| Domain | Best-supported finding | Evidence type | Key ontology/identifier | Important limitation |
|---|---|---|---|---|
| Disease identity | CMD1R denotes ACTC1-related familial dilated cardiomyopathy, a rare sarcomeric cardiomyopathy characterized by ventricular dilation and systolic dysfunction. | Aggregated disease-level resources plus human pedigrees | ACTC1: **MIM 102540**; DCM: MONDO:0005021 | The requested **MONDO:0013261** should be independently verified before database ingestion; some resources map ACTC1 to broad familial DCM rather than a uniquely resolved CMD1R concept. (pqac-00000000, pqac-00000017) |
| Genetic architecture | Best-established disease mechanism is heterozygous germline **missense** variation with autosomal-dominant segregation; de novo cases also occur. | Human familial segregation and case reports | ACTC1; chr15q14; AD inheritance | Penetrance and phenotype are variant-specific; an ACTC1 variant associated with another phenotype cannot automatically be classified as pathogenic for DCM. (pqac-00000001, pqac-00000006, pqac-00000016) |
| Foundational evidence | Olson et al. identified ACTC1 missense variants cosegregating with hereditary idiopathic DCM in two unrelated families and proposed defective force transmission through Z-band/intercalated-disc interfaces. | Primary human genetic study | Science, May 1998; DOI: [10.1126/science.280.5364.750](https://doi.org/10.1126/science.280.5364.750) | Small pedigree-based discovery study predating modern population databases and ACMG/AMP classification. (pqac-00000008) |
| Quantitative familial evidence | **p.Gly247Asp** was present in 15 affected relatives and absent from 63 unaffected relatives; ASD-II occurred in about 88% of carriers, while DCM generally emerged in the fourth–fifth decades. Outcomes included transplantation at ages 51 and 55 and sudden death at 63. | Human linkage, segregation, imaging, and myocardial pathology | ACTC1 p.Gly247Asp; ASD: HP:0001631; DCM: HP:0001644 | “Fully penetrant” referred to the combined familial phenotype; DCM itself affected only a subset and was age-dependent. (pqac-00000001, pqac-00000002) |
| 2023 phenotypic expansion | Five families with heterozygous ACTC1 missense variants established a syndromic spectrum of distal arthrogryposis with congenital heart defects; one p.Arg185Trp carrier had borderline LV systolic function (LVEF 52%) and reduced strain. | Human case series plus molecular-dynamics modeling | DOI: [10.1016/j.xhgg.2023.100213](https://doi.org/10.1016/j.xhgg.2023.100213); ACTC1 MIM 102540 | This is not a classical isolated-CMD1R cohort; it demonstrates allelic and tissue pleiotropy rather than DCM prevalence. (pqac-00000004, pqac-00000006, pqac-00000017) |
| 2024 infant case | A 1-year-old with severe LV dilation/dysfunction and sudden death carried apparently de novo **ACTC1 c.664G>A (p.Ala222Thr)** plus paternally inherited **TTN p.Glu11084Lys**. | Single human case; NGS, Sanger validation, and computational modeling | DOI: [10.1155/crig/9517735](https://doi.org/10.1155/crig/9517735); HP:0001644; HP:0001699 | Causality cannot be assigned to ACTC1 alone because of the co-occurring TTN variant and absence of direct functional validation. (pqac-00000003, pqac-00000016) |
| Mechanism | Mutant α-cardiac actin can impair actin polymerization/turnover, thin-filament organization, actomyosin regulation, and force transmission, leading to hypocontractility, sarcomeric disarray, myofibrillar degeneration, apoptosis, extracellular-matrix expansion, remodeling, and heart failure. | Human myocardial pathology, cultured rat cardiomyocytes, purified-protein assays, and computational modeling | Suggested GO: actin filament organization (GO:0007015), muscle contraction (GO:0006936), cardiac muscle contraction (GO:0060048), apoptotic process (GO:0006915) | Mechanisms differ among substitutions; calcium-desensitization and dominant-negative models are plausible but not universal across ACTC1 variants. (pqac-00000001, pqac-00000002, pqac-00000007, pqac-00000018) |
| Diagnosis | Diagnosis requires DCM phenotyping with history/pedigree, ECG, echocardiography, ambulatory rhythm monitoring, and usually CMR, followed by a curated cardiomyopathy panel including ACTC1 and ACMG/AMP variant interpretation; a pathogenic familial variant enables cascade testing. | Contemporary cardiomyopathy guidance extrapolated to ACTC1 | DCM: HP:0001644; reduced LVEF: HP:0012664; genetic testing intervention | No ACTC1-specific diagnostic threshold exists; a VUS must not establish diagnosis or direct predictive testing. (pqac-00000012, pqac-00000013, pqac-00000014) |
| Treatment | Management is phenotype-based guideline-directed therapy for HFrEF and complications: neurohormonal therapy, diuretics for congestion, rhythm/thromboembolism management, ICD/CRT when standard criteria are met, and mechanical support or transplantation for refractory advanced disease. | General DCM/heart-failure guidelines and limited ACTC1 case experience | Suggested NCIT: pharmacologic therapy, implantable cardioverter-defibrillator, cardiac resynchronization therapy, heart transplantation | No drug, device criterion, or pharmacogenomic recommendation is validated specifically for ACTC1-CMD1R. (pqac-00000011, pqac-00000013) |
| Epidemiology | ACTC1-CMD1R is exceptionally rare; no reliable disease-specific prevalence, incidence, carrier frequency, sex ratio, founder effect, or geographic enrichment has been established. | Evidence-gap assessment from sparse pedigrees/cases | Orphan/Mendelian disease; broad DCM only: MONDO:0005021 | General DCM estimates must not be reported as ACTC1-specific epidemiology. (pqac-00000000, pqac-00000003) |
| Clinical trials | No interventional trial specifically targeting ACTC1-CMD1R was identified; available genetic/familial DCM studies enroll mixed genotypes and test early neurohormonal or precision-care strategies. | Clinical-trial registry search | Example mixed-genotype study: NCT05321875 | Results from unselected or mixed-genotype DCM trials cannot be assumed to show ACTC1-specific efficacy. (pqac-00000009, pqac-00000015) |


*Table: Compact evidence table distinguishing well-supported ACTC1-specific findings from general DCM guidance and unresolved evidence gaps. It highlights foundational pedigrees, recent phenotypic expansion, mechanisms, and the absence of disease-specific epidemiology or therapy.*