MYBPC3 (Cardiac Myosin Binding Protein C)
Contents. #Details · #Key Facts · #Contradictions / Open Questions · #Connections · #Sources
Detailed pages. concepts/Sarcomere-Biology · concepts/Haploinsufficiency
Parent. concepts/HCM-Genetics-and-Phenotypes — the HCM genetics spoke. Protein-level mechanism is on concepts/HCM-Mechanism.
Details
MYBPC3 encodes cardiac myosin-binding protein C (cMyBP-C), a thick-filament regulatory protein of the cardiac sarcomere that modulates crossbridge cycling, diastolic relaxation, and filament state transitions via phosphorylation-dependent binding switches. It is the most frequently mutated gene in HCM, accounting for 40–50% of all pathogenic HCM variants; >60% of mutations are truncating and produce haploinsufficiency through NMD/UPS/autophagy-mediated degradation of the truncated protein. MYBPC3 mutations also cause DCM (13% of genetic DCM cases), LVNC, and restrictive CMP, and bi-allelic truncating mutations cause uniformly fatal neonatal cardiomyopathy. A 25-bp South Asian founder deletion present in 4% of South Asians confers a 6.99-fold increased heart failure risk, making MYBPC3 among the most globally important cardiomyopathy genes.
Key Facts
Mutation Landscape
- Frequency in HCM: >350 individual MYBPC3 mutations; 40–50% of all HCM mutations — the most frequently mutated HCM gene, followed by MYH7 (~25–40%). >60% are truncating (nonsense, indels, splice/branch-point), producing COOH-terminally truncated cMyBP-C lacking major myosin/titin-binding sites. Most heterozygous mutations associate with late onset and often benign progression. (sources/mybpc3-gene-2015, sources/HCM-VA-FCVMed-2022, rating: medium/high)
- Bi-allelic truncating mutations: All 26 reported cases of homozygotes/compound heterozygotes with double truncating mutations presented with neonatal cardiomyopathy → heart failure and death within the first year of life; cardiac transplantation is the only curative option. Gene-dosage effect: 14% of childhood-onset HCM is caused by compound genetic variants. (sources/mybpc3-gene-2015)
- MYBPC3 in DCM and LVNC: MYBPC3 mutations represented the second highest frequency of disease-causing mutations in a European multi-centre DCM cohort (38/294, 13%; Haas et al. 2014). MYBPC3 mutations also cause LVNC; both missense and truncating mutations occur across HCM, DCM, and LVNC. (sources/mybpc3-gene-2015)
- South Asian founder variant: A 25-bp deletion in MYBPC3 intron 32 (delta25, frameshift) is present in 4% of the South Asian population and confers a 6.99-fold increased risk of heart failure (Dhandapany et al. 2009). Found in 13.8% of patients across HCM, DCM, and restrictive CMP in South Asian populations — clinically important for pre-test probability assessment in this group. (sources/mybpc3-gene-2015)
Founder Mutations by Population
All identified founder MYBPC3 mutations are truncating, lacking the M-motif phosphorylation sites and/or major binding domains: (sources/mybpc3-gene-2015, rating: medium)
- Iceland c.927-2A>G (intron 11 splice, arose >550 years ago): 58% of Icelandic HCM
- Veneto, Italy c.912_913delTT (exon 11): 19.5% of HCM probands
- Netherlands c.2373_2374insG: 17% of Dutch HCM (plus 2 additional founder mutations at 2.6% and 1.6%)
- Finland c.3183C>T / Gln1061X (exon 29): 17% of cases
- Japan c.1775delT / Val592fs/8 (exon 18): 16% of HCM probands
- Tuscany, Italy c.772G>A / Glu258Lys (exon 6): 14% of cases; used in Hamburg knock-in mouse model
- Center-East France c.1898-2A>G (intron 20, arose ~10 centuries ago): 8.4% of cases
- High founder prevalence increases compound heterozygote/homozygote likelihood and therefore the risk of severe pediatric cardiomyopathy in these populations.
