance or outcome distributions. General HCM prognosis is heterogeneous. Risk assessment considers wall thickness, LVOT gradient, family history, unexplained syncope, nonsustained VT, LVEF, apical aneurysm, and fibrosis; LGE ≥15% of LV mass is an additional risk marker. A 2024 cohort found genotype-positive status alone did not independently predict mortality, heart-failure progression, or SCD. (verheyen2024austrianconsensusstatement pages 9-11, seferovic2023stateoftheartdocumenton pages 13-13) Insufficient subtype evidence. Use validated clinical risk markers and longitudinal patient data. General HCM event rates, genotype-outcome estimates, and survival figures must not be encoded as VCL/HCM15-specific prognosis.
Models Cardiomyocyte-specific Vcl knockout mice directly demonstrate loss-of-function consequences: abnormal intercalated discs, myofibril detachment, reduced cadherin/β1D-integrin, connexin-43 redistribution, conduction slowing, ventricular tachycardia, and sudden death; 49% died before about 3 months, while survivors developed DCM and died before 6 months. (zemljicharpf2007cardiacmyocytespecificexcisionof pages 8-11, zemljicharpf2007cardiacmyocytespecificexcisionof pages 11-12, zemljicharpf2007cardiacmyocytespecificexcisionof pages 1-2) The model supports vinculin’s necessity for cardiac mechanical and electrical integrity but models near-complete cardiomyocyte loss and predominantly arrhythmic/DCM outcomes, not a specific heterozygous human HCM15 allele. High confidence for Vcl-loss biology; limited disease fidelity. Record as a mechanistic VCL model, not a complete HCM15 phenocopy. Do not transfer mouse lethality, timing, sex effects, or DCM frequency to affected humans.

Table: This table separates VCL/HCM15-specific findings from parent-level HCM evidence used only for clinical context. It highlights which claims can be encoded directly and which must not be represented as VCL-specific frequencies, treatment responses, or outcomes.

1. Disease information

Definition

HCM15 is a proposed autosomal-dominant, VCL-associated form of familial hypertrophic cardiomyopathy. At the parent-disease level, HCM is defined by increased left-ventricular wall thickness that is not explained solely by loading conditions or another cardiac, systemic, metabolic, infiltrative, or storage disorder. Contemporary adult criteria are maximal end-diastolic LV wall thickness ≥15 mm, or ≥13 mm in a first-degree relative of an affected person or in a carrier of a confirmed disease-causing variant. (verheyen2024austrianconsensusstatement pages 6-7, verheyen2024austrianconsensusstatement pages 1-2)

Identifiers and terminology

  • MONDO: MONDO:0013200, as supplied; verify against the live release.
  • Preferred name: hypertrophic cardiomyopathy 15.
  • Synonyms: HCM15; familial hypertrophic cardiomyopathy 15; VCL-related hypertrophic cardiomyopathy; vinculin-related cardiomyopathy.
  • Parent disease: hypertrophic cardiomyopathy, MONDO:0005045 in Open Targets. (OpenTargets Search: hypertrophic cardiomyopathy-VCL)
  • OMIM: the subtype has historically been associated with the VCL locus; the exact current phenotype record should be confirmed directly in OMIM because numbered HCM assignments are periodically revised.
  • ICD-10-CM: I42.1, obstructive HCM; I42.2, other HCM. These codes do not distinguish HCM15.
  • ICD-11: cardiomyopathy hierarchy, hypertrophic-cardiomyopathy category; no VCL-specific code.
  • MeSH: Cardiomyopathy, Hypertrophic.

This is an aggregated disease-level synthesis, not an individual EHR record. The foundational subtype evidence derives from small human genetic observations; modern diagnostic and therapeutic statements derive predominantly from aggregated HCM cohorts, trials, and guidelines.

2. Etiology

Causal factor

The initiating lesion is a heterozygous germline VCL variant with sufficient pathogenic evidence. Vinculin is an actin-binding adhesion protein concentrated at cardiomyocyte costameres and intercalated discs; metavinculin is a muscle-enriched alternatively spliced isoform. VCL links the actin cytoskeleton and contractile apparatus to cell–matrix and cell–cell adhesion systems. Complete cardiomyocyte loss in mice demonstrates that this function is essential for junctional and electrical integrity. (zemljicharpf2007cardiacmyocytespecificexcisionof pages 1-2, zemljicharpf2007cardiacmyocytespecificexcisionof pages 2-3)

A rare VCL variant should not automatically be considered causal. A defensible molecular diagnosis requires ACMG/AMP classification, phenotype concordance, segregation, population rarity, and ideally variant-specific functional evidence. A VUS does not establish HCM15.

Risk factors

Genetic:

  • A pathogenic/likely pathogenic VCL allele is the principal proposed risk factor.
  • Autosomal-dominant transmission implies a 50% probability of allele transmission, not 50% certainty of clinical disease, because penetrance is likely incomplete and age dependent.
  • Family history of HCM or sudden cardiac death increases clinical suspicion, but absence of family history does not exclude disease because of reduced penetrance or a de novo variant. General monogenic HCM shows variable penetrance and expressivity. (verheyen2024austrianconsensusstatement pages 11-12, verheyen2024austrianconsensusstatement pages 9-11)
  • No validated HCM15-specific modifier gene, polygenic score, founder allele, carrier frequency, or ancestry-specific susceptibility estimate is available.

Environmental and physiologic modifiers:

Hypertension, obesity, valvular disease, ischemia, pregnancy-related hemodynamic loading, and intense exercise may alter hypertrophy, symptoms, or arrhythmic burden in HCM generally, but none is established as a cause of VCL-HCM15. Hypertension and athlete’s heart are especially important diagnostic confounders. In mild-to-moderate hypertension, LV thickness ≥15 mm is uncommon, reported in under 5% in the cited consensus. (verheyen2024austrianconsensusstatement pages 11-12)

Protective factors and gene–environment interaction

No replicated VCL-specific protective allele, diet, medication, or exposure is known to prevent disease penetrance. Control of hypertension and other cardiovascular comorbidities, avoidance of dehydration in obstructive physiology, and individualized exercise are prudent tertiary-risk measures rather than primary prevention of the mutation.

