| Domain | MYL2-specific evidence | Quantitative finding | Evidence type | Key limitation |
|---|---|---|---|---|
| Founder allele and modifiers | **MYL2 c.64G>A, p.Glu22Lys** occurred in 14 HCM families sharing a founder haplotype. Hypertension, obesity, or another sarcomeric variant increased disease expression. (pqac-00000002, pqac-00000003) | 38 carriers; HCM in **89%** of carriers with an additional hypertrophy-promoting factor; hypertension in **71%** of affected carriers with an additional factor. | Human family and segregation study | Low penetrance and generally mild phenotype when isolated; estimates may be founder-population dependent. |
| Familial restrictive phenotype | **MYL2 c.496G>C, p.Asp166His** segregated with HCM and was associated with restrictive filling, atrial enlargement, atrial fibrillation, heart failure, and embolic or arrhythmic events. (pqac-00000000, pqac-00000001) | 12 additional carriers: **11 with HCM** and 1 borderline; LOD **5.35**; AF **62%**; restrictive filling **38%**; no LV outflow obstruction. | Human multigenerational family study with structural modelling | Single-family phenotype may reflect shared genetic or environmental modifiers; classified as likely pathogenic in the study. |
| Patient-cell phenotype | Patient-derived cardiomyocytes carrying **MYL2 p.Arg58Gln (R58Q)** reproduced hypertrophy, myofibrillar disarray, abnormal calcium handling, and irregular beating. (pqac-00000006, pqac-00000008) | Cell area **4100 ± 171 versus 3200 ± 144 μm²**; disarray **42% versus 21%**; irregular beating **30.3% versus 2.4%**; L-type calcium-current density reduced **45.3%**. | Human patient-derived iPSC cardiomyocytes and myectomy tissue | Single-patient line compared with a maternal control; cells were immature and not reported as an isogenic pair. |
| Phosphorylation rescue | In R58Q biochemical and muscle-fibre systems, a **Ser15-to-Asp phosphomimetic** restored actin interaction, ATPase activity, and force while shifting myosin toward the disordered-relaxed state. (pqac-00000005) | MLCK phosphorylation increased maximal active isometric force by approximately **30%** in prior R58Q trabecula experiments; phosphomimetic measures approached wild-type levels. | Recombinant protein, reconstituted porcine cardiac fibres, and transgenic-mouse tissue | Preclinical in vitro or ex vivo rescue only; no S15D-R58Q animal or human therapeutic study. |
| Contemporary clinical guidance | **2023 ESC** and **2024 AHA/ACC multisociety** guidance supports phenotype-led imaging, genetic testing and counselling, cascade screening, sudden-death risk assessment, and treatment of eligible HCM. (pqac-00000013, pqac-00000015) | Guideline-level recommendations; no MYL2-specific treatment-effect estimate was reported. | Evidence-based clinical-practice guidelines | **Generic HCM evidence is not genotype-stratified for MYL2-HCM10** and does not establish variant-specific efficacy or prognosis. |


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