MYBPC3

Chr 11ADAR

myosin binding protein C3

Also known as: CMD1MM, CMH4, FHC, LVNC10, MYBP-C, cMyBP-C

NCBI Gene: 4607 ENSG00000134571 UniProt: Q14896 OMIM: 600958

The protein regulates cardiac muscle contraction as a key component of the sarcomere's myosin-binding complex in heart muscle. Mutations cause hypertrophic cardiomyopathy, dilated cardiomyopathy, and left ventricular noncompaction through both autosomal dominant and autosomal recessive inheritance patterns. The pathogenic mechanism involves gain-of-function effects that disrupt normal cardiac contractility.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, Mechanism

MYBPC3 encodes the cardiac isoform of myosin-binding protein C. Myosin-binding protein C is a myosin-associated protein found in the cross-bridge-bearing zone (C region) of A bands in striated muscle. MYBPC3 is expressed exclusively in heart muscle and is a key regulator of cardiac contraction. Mutations in this gene are a frequent cause of familial hypertrophic cardiomyopathy. [provided by RefSeq, May 2022]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismAD/ARLOEUF 0.593 OMIM phenotypes

Clinical Summary— MYBPC3

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Gene-Disease Validity (ClinGen)

arrhythmogenic right ventricular cardiomyopathy · ADLimited

Limited evidence — not for standalone diagnostic reporting

5 total gene-disease associations curated

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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Clinical Trials

3 active or recruiting trials — potential therapeutic options may be available

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GeneReview available — MYBPC3

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.59LOEUF

pLI 0.000

Z-score 4.32

OE 0.43 (0.32–0.59)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.45Z-score

OE missense 0.86 (0.80–0.91)

679 obs / 794.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.43 (0.32–0.59)

0≤0.351.4

Missense OE?0.86 (0.80–0.91)

0≤0.61.4

Synonymous OE?1.02

0≤1.21.6

LoF obs/exp: 29 / 67.3Missense obs/exp: 679 / 794.1Syn Z: -0.22

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

limitedMYBPC3-related dilated cardiomyopathyOTHERAD

limitedMYBPC3-related arrhythmogenic right ventricular cardiomyopathyOTHERAD

definitiveMYBPC3-related hypertrophic cardiomyopathyLOFAD

This gene — mechanism propensity

0.7132th %ile

GOF

0.6931th %ile

LOF

0.3649th %ile

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, dominant-negative and gain-of-function). The Badonyi & Marsh model scores dominant-negative highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF1 literature citation · ClinGen HI: Sufficient evidence for dosage pathogenicity

DNprediction above median

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

LOFMutations in the cardiac myosin binding protein-C gene on chromosome 11 cause familial hypertrophic cardiomyopathy1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References