Vinculin is load responsive: mechanical stress alters adhesion-complex recruitment. Therefore, a VCL defect plausibly interacts with hemodynamic load through impaired mechanotransduction, but a quantitative human VCL × environment interaction has not been demonstrated. (zemljicharpf2007cardiacmyocytespecificexcisionof pages 2-3)

3. Phenotypes

Published evidence does not support HCM15-specific percentages. The following are expected HCM phenotypes, to be recorded as observed rather than assumed in a VCL carrier.

Phenotype Type/course and impact Suggested HPO term
Unexplained LV hypertrophy, often asymmetric septal but potentially concentric or apical Clinical/imaging sign; may be absent early and develop with age; severity variable HP:0001712 Left ventricular hypertrophy; HP:0001670 Asymmetric septal hypertrophy
LV outflow-tract obstruction and systolic anterior motion Dynamic sign, resting or provoked; obstruction/SAM can occur in up to 75% of general HCM but is not HCM15-specific HP:0001685 Dynamic LV outflow obstruction; HP:0004382 Mitral-valve systolic anterior motion
Diastolic dysfunction and left-atrial enlargement Progressive or load dependent; contributes to exertional dyspnea and AF HP:0005117 Elevated LV filling pressure; HP:0031640 Left-atrial enlargement
Exertional dyspnea, exercise intolerance, fatigue Symptoms ranging from mild to disabling; reduce work, sport, and daily activity HP:0002094 Dyspnea; HP:0003546 Exercise intolerance; HP:0012378 Fatigue
Chest pain/ischemia Episodic; may reflect microvascular ischemia rather than epicardial coronary disease HP:0100749 Chest pain; HP:0001677 Coronary microvascular dysfunction where supported
Palpitations, AF, nonsustained or sustained VT Episodic; AF can worsen filling and thromboembolic risk; ventricular arrhythmia can cause SCD HP:0001962 Palpitations; HP:0005110 Atrial fibrillation; HP:0004756 Ventricular tachycardia
Presyncope/syncope Episodic; exertional or unexplained syncope is prognostically important HP:0001279 Syncope
Myocardial fibrosis/disarray Histologic/CMR abnormality; LGE is present in roughly 50–60% of general HCM HP:0031294 Myocardial fibrosis
Heart failure, rarely end-stage systolic dysfunction Chronic progressive phenotype; may remain preserved-EF or evolve to LVEF <50% HP:0001635 Congestive heart failure; HP:0001723 Restrictive cardiomyopathy phenotype when documented
Sudden cardiac death/cardiac arrest Rare but severe outcome, particularly relevant in younger patients HP:0001645 Sudden cardiac death; HP:0001695 Cardiac arrest

HCM quality-of-life impairment is driven by dyspnea, fatigue, exercise limitation, anxiety about SCD, medication effects, and activity restrictions. The 2024 Austrian consensus states that HCM can cause a “substantial reduction in quality of life,” but no HCM15-specific EQ-5D, SF-36, KCCQ, or HCMSQ data exist. (verheyen2024austrianconsensusstatement pages 1-2)

4. Genetic and molecular information

Causal gene

  • Gene: VCL, vinculin.
  • Ensembl: ENSG00000035403. (OpenTargets Search: hypertrophic cardiomyopathy-VCL)
  • Gene product: ubiquitous vinculin and muscle-specific metavinculin.
  • Origin: germline for inherited HCM15; somatic VCL mutation is not an established cause.
  • Inheritance: proposed autosomal dominant.

Pathogenic variants

The accessible evidence did not provide a sufficiently verified, current list of HCM15 variants with transcript, HGVS expression, ClinVar assertion, gnomAD frequency, segregation, and functional status. A knowledge-base implementation should therefore import variants directly from current ClinVar/ClinGen and retain:

  1. reference transcript and genome build;
  2. genomic, coding, and protein HGVS;
  3. submitter/date and review status;
  4. ACMG/AMP class;
  5. gnomAD ancestry-specific frequency;
  6. segregation and phenotype;
  7. functional-assay type;
  8. whether vinculin, metavinculin, or both are affected.

Reported VCL cardiomyopathy alleles have included missense and splice/isoform-affecting variants, but the disease spectrum includes both hypertrophic and dilated cardiomyopathy. Thus, variant-specific evidence is essential. Open Targets’ supporting literature includes PMIDs 16712796, 20052757, 21779496, 22826437, and 24937142. (OpenTargets Search: hypertrophic cardiomyopathy-VCL)

Functional consequence

Possible mechanisms include loss of function, altered actin binding, disturbed head–tail autoinhibition, defective recruitment to costameres/intercalated discs, or altered mechanosensing. Complete Vcl deletion is clearly loss of function, but it must not be assumed that every human heterozygous missense allele acts identically.

Modifiers, epigenetics, and chromosomal abnormalities

  • Modifier genes: none validated specifically for HCM15.
  • Epigenetics: no reproducible VCL-HCM15 methylation, chromatin, or histone signature identified.
  • Structural variants: no recurrent HCM15-associated deletion, duplication, inversion, or translocation established.
  • Anticipation: not established; VCL disease is not a repeat-expansion disorder.
  • Mosaicism: theoretically possible but not quantified.

5. Environmental information

No toxin, pollutant, radiation exposure, occupation, or infectious agent is known to cause HCM15. Viral myocarditis and other acquired myocardial diseases can mimic or aggravate cardiomyopathy but are not defining etiologies. Smoking, excess alcohol, obesity, hypertension, sleep apnea, and sedentary behavior should be managed for overall cardiovascular health; none has demonstrated VCL-specific penetrance modification.

