| 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. (pqac-00000000) | 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. (pqac-00000012, pqac-00000013) | **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. (pqac-00000000) | 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. (pqac-00000012, pqac-00000015) | **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. (pqac-00000006, pqac-00000010) | 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%. (pqac-00000016) | **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. (pqac-00000012, pqac-00000015, pqac-00000016) | **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. (pqac-00000002, pqac-00000017) | **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. (pqac-00000013, pqac-00000018) | **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. (pqac-00000004, pqac-00000005, pqac-00000006) | 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.*