Protein and Regulatory Biology — See concepts/HCM-Mechanism
- cMyBP-C is a thick-filament brake. Eight immunoglobulin-like and three fibronectin-like domains, an N-terminal C0, and an M-motif between C1 and C2 carrying the regulatory phosphorylation sites; it tethers myosin S1 heads to myosin S2 and limits loaded shortening velocity and power output. cMyBP-C also prevents residual crossbridge cycling at low diastolic calcium, so reduced protein impairs relaxation before any hypertrophy appears. (sources/mybpc3-gene-2015, rating: medium)
- Phosphorylation at Ser273/Ser282/Ser302 releases the brake, with Ser282 as the hierarchical switch; PKA is the principal kinase. Phosphorylation falls in heart failure and phosphomimetic protein is cardioprotective, whereas acetylation and S-glutathiolation may act in the opposite direction.
- Truncating variants produce haploinsufficiency, not a toxic fragment. The truncated protein is undetectable in human myocardium and degraded by NMD, the ubiquitin–proteasome system and autophagy, leaving roughly half-normal protein; reduced cMyBP-C raises myofilament calcium sensitivity. Missense variants may instead form stable poison polypeptides, which is the distinction that decides whether gene replacement or gene silencing is the appropriate therapy. The full account — calcium sensitivity, the RyR2 interaction and proteostasis failure — is on concepts/HCM-Mechanism and concepts/Haploinsufficiency.
Arrhythmia and Electrophysiology
- Arrhythmia risk in HCM: Japanese HCM studies found MYBPC3 mutation carriers have a higher incidence of ventricular arrhythmia and syncope compared to carriers of other sarcomere mutations. (sources/HCM-VA-FCVMed-2022, rating: high)
- K⁺ current finding (mouse only): Mybpc3-KI mice show reduced K⁺ currents as the dominant proarrhythmic mechanism. This was NOT replicated in human MYBPC3-homozygous EHT or LV septum samples from HCM patients at myectomy — illustrating a critical species translational gap. See Contradictions. (sources/HCM-VA-FCVMed-2022)
- Atrial fibrosis substrate: MYBPC3 variant–positive HCM patients undergoing AF ablation have significantly more LA low-voltage areas than gene-negative HCM controls (normal voltage 85.6% vs. 94.3%; intermediate scar 7.12% vs. 3.07%; dense scar 7.31% vs. 2.61%), despite similar LA pressures — supporting primary atrial myopathy driven by the MYBPC3 variant, independent of haemodynamic loading. (sources/MYBPC3-MYH7-JACCEP-2024, rating: medium)
- Greater LV mass in MYBPC3 vs. MYH7 carriers: MYBPC3 variant–positive patients had significantly greater LV mass index (145.7 ± 48.4 vs. 86.6 ± 27.3 g/m² in MYH7; P=0.04), contributing to thicker LA walls, higher rates of non-transmural ablation lesions, and pulmonary vein reconnection. (sources/MYBPC3-MYH7-JACCEP-2024)
- AF ablation outcomes: Freedom from AF at 12 months in MYBPC3-positive HCM (66.7%) was similar to controls (73.3%; P=0.92) but required more procedures on average; all gene-positive patients remained on AADs post-ablation. (sources/MYBPC3-MYH7-JACCEP-2024)
Penetrance and Clinical Genetics
- Incomplete penetrance and variable expressivity: MYBPC3 mutations show highly variable penetrance; a genotype-positive first-degree relative of an HCM proband may never develop phenotypic disease. MYBPC3 is a primary target for cascade family screening — genotype-positive/phenotype-negative relatives require longitudinal surveillance but not pre-emptive ICD. (sources/HCM-VA-FCVMed-2022, rating: high)
- Lifetime penetrance roughly 55% — the low end of the cardiomyopathy range, and the reason a MYBPC3 variant is compatible with a normal pregnancy and a normal ejection fraction for decades. Compare LMNA at 90–95% by age 60. (sources/cmp-pregnancy-jaccadv-2026, rating: medium)