Lifestyle advice should be phenotype based. Low-to-moderate recreational exercise is generally safe and beneficial. High-intensity sport should be assessed through shared decision-making, particularly when there is prior cardiac arrest, unexplained syncope, exercise-induced arrhythmia, significant LVOTO, or elevated SCD risk. (verheyen2024austrianconsensusstatement pages 19-21)

6. Mechanism and pathophysiology

Ordered causal chain

  1. A pathogenic heterozygous VCL lesion leads to deficient or abnormal vinculin/metavinculin localization or function at cardiomyocyte costameres and intercalated discs; this first step is established for Vcl loss but remains variant-specific in humans.
  2. Abnormal vinculin leads to impaired linkage of actin/myofibrils to integrin-containing cell–matrix adhesions and cadherin-containing cell–cell junctions.
  3. Impaired adhesion results in defective force transmission, mechanosensing, and intercalated-disc stability; conditional Vcl-null mouse hearts show reduced cadherin and β1D-integrin, myofibril detachment, and abnormal discs. (zemljicharpf2007cardiacmyocytespecificexcisionof pages 8-11, zemljicharpf2007cardiacmyocytespecificexcisionof pages 11-12)
  4. Junctional disruption leads to connexin-43 redistribution, heterogeneous coupling, local conduction slowing, ventricular ectopy, polymorphic VT, and sudden death in the knockout model. (zemljicharpf2007cardiacmyocytespecificexcisionof pages 8-11, zemljicharpf2007cardiacmyocytespecificexcisionof pages 12-14)
  5. Mechanical branch—partly inferred for human HCM15: chronic force-transmission inefficiency and load-responsive focal-adhesion signaling lead to compensatory cardiomyocyte hypertrophy, energetic stress, and maladaptive remodeling.
  6. Structural branch: repeated mechanical injury results in myocyte loss, replacement fibrosis, and altered ventricular compliance.
  7. Hypertrophy, disarray, fibrosis, and small-vessel/energetic dysfunction lead to diastolic dysfunction, microvascular ischemia, dynamic LVOTO, atrial enlargement, and heart-failure symptoms.
  8. Fibrosis plus electrical uncoupling results in atrial and ventricular arrhythmia and creates the substrate for SCD.
  9. In advanced disease, progressive myocyte loss and remodeling may lead to systolic dysfunction, dilation, or a restrictive end-stage phenotype; the direct Vcl-null model predominantly evolves toward DCM rather than faithfully reproducing heterozygous HCM15.

Molecular and cellular detail

Vinculin occupies costameres, which align with Z-discs and transmit sarcomeric force to extracellular matrix, and intercalated discs, which provide end-to-end mechanical and electrical coupling. Relevant signaling context includes integrin–FAK/Src, PI3K–AKT, Wnt/β-catenin, cytoskeletal tension, and hypertrophic gene programs. These pathways are biologically relevant to focal-adhesion mechanotransduction but have not been demonstrated as a complete allele-to-phenotype chain in HCM15.

In conditional cardiomyocyte Vcl-knockout mice, structural abnormalities preceded overt dysfunction: serrated, less electron-dense intercalated discs, separation of myofibrils, disorganized mitochondria, reduced cadherin/β1D-integrin, and lateralized connexin-43 were observed. Telemetry showed heart block and polymorphic VT; 86% of isolated knockout hearts had spontaneous ventricular ectopy. (zemljicharpf2007cardiacmyocytespecificexcisionof pages 8-11, zemljicharpf2007cardiacmyocytespecificexcisionof pages 11-12)

Suggested GO biological processes:

  • GO:0007155 cell adhesion
  • GO:0007160 cell–matrix adhesion
  • GO:0007156 homophilic cell adhesion
  • GO:0055002 striated-muscle-cell development
  • GO:0007512 adult heart development
  • GO:0006936 muscle contraction
  • GO:0003015 heart process
  • GO:0006979 response to oxidative stress
  • GO:0060048 cardiac muscle contraction
  • GO:0007507 heart development
  • GO:0035994 response to muscle stretch

Suggested GO cellular components: focal adhesion (GO:0005925), cell–substrate junction (GO:0030055), adherens junction (GO:0005912), intercalated disc (GO:0014704), costamere (GO:0043034), actin cytoskeleton (GO:0015629), Z disc (GO:0030018), mitochondrion (GO:0005739).

Suggested Cell Ontology terms: cardiomyocyte (CL:0000746), ventricular cardiomyocyte (CL:0002129), cardiac fibroblast, vascular endothelial cell (CL:0000115), vascular smooth-muscle cell (CL:0000359), cardiac conduction cell where appropriate.

Molecular profiling and advanced technologies

No HCM15-specific bulk transcriptomic, single-cell, spatial, proteomic, metabolomic, lipidomic, methylomic, or CRISPR-screen signature was identified. A 2023 spatial multiomic atlas mapped cellular niches across eight normal human heart regions, and a 2024 review emphasized that single-cell/spatial technologies now resolve cardiac cellular diversity, but these resources do not establish a VCL-HCM15 molecular signature. Therefore, such evidence should be treated as enabling context, not disease-specific annotation.

7. Anatomical structures affected

Primary organ: heart, principally the left-ventricular myocardium and interventricular septum.

Structures:

  • left ventricle — UBERON:0002084;
  • interventricular septum — UBERON:0002094;
  • myocardium — UBERON:0002349;
  • papillary muscles and mitral-valve apparatus when SAM/LVOTO is present;
  • left atrium secondarily from elevated filling pressure;
  • right ventricle occasionally through hypertrophy, loading, or advanced disease.

Tissue/cell level: striated cardiac muscle, ventricular cardiomyocytes, interstitial fibroblasts, intramural coronary microvasculature, conduction-system cells.

Subcellular level: intercalated discs, fascia adherens, costameres, focal adhesions, actin cytoskeleton, sarcomere/Z-disc interfaces, gap junctions, and secondarily mitochondria. The Vcl-knockout study directly showed abnormal intercalated discs, myofibril detachment, connexin-43 redistribution, and mitochondrial disorganization. (zemljicharpf2007cardiacmyocytespecificexcisionof pages 8-11, zemljicharpf2007cardiacmyocytespecificexcisionof pages 11-12)

HCM is usually diffuse or regionally asymmetric rather than unilateral; lateralization is not applicable.

8. Temporal development

HCM15-specific onset is unknown. General inherited HCM may be detectable in childhood, adolescence, adulthood, or late life; onset is often insidious and penetrance is age dependent. A genotype-positive person may remain phenotype negative for years.

A practical temporal model is:

  1. Preclinical: pathogenic-variant carrier, normal wall thickness; subtle ECG, strain, crypt, or CMR abnormalities may occur.
  2. Early phenotype: localized or mild LV hypertrophy, preserved LVEF, few symptoms.
  3. Established HCM: greater hypertrophy with diastolic dysfunction, possible LVOTO/SAM, symptoms, AF or ventricular ectopy.
  4. Advanced disease: fibrosis, atrial enlargement, recurrent arrhythmia, heart failure, apical aneurysm, or LVEF <50%.
  5. End stage: restrictive or dilated/systolic phenotype, transplantation consideration.

The course is chronic and lifelong but highly variable, not classically relapsing–remitting. There is no established spontaneous molecular remission. Obstruction and symptoms can improve with treatment.

Genotype-positive/phenotype-negative children and adolescents should generally undergo ECG and imaging every 1–2 years, and adults every 3–5 years. Stable phenotype-positive patients generally receive clinical review, ECG/Holter, and echocardiography every 1–2 years, with earlier reassessment after symptom change. (verheyen2024austrianconsensusstatement pages 21-22, verheyen2024austrianconsensusstatement pages 19-21)

9. Inheritance and population

Inheritance

  • Pattern: autosomal dominant.
  • Transmission risk: 50% per pregnancy from a heterozygous parent.
  • Penetrance: insufficiently characterized for VCL; likely incomplete and age dependent by analogy with inherited HCM.
  • Expressivity: variable; VCL variation has been associated with a cardiomyopathy spectrum rather than one invariant morphology.
  • Anticipation: not established.
  • Germline mosaicism: possible in principle, unquantified.
  • Consanguinity: not expected to be a principal factor in dominant HCM15.
  • Founder effects/carrier frequency: unknown.

Epidemiology

No HCM15-specific prevalence or incidence estimate exists. Parent-level phenotype-defined unexplained LV thickening affects approximately 0.16–0.23% of adults; inclusion of genotype-positive/phenotype-negative people may raise general HCM prevalence toward 0.6%. These values must not be assigned to HCM15. (verheyen2024austrianconsensusstatement pages 1-2)

No reliable HCM15-specific sex ratio, age distribution, ancestry enrichment, or geographic clustering is known. General cohorts can show referral-related male predominance, which should not be interpreted as Mendelian sex limitation.

10. Diagnostics

Clinical diagnostic pathway

  1. Obtain symptoms, blood pressure, loading conditions, medications, and a three-generation pedigree including HCM, heart failure, unexplained death, and SCD.
  2. Perform 12-lead ECG, transthoracic echocardiography, and 24–48-hour ambulatory ECG. Longer monitoring is appropriate for intermittent palpitations, presyncope, or suspected AF/VT. (verheyen2024austrianconsensusstatement pages 6-7)
  3. Measure maximal LV thickness in all segments and assess systolic/diastolic function, left-atrial size, mitral anatomy, SAM, and resting/provoked LVOT gradient.
  4. Use Valsalva, standing, squat-to-stand, or exercise provocation when resting obstruction is absent; dobutamine stress is not recommended for this purpose. (verheyen2024austrianconsensusstatement pages 6-7)
  5. Obtain CMR when echocardiography is incomplete or to define morphology, apical disease/aneurysm, crypts, LVEF, and fibrosis by LGE/T1/ECV.
  6. Conduct exercise testing or cardiopulmonary exercise testing for latent obstruction, symptoms, blood-pressure response, functional capacity, and advanced-heart-failure assessment.
  7. Exclude phenocopies and alternative loading causes.
  8. Offer genetic counselling and a curated cardiomyopathy panel. Molecular HCM15 requires a P/LP VCL variant plus a compatible phenotype or robust familial evidence.

CMR detects focal fibrosis; LGE is reported in approximately 50–60% of general HCM, and involvement of ≥15% of LV mass is an additional SCD-risk marker. CMR can be repeated every 3–5 years when useful for risk reassessment. (verheyen2024austrianconsensusstatement pages 9-11, verheyen2024austrianconsensusstatement pages 21-22)

Laboratory and biomarkers

No diagnostic enzyme assay or VCL-specific circulating biomarker exists. Useful phenotype/severity biomarkers include NT-proBNP/BNP and high-sensitivity troponin, but neither establishes HCM15. Baseline renal, liver, thyroid, iron, CK, and metabolic testing is selected according to differential diagnosis and treatment.

Genetic testing

  • Preferred first line: phenotype-focused multigene cardiomyopathy panel containing validated HCM genes, phenocopy genes, and VCL with deletion/duplication analysis where validated.
  • Single-gene VCL testing: reasonable when a familial P/LP VCL variant is already known.
  • WES/WGS: useful after a negative panel in strongly familial disease, for structural/noncoding variants, blended phenotypes, or research reanalysis; interpretation remains the limiting step.
  • CMA/karyotype/FISH: not routine for isolated HCM; use when syndromic features suggest a chromosomal disorder.
  • mtDNA/repeat-expansion tests: not routine unless the phenotype suggests mitochondrial or repeat-expansion disease.
  • RNA sequencing: potentially resolves splice variants but is not a standard HCM15 diagnostic and cardiac tissue is rarely available.

Cascade testing should target the known familial P/LP variant. Genotype-negative relatives can usually be released from serial familial surveillance when the familial variant is definitively causal; VUS-based predictive testing should not be used for reassurance or irreversible decisions.

Differential diagnosis

Hypertensive remodeling, aortic stenosis, athlete’s heart, transthyretin or AL amyloidosis, Fabry disease, Danon disease, Pompe disease, PRKAG2 glycogenosis, mitochondrial disease, Noonan/RASopathy, Friedreich ataxia, and cardiac tumors or subaortic membrane should be considered. Morphology, extracardiac features, ECG voltage, strain, CMR, biomarkers, and molecular testing distinguish these entities. (verheyen2024austrianconsensusstatement pages 11-12, verheyen2024austrianconsensusstatement pages 6-7)

11. Outcome and prognosis

There are no valid HCM15-specific 5- or 10-year survival estimates, annual SCD rate, transplant rate, or life-expectancy figures. Prognosis must be individualized from phenotype rather than VCL status alone.