- Hypertrabeculation in 54.6% (6 of 11) of MYBPC3-DCM — within the motor sarcomeric group, and the second-highest gene-level prevalence after MYH7 (71%). Caveat: the authors of that cohort concede some MYBPC3 carriers may have had end-stage HCM rather than DCM. (sources/trabeculation-dcm-circ-2026, rating: high)
- Genotype-phenotype complexity: Incomplete penetrance predictors are lacking, meaning genotype-positive individuals carry a labelled diagnosis with uncertain individual risk — with implications for insurance, employment, and psychological wellbeing. (sources/HCM-VA-FCVMed-2022)
ACMG Secondary Findings — Lifespan and Cause-of-Death Data (Iceland WGS)
- MYBPC3 is listed in the ACMG SF v3.0 cardiovascular gene group — among the cardiomyopathy genes for which LP/P variants must be reported as secondary findings in clinical exome/genome sequencing. (sources/genotype-lifespan-nejm-2023 — high)
- Population lifespan impact (n=57,933 Icelandic WGS): MYBPC3 actionable genotype carriers had a lifespan −2.18 years shorter (95% CI −3.44 to −0.92) than noncarriers. (sources/genotype-lifespan-nejm-2023 — high)
- Cardiomyopathy as cause of death: 10.4% of MYBPC3 actionable genotype carriers had cardiomyopathy listed on the death certificate vs 0.8% of noncarriers (OR 14.04; 95% CI 5.44 to 36.23). (sources/genotype-lifespan-nejm-2023 — high)
- Composite dilution effect: When combining all MYBPC3-associated conditions (cardiomyopathy + SCD + AF + HF), the cause-of-death OR was diluted to 1.34 (NS) — confirming that cardiomyopathy is the specific mechanism driving mortality, not the broader composite of MYBPC3-associated diseases. This has implications for how MYBPC3-related death should be analysed in future mortality studies. (sources/genotype-lifespan-nejm-2023 — high)
- MYBPC3 is one of only two cardiovascular ACMG SF genes (alongside LDLR/FH) with an individual lifespan signal in the Iceland WGS cohort — the remaining 75% of cardiovascular gene group carriers show no group-level survival difference. (sources/genotype-lifespan-nejm-2023 — high)
Gene Therapy
- Exon skipping (AON/AAV9): AONs targeting exons 5 and 6 packaged under the U7 promoter in AAV9 induce an in-frame deletion → expression of an alternatively spliced Mybpc3 variant. Systemic administration to newborn Mybpc3 knock-in mice prevented systolic dysfunction and LV hypertrophy (Gedicke-Hornung et al. 2013). For human MYBPC3, 6 single or 5 double exon skips would preserve functionally important phosphorylation and binding sites, addressing ~50% of mutations including 35 within exon 25. (sources/mybpc3-gene-2015, rating: medium)
- RNA trans-splicing: Two pre-trans-splicing molecules (targeting 5' and 3' of MYBPC3 pre-mRNA) produce repaired full-length mRNA. Feasibility demonstrated in cells and in vivo, but efficiency was too low to prevent the disease phenotype in homozygous knock-in mice (Mearini et al. 2013). Theoretically the most powerful approach — only 2 molecules bypass all MYBPC3 mutations — but requires substantial efficiency improvement. (sources/mybpc3-gene-2015)
- Gene replacement (AAV-mediated): Full-length Mybpc3 transfer dose-dependently prevented cardiac hypertrophy and dysfunction over 34 weeks in homozygous knock-in mice (Mearini et al. 2014). Unexpectedly, exogenous Mybpc3 expression down-regulated endogenous mutant Mybpc3, likely through sarcomeric protein competition. Proof-of-concept established for larger animal models (HCM cat model) and pediatric translation for bi-allelic mutations. (sources/mybpc3-gene-2015)