General adverse outcomes include AF and stroke, ventricular arrhythmia/SCD, progressive heart failure, apical aneurysm/thrombus, end-stage systolic dysfunction, and need for septal reduction or transplantation. Apical aneurysm occurs in approximately 2% of general HCM and was associated in cited data with annual SCD and thromboembolism rates of 4.7% and 1.1%, respectively. (verheyen2024austrianconsensusstatement pages 9-11)

SCD assessment includes age, maximal wall thickness, LVOT gradient, left-atrial diameter, family history, unexplained syncope, and nonsustained VT. Additional markers include LVEF <50%, apical aneurysm, extensive LGE, and selected pathogenic sarcomeric variants. The ESC framework considers an ICD at a 5-year risk ≥6% and may consider it at 4–<6%; the AHA/ACC approach emphasizes major risk markers such as prior arrest/sustained VT, early familial SCD, wall thickness ≥30 mm, recent unexplained syncope, apical aneurysm, and LVEF <50%. (seferovic2023stateoftheartdocumenton pages 13-13)

A 2024 German cohort of 283 adults observed 14 SCD-equivalent events over median 5.77 years; adding genetic status improved model AUC to 0.76, but this was not VCL specific. Conversely, a separate 2024 international cohort of 1,468 patients found genotype-positive status was not independently predictive of mortality, heart-failure progression, or SCD. Genotype alone should therefore not dictate prognosis.

12. Treatment

No VCL-specific approved therapy or validated pharmacogenomic algorithm exists. Management is driven by obstruction, symptoms, arrhythmia, heart-failure state, and SCD risk.

Pharmacotherapy

  • Nonvasodilating β-blocker: first-line symptom/gradient control in obstructive HCM; NCIT concept: beta-adrenergic blocker therapy.
  • Verapamil or diltiazem: alternatives when β-blockers are ineffective or not tolerated, with caution in severe obstruction/hypotension; NCIT: calcium-channel-blocker therapy.
  • Disopyramide: negative inotrope added in selected symptomatic obstruction, with QT and anticholinergic monitoring; NCIT: antiarrhythmic-agent therapy.
  • Mavacamten: selective allosteric cardiac-myosin ATPase inhibitor for eligible symptomatic obstructive HCM; reduces excessive actin–myosin cross-bridging. NCIT: cardiac myosin inhibitor therapy.
  • AF: rate/rhythm management and anticoagulation because HCM-associated AF has clinically important embolic risk; NCIT: anticoagulant therapy/catheter ablation as applicable.
  • Advanced LVEF <50%: guideline-directed reduced-EF heart-failure therapy; discontinue negative inotropes when inappropriate and assess for CRT/transplantation.

In EXPLORER-HCM, 37% receiving mavacamten versus 17% receiving placebo met the primary functional endpoint; 65% versus 31% improved at least one NYHA class, and postexercise LVOT gradient fell by 36 mmHg. Transient LVEF <50% occurred in 6% and resolved after withdrawal. (seferovic2023stateoftheartdocumenton pages 11-12)

In VALOR-HCM, 17.9% of mavacamten-treated versus 76.8% of placebo-treated patients met criteria for or underwent septal reduction at 16 weeks. These are general obstructive-HCM data, not evidence of VCL-specific response. (pagel2025advancesincardiovascular pages 5-6)

Mavacamten requires serial echocardiographic LVEF/gradient surveillance and careful review of CYP2C19/CYP3A4 interactions because excessive myosin inhibition can cause systolic dysfunction.

Surgical and interventional treatment

  • Surgical septal myectomy: preferred at experienced centers for severe, drug-refractory symptomatic LVOTO, especially with complex mitral/subvalvular anatomy; NCIT: ventricular septal myectomy.
  • Alcohol septal ablation: catheter alternative in selected adults with suitable septal-perforator anatomy or elevated surgical risk; NCIT: alcohol septal ablation.
  • ICD: secondary prevention after arrest/sustained VT and primary prevention after individualized risk assessment; NCIT: implantable cardioverter-defibrillator placement.
  • Pacemaker/CRT, AF ablation, transplantation: phenotype-specific indications.

Exercise and rehabilitation

A 2023 randomized trial enrolled 15 completers. Five months of moderate- or progressive high-intensity training improved peak VO₂ by 1.3 mL/kg/min overall (P=0.009), without serious arrhythmia or adverse cardiac events, although it was underpowered for safety. A 2024 systematic review of five studies and 235 participants reported functional-capacity improvements up to 46% and no sustained tachyarrhythmia, ICD discharge, or SCD during the studied programs. These data support supervised, individualized rehabilitation rather than universal inactivity.

Experimental therapy and trials

Gene replacement, allele-specific silencing, base/prime editing, and RNA therapies are preclinical concepts for inherited HCM; none has demonstrated benefit for VCL-HCM15. Current HCM implementation studies include the multinational real-world COLLIGO-HCM, NCT06372457 (331 participants) and phase-3 mavacamten studies such as NCT05414175. Aficamten trials are active across obstructive and nonobstructive phenotypes. Trial eligibility is phenotype based, not VCL specific.

13. Prevention

Primary prevention

The germline variant cannot currently be prevented pharmacologically. Reproductive options after identification of a familial P/LP variant include genetic counselling, prenatal diagnosis, and preimplantation genetic testing for monogenic disease. These require discussion of uncertain penetrance and variable severity.

Secondary prevention

  • Cascade genetic testing and clinical screening of first-degree relatives.
  • ECG and imaging every 1–2 years in genotype-positive children/adolescents and every 3–5 years in genotype-positive adults without phenotype. (verheyen2024austrianconsensusstatement pages 21-22)
  • Prompt assessment of exertional syncope, palpitations, chest pain, or family SCD.
  • Periodic Holter monitoring, exercise testing, and CMR-based fibrosis/morphology assessment.

Tertiary prevention

  • Treat obstruction, AF, hypertension, and heart failure.
  • Anticoagulate clinically documented AF according to HCM recommendations.
  • Use an ICD for secondary prevention and selected high-risk primary prevention.
  • Maintain hydration and avoid unmonitored drugs that markedly reduce preload/afterload in severe obstruction.
  • Encourage individualized low-to-moderate exercise and shared decisions regarding vigorous sport. (verheyen2024austrianconsensusstatement pages 19-21)

Vaccination has no disease-specific preventive role, although routine immunization reduces general infectious risk. Population newborn screening is not recommended because HCM15 is exceptionally rare and no validated biochemical marker exists.

14. Other species and natural disease

  • Human: Homo sapiens, NCBI Taxonomy 9606.
  • Mouse model species: Mus musculus, NCBI Taxonomy 10090; orthologue Vcl.

Naturally occurring HCM is recognized in cats and occurs in other animals, but no well-established naturally occurring veterinary disease was identified that is specifically caused by an orthologous VCL allele and faithfully corresponds to human HCM15. Accordingly, cat HCM should not be annotated automatically as VCL-HCM15. No zoonotic or transmissible potential exists.

Vinculin’s adhesion and mechanotransduction functions are evolutionarily conserved, supporting comparative study. Species differences in heart rate, loading, isoform expression, and remodeling limit direct translation.

15. Model organisms and experimental systems

Conditional cardiomyocyte Vcl-knockout mouse

The strongest direct model is the ventricular-cardiomyocyte-specific Vcl knockout created by Cre-mediated exon-3 excision. Vinculin/metavinculin were lost from cardiomyocytes while remaining in nonmyocytes and vessels. Before overt physiological dysfunction, animals developed abnormal intercalated discs, detachment of myofibrils, mitochondrial disorganization, reduced cadherin and β1D-integrin, and connexin-43 redistribution. Electrical mapping showed irregular wavefronts and local conduction slowing; telemetry documented heart block and polymorphic VT. (zemljicharpf2007cardiacmyocytespecificexcisionof pages 8-11, zemljicharpf2007cardiacmyocytespecificexcisionof pages 11-12, zemljicharpf2007cardiacmyocytespecificexcisionof pages 3-4)

The abstract-level result is especially informative: “49% died suddenly before 3 months, despite preserved contractile function”; surviving animals subsequently developed DCM and died before six months. At 14 weeks, male survival was 51% and female survival 71%; no males survived beyond 32 weeks. (zemljicharpf2007cardiacmyocytespecificexcisionof pages 1-2, zemljicharpf2007cardiacmyocytespecificexcisionof pages 7-8)

Recapitulated features: cardiomyocyte junctional disease, conduction defects, ventricular arrhythmia, sudden death, early mild hypertrophy, fibrosis, and progressive cardiomyopathy.

Limitations: near-complete cardiomyocyte knockout is more severe than a heterozygous human missense allele; the dominant late phenotype is DCM, not isolated HCM; mouse timing and lethality cannot be transferred to humans.

Citation: Zemljic-Harpf et al., Molecular and Cellular Biology, November 2007; DOI: 10.1128/MCB.00728-07. (zemljicharpf2007cardiacmyocytespecificexcisionof pages 8-11, zemljicharpf2007cardiacmyocytespecificexcisionof pages 1-2)

Other model systems

Human iPSC-derived cardiomyocytes carrying rigorously classified VCL variants, engineered heart tissues, and isogenic CRISPR-corrected controls would be the most informative future systems for variant-specific contractility, adhesion, conduction, and mechanoload studies. No sufficiently validated HCM15-specific iPSC, organoid, zebrafish, Drosophila, or large-animal model was identified in the retrieved evidence.

Knowledge-base recommendations

  1. Store HCM15–VCL as a historically reported gene–disease assertion with provenance and periodic re-evaluation, not as an unconditional fact for every VCL variant.
  2. Separate genotype, HCM phenotype, and molecular diagnosis fields.
  3. Do not assign general-HCM phenotype frequencies, prevalence, prognosis, or mavacamten response to HCM15.
  4. Encode mechanistic steps as demonstrated in Vcl-loss mouse versus inferred in heterozygous human HCM15.
  5. Require P/LP status for cascade testing; retain VUS as non-diagnostic.
  6. Mark HCM15-specific penetrance, incidence, sex ratio, carrier frequency, protective factors, omics signatures, natural veterinary disease, and treatment response as not currently available.

Key recent and foundational sources

  • Verheyen N, et al. “Austrian consensus statement on the diagnosis and management of hypertrophic cardiomyopathy.” Published October 2024. DOI/URL: 10.1007/s00508-024-02442-1. (verheyen2024austrianconsensusstatement pages 11-12, verheyen2024austrianconsensusstatement pages 6-7, verheyen2024austrianconsensusstatement pages 1-2)
  • Seferović PM, et al. “State-of-the-Art Document on Optimal Contemporary Management of Cardiomyopathies.” Published September 2023. DOI/URL: 10.1002/ejhf.2979. (seferovic2023stateoftheartdocumenton pages 11-12, seferovic2023stateoftheartdocumenton pages 13-13)
  • MacNamara JP, et al. Randomized moderate- versus high-intensity exercise trial in HCM. Published October 2023. DOI/URL: 10.1161/JAHA.123.031399.
  • Braunwald E, et al. “Mavacamten: a first-in-class myosin inhibitor for obstructive hypertrophic cardiomyopathy.” Published October 2023. DOI/URL: 10.1093/eurheartj/ehad637.
  • Zemljic-Harpf AE, et al. “Cardiac-Myocyte-Specific Excision of the Vinculin Gene Disrupts Cellular Junctions, Causing Sudden Death or Dilated Cardiomyopathy.” Published November 2007. DOI/URL: 10.1128/MCB.00728-07. (zemljicharpf2007cardiacmyocytespecificexcisionof pages 8-11, zemljicharpf2007cardiacmyocytespecificexcisionof pages 1-2)

Overall, HCM15 is best treated as a rare, incompletely validated VCL-associated HCM entity embedded within the broader clinical HCM framework. The most secure biology concerns vinculin’s role in cardiomyocyte adhesion, force transmission, intercalated-disc integrity, and conduction; the least secure domains are variant-level causality, penetrance, epidemiology, and genotype-specific therapeutic response.

References

  1. (OpenTargets Search: hypertrophic cardiomyopathy-VCL): Open Targets Query (hypertrophic cardiomyopathy-VCL, 7 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

  2. (verheyen2024austrianconsensusstatement pages 11-12): Nicolas Verheyen, Johannes Auer, Nikolaos Bonaros, Tamara Buchacher, Daniel Dalos, Michael Grimm, Agnes Mayr, Anna Rab, Sebastian Reinstadler, Daniel Scherr, Gabor G Toth, Thomas Weber, David K. Zach, Marc-Michael Zaruba, Daniel Zimpfer, Peter P Rainer, and Gerhard Pölzl. Austrian consensus statement on the diagnosis and management of hypertrophic cardiomyopathy. Wiener Klinische Wochenschrift, 136:571-597, Oct 2024. URL: https://doi.org/10.1007/s00508-024-02442-1, doi:10.1007/s00508-024-02442-1. This article has 6 citations and is from a peer-reviewed journal.