- CRISPR/Cas9: Not evaluated for MYBPC3 at time of the 2015 review; under investigation in iPSC lines at that stage. Applicable per-founder mutation. For updated CRISPR cardiac data, see sources/gene-therapy-arrhythmia-2025. (sources/mybpc3-gene-2015)
Contradictions / Open Questions
- MYBPC3 cause-of-death signal — cardiomyopathy specific, composite diluted: The strong cardiomyopathy cause-of-death association (OR 14.04) dissolves when the composite of all MYBPC3-associated conditions (including AF and HF) is analysed (OR 1.34; NS). This illustrates that HF and AF are common enough in the general population to dilute a gene-specific death signal — and underscores the methodological importance of selecting condition-specific (not composite) death analyses for ACMG gene mortality studies. (sources/genotype-lifespan-nejm-2023 — high)
- K⁺ current reduction — mouse finding not replicated in human: Mybpc3 knock-in mice show reduced K⁺ currents as the dominant proarrhythmic mechanism in HCM. This finding was NOT replicated in human MYBPC3-homozygous engineered heart tissue (EHT) or LV septum samples from HCM patients undergoing surgical myectomy. The translational gap undermines using mouse Mybpc3 models to guide antiarrhythmic drug development for human HCM. (sources/HCM-VA-FCVMed-2022)
- Incomplete penetrance — no validated predictors: MYBPC3 mutations show variable expressivity and incomplete penetrance. A genotype-positive relative may never develop phenotypic disease; current guidelines recommend surveillance but not pre-emptive ICD. No validated tool exists to predict individual penetrance — genotype-positive individuals carry a labelled diagnosis with uncertain personal risk, with implications for insurance, employment, and psychological wellbeing. (sources/HCM-VA-FCVMed-2022)
- Haploinsufficiency vs. dominant-negative — therapeutically critical but unresolved per variant: Most truncating variants produce haploinsufficiency (truncated protein absent by Western blot, degraded via NMD/UPS/autophagy). Some missense variants likely produce stable dominant-negative poison polypeptides incorporated into the sarcomere. The therapeutic implications differ — gene replacement addresses haploinsufficiency; gene silencing or exon skipping is needed for dominant-negative. Distinguishing the mechanism for individual variants is not routinely performed in clinical practice. (sources/HCM-VA-FCVMed-2022, sources/mybpc3-gene-2015)
- The 55% penetrance figure is doing an enormous amount of clinical work with very little support. It is what justifies reassuring a genotype-positive woman that pregnancy is reasonable, and it is a population average over a lifetime — not a prediction for her. No validated individual penetrance tool exists for MYBPC3, which the entry above already concedes for cascade counselling. (sources/cmp-pregnancy-jaccadv-2026, rating: medium)
Connections
- Related to concepts/ACMG-Secondary-Findings — MYBPC3 in cardiovascular ACMG SF group; lifespan and cause-of-death data
- Related to entities/HCM
- Related to entities/DCM
- Related to entities/MYH7
- Related to entities/RYR2
- Related to concepts/HCM-Calcium-Homeostasis
- Related to concepts/HCM-Ion-Channel-Remodeling
- Related to concepts/HCM-Risk-SCD
- Related to concepts/HCM-Atrial-Myopathy
- Related to concepts/Catheter-Ablation-AF
- Related to concepts/AAV-Gene-Delivery
- Related to concepts/Sarcomere-Biology
- Related to concepts/Cascade-Family-Screening
- Related to concepts/Pregnancy-in-Genetic-Cardiomyopathy — 55% lifetime penetrance in preconception counselling
- Related to concepts/LV-Hypertrabeculation — 55% prevalence in MYBPC3-DCM
- Related to sources/HCM-VA-FCVMed-2022
- Related to sources/MYBPC3-MYH7-JACCEP-2024
- Related to sources/mybpc3-gene-2015
- Related to sources/gene-therapy-arrhythmia-2025