  3. (verheyen2024austrianconsensusstatement pages 9-11): Nicolas Verheyen, Johannes Auer, Nikolaos Bonaros, Tamara Buchacher, Daniel Dalos, Michael Grimm, Agnes Mayr, Anna Rab, Sebastian Reinstadler, Daniel Scherr, Gabor G Toth, Thomas Weber, David K. Zach, Marc-Michael Zaruba, Daniel Zimpfer, Peter P Rainer, and Gerhard Pölzl. Austrian consensus statement on the diagnosis and management of hypertrophic cardiomyopathy. Wiener Klinische Wochenschrift, 136:571-597, Oct 2024. URL: https://doi.org/10.1007/s00508-024-02442-1, doi:10.1007/s00508-024-02442-1. This article has 6 citations and is from a peer-reviewed journal.

  4. (verheyen2024austrianconsensusstatement pages 6-7): Nicolas Verheyen, Johannes Auer, Nikolaos Bonaros, Tamara Buchacher, Daniel Dalos, Michael Grimm, Agnes Mayr, Anna Rab, Sebastian Reinstadler, Daniel Scherr, Gabor G Toth, Thomas Weber, David K. Zach, Marc-Michael Zaruba, Daniel Zimpfer, Peter P Rainer, and Gerhard Pölzl. Austrian consensus statement on the diagnosis and management of hypertrophic cardiomyopathy. Wiener Klinische Wochenschrift, 136:571-597, Oct 2024. URL: https://doi.org/10.1007/s00508-024-02442-1, doi:10.1007/s00508-024-02442-1. This article has 6 citations and is from a peer-reviewed journal.

  5. (zemljicharpf2007cardiacmyocytespecificexcisionof pages 1-2): Alice E. Zemljic-Harpf, Joel C. Miller, Scott A. Henderson, Adam T. Wright, Ana Maria Manso, Laila Elsherif, Nancy D. Dalton, Andrea K. Thor, Guy A. Perkins, Andrew D. McCulloch, and Robert S. Ross. Cardiac-myocyte-specific excision of the vinculin gene disrupts cellular junctions, causing sudden death or dilated cardiomyopathy. Molecular and Cellular Biology, 27:7522-7537, Nov 2007. URL: https://doi.org/10.1128/mcb.00728-07, doi:10.1128/mcb.00728-07. This article has 245 citations and is from a domain leading peer-reviewed journal.

  6. (zemljicharpf2007cardiacmyocytespecificexcisionof pages 2-3): Alice E. Zemljic-Harpf, Joel C. Miller, Scott A. Henderson, Adam T. Wright, Ana Maria Manso, Laila Elsherif, Nancy D. Dalton, Andrea K. Thor, Guy A. Perkins, Andrew D. McCulloch, and Robert S. Ross. Cardiac-myocyte-specific excision of the vinculin gene disrupts cellular junctions, causing sudden death or dilated cardiomyopathy. Molecular and Cellular Biology, 27:7522-7537, Nov 2007. URL: https://doi.org/10.1128/mcb.00728-07, doi:10.1128/mcb.00728-07. This article has 245 citations and is from a domain leading peer-reviewed journal.

  7. (verheyen2024austrianconsensusstatement pages 1-2): Nicolas Verheyen, Johannes Auer, Nikolaos Bonaros, Tamara Buchacher, Daniel Dalos, Michael Grimm, Agnes Mayr, Anna Rab, Sebastian Reinstadler, Daniel Scherr, Gabor G Toth, Thomas Weber, David K. Zach, Marc-Michael Zaruba, Daniel Zimpfer, Peter P Rainer, and Gerhard Pölzl. Austrian consensus statement on the diagnosis and management of hypertrophic cardiomyopathy. Wiener Klinische Wochenschrift, 136:571-597, Oct 2024. URL: https://doi.org/10.1007/s00508-024-02442-1, doi:10.1007/s00508-024-02442-1. This article has 6 citations and is from a peer-reviewed journal.

  8. (pagel2025advancesincardiovascular pages 5-6): Paul S. Pagel, Dustin Hang, Julie K. Freed, and George J. Crystal. Advances in cardiovascular pharmacotherapy. i. cardiac myosin inhibitors. Journal of cardiothoracic and vascular anesthesia, Feb 2025. URL: https://doi.org/10.1053/j.jvca.2025.02.009, doi:10.1053/j.jvca.2025.02.009. This article has 3 citations and is from a peer-reviewed journal.

  9. (seferovic2023stateoftheartdocumenton pages 11-12): Petar M. Seferović, Marija Polovina, Giuseppe Rosano, Biykem Bozkurt, Marco Metra, Stephane Heymans, Wilfried Mullens, Johann Bauersachs, Karen Sliwa, Rudolf A. de Boer, Dimitrios Farmakis, Thomas Thum, Iacopo Olivotto, Claudio Rapezzi, Aleš Linhart, Domenico Corrado, Carsten Tschöpe, Ivan Milinković, Antoni Bayes Genis, Gerasimos Filippatos, Andre Keren, Milika Ašanin, Gordana Krljanac, Ružica Maksimović, Hadi Skouri, Tuvia Ben Gal, Brenda Moura, Maurizio Volterrani, Magdy Abdelhamid, Yuri Lopatin, Ovidiu Chioncel, and Andrew J.S. Coats. State-of-the-art document on optimal contemporary management of cardiomyopathies. Sep 2023. URL: https://doi.org/10.1002/ejhf.2979, doi:10.1002/ejhf.2979. This article has 18 citations and is from a highest quality peer-reviewed journal.

  10. (seferovic2023stateoftheartdocumenton pages 13-13): Petar M. Seferović, Marija Polovina, Giuseppe Rosano, Biykem Bozkurt, Marco Metra, Stephane Heymans, Wilfried Mullens, Johann Bauersachs, Karen Sliwa, Rudolf A. de Boer, Dimitrios Farmakis, Thomas Thum, Iacopo Olivotto, Claudio Rapezzi, Aleš Linhart, Domenico Corrado, Carsten Tschöpe, Ivan Milinković, Antoni Bayes Genis, Gerasimos Filippatos, Andre Keren, Milika Ašanin, Gordana Krljanac, Ružica Maksimović, Hadi Skouri, Tuvia Ben Gal, Brenda Moura, Maurizio Volterrani, Magdy Abdelhamid, Yuri Lopatin, Ovidiu Chioncel, and Andrew J.S. Coats. State-of-the-art document on optimal contemporary management of cardiomyopathies. Sep 2023. URL: https://doi.org/10.1002/ejhf.2979, doi:10.1002/ejhf.2979. This article has 18 citations and is from a highest quality peer-reviewed journal.

  11. (zemljicharpf2007cardiacmyocytespecificexcisionof pages 8-11): Alice E. Zemljic-Harpf, Joel C. Miller, Scott A. Henderson, Adam T. Wright, Ana Maria Manso, Laila Elsherif, Nancy D. Dalton, Andrea K. Thor, Guy A. Perkins, Andrew D. McCulloch, and Robert S. Ross. Cardiac-myocyte-specific excision of the vinculin gene disrupts cellular junctions, causing sudden death or dilated cardiomyopathy. Molecular and Cellular Biology, 27:7522-7537, Nov 2007. URL: https://doi.org/10.1128/mcb.00728-07, doi:10.1128/mcb.00728-07. This article has 245 citations and is from a domain leading peer-reviewed journal.

  12. (zemljicharpf2007cardiacmyocytespecificexcisionof pages 11-12): Alice E. Zemljic-Harpf, Joel C. Miller, Scott A. Henderson, Adam T. Wright, Ana Maria Manso, Laila Elsherif, Nancy D. Dalton, Andrea K. Thor, Guy A. Perkins, Andrew D. McCulloch, and Robert S. Ross. Cardiac-myocyte-specific excision of the vinculin gene disrupts cellular junctions, causing sudden death or dilated cardiomyopathy. Molecular and Cellular Biology, 27:7522-7537, Nov 2007. URL: https://doi.org/10.1128/mcb.00728-07, doi:10.1128/mcb.00728-07. This article has 245 citations and is from a domain leading peer-reviewed journal.

  13. (verheyen2024austrianconsensusstatement pages 19-21): Nicolas Verheyen, Johannes Auer, Nikolaos Bonaros, Tamara Buchacher, Daniel Dalos, Michael Grimm, Agnes Mayr, Anna Rab, Sebastian Reinstadler, Daniel Scherr, Gabor G Toth, Thomas Weber, David K. Zach, Marc-Michael Zaruba, Daniel Zimpfer, Peter P Rainer, and Gerhard Pölzl. Austrian consensus statement on the diagnosis and management of hypertrophic cardiomyopathy. Wiener Klinische Wochenschrift, 136:571-597, Oct 2024. URL: https://doi.org/10.1007/s00508-024-02442-1, doi:10.1007/s00508-024-02442-1. This article has 6 citations and is from a peer-reviewed journal.

  14. (zemljicharpf2007cardiacmyocytespecificexcisionof pages 12-14): Alice E. Zemljic-Harpf, Joel C. Miller, Scott A. Henderson, Adam T. Wright, Ana Maria Manso, Laila Elsherif, Nancy D. Dalton, Andrea K. Thor, Guy A. Perkins, Andrew D. McCulloch, and Robert S. Ross. Cardiac-myocyte-specific excision of the vinculin gene disrupts cellular junctions, causing sudden death or dilated cardiomyopathy. Molecular and Cellular Biology, 27:7522-7537, Nov 2007. URL: https://doi.org/10.1128/mcb.00728-07, doi:10.1128/mcb.00728-07. This article has 245 citations and is from a domain leading peer-reviewed journal.

  15. (verheyen2024austrianconsensusstatement pages 21-22): Nicolas Verheyen, Johannes Auer, Nikolaos Bonaros, Tamara Buchacher, Daniel Dalos, Michael Grimm, Agnes Mayr, Anna Rab, Sebastian Reinstadler, Daniel Scherr, Gabor G Toth, Thomas Weber, David K. Zach, Marc-Michael Zaruba, Daniel Zimpfer, Peter P Rainer, and Gerhard Pölzl. Austrian consensus statement on the diagnosis and management of hypertrophic cardiomyopathy. Wiener Klinische Wochenschrift, 136:571-597, Oct 2024. URL: https://doi.org/10.1007/s00508-024-02442-1, doi:10.1007/s00508-024-02442-1. This article has 6 citations and is from a peer-reviewed journal.

  16. (zemljicharpf2007cardiacmyocytespecificexcisionof pages 3-4): Alice E. Zemljic-Harpf, Joel C. Miller, Scott A. Henderson, Adam T. Wright, Ana Maria Manso, Laila Elsherif, Nancy D. Dalton, Andrea K. Thor, Guy A. Perkins, Andrew D. McCulloch, and Robert S. Ross. Cardiac-myocyte-specific excision of the vinculin gene disrupts cellular junctions, causing sudden death or dilated cardiomyopathy. Molecular and Cellular Biology, 27:7522-7537, Nov 2007. URL: https://doi.org/10.1128/mcb.00728-07, doi:10.1128/mcb.00728-07. This article has 245 citations and is from a domain leading peer-reviewed journal.

  17. (zemljicharpf2007cardiacmyocytespecificexcisionof pages 7-8): Alice E. Zemljic-Harpf, Joel C. Miller, Scott A. Henderson, Adam T. Wright, Ana Maria Manso, Laila Elsherif, Nancy D. Dalton, Andrea K. Thor, Guy A. Perkins, Andrew D. McCulloch, and Robert S. Ross. Cardiac-myocyte-specific excision of the vinculin gene disrupts cellular junctions, causing sudden death or dilated cardiomyopathy. Molecular and Cellular Biology, 27:7522-7537, Nov 2007. URL: https://doi.org/10.1128/mcb.00728-07, doi:10.1128/mcb.00728-07. This article has 245 citations and is from a domain leading peer-reviewed journal.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 6
Resolved 6
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 6
On topic 3
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 48
Resolved 48
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 0
Terms whose name was checked 1
Terms named correctly 0
Terms named as a different term 1

Terms the report names something else

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

  • MONDO:0013200 (4 mentions) - the report calls it "if available"; MONDO calls it hypertrophic cardiomyopathy 15