MYBPC3

Gene Facts

• HGNC Symbol: MYBPC3 (HGNC:7551)
• HGNC Name: myosin binding protein C3
• Gene type: protein-coding gene
• Locus type: gene with protein product
• Previous symbols: CMH4
• Alias symbols: FHC, cMyBP-C
• %HI: 41.39
• pLI: 0
• LOEUF: 0.92
• Cytoband: 11p11.2
• Genomic Coordinates:

  GRCh37/hg19:	chr11:47352957-47374253
  GRCh38/hg38:	chr11:47331406-47352702

• MANE Select Transcript: NM_000256.3 ENST00000545968.6
• Function: Thick filament-associated protein located in the crossbridge region of vertebrate striated muscle a bands. In vitro it binds MHC, F- actin and native thin filaments, and modifies the activity of actin- activated myosin ATPase. It may modulate muscle contraction or may play a more structural role. (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

• Dosage ID: ISCA-16036
• ClinGen Curation ID: CCID:007500
• Curation Status: Complete
• Issue Type: Dosage Curation - Gene
• Haploinsufficiency: Sufficient Evidence for Haploinsufficiency (3)
• Triplosensitivity: No Evidence for Triplosensitivity (0)
• Assoc. with Reduced Penetrance: Yes
  PMIDs: 7493026, 23870641, 9562578 Bonne et al (1995) identified splicing variants in two families which co-segregated with familial hypertrophic cardiomyopathy. The same variants were not seen in most of the unaffected individuals and none of the 200 unrelated normal chromosomes. In one family, the affected haplotype was seen in 6 healthy individuals and in 3 individuals with "unknown" diagnosis. In the other family, there 2 individuals with the affected haplotype, but "unknown" diagnosis. These individuals are believed to reflect the reduced penetrance of variants in this gene. Niimura et al (1998) also identified 12 novel mutations in 16 families, eight of these mutations were predicted to result in a truncated protein. 574 at-risk family members were genotyped and 91 unaffected individuals were found to be mutation positive. This supported the observed low penetrance through the fifth decade of life, in contrast to other cardiomyopathy genes. Other evidence of low penetrance was reported by Reguero et al (2013) showing discordant monozygotic twins (only one affected at age 39 despite no difference in lifestyles) with compound heterozygosity for a nonsense and a missense mutation and their unaffected 49 year old sister with the same genotype.
• Last Evaluated: 01/10/2023

Haploinsufficiency (HI) Score Details

• HI Score: 3
• HI Evidence Strength: Sufficient Evidence for Haploinsufficiency

HI Disease

• hypertrophic cardiomyopathy 4

HI Evidence

• PUBMED: 22820391
  Pezzoli et al (2012) detected a 3.5 kb partial deletion involving MYBPC3 in a young adult male patient with severely obstructive hypertrophic cardiomyopathy (HCM). The deletion is predicted to result in haploinsufficiency of MYBPC3. Targeted next-generation sequencing (NGS) of 88 cardiomyopathy-associated genes did not identify any additional mutations. Per family history, the deletion is also present in the patient’s sibling and nephew, both of whom also have diagnosed HCM.
• PUBMED: 23816408
  Meyer et al (2013) detected an intragenic duplication (26 bp) in a 54-year-old female patient leading to a frameshift and premature truncation, leading to functional haploinsufficiency. Her father also dx w/ HCM and died of myocardial infarction at the age of 66, while her healthy brother showed no signs of heart failure. This study also detected a 2bp deletion resulting in frameshift leading to functional haploinsufficiency in another patient in this same cohort. An identical intragenic duplication to the first patient was also picked up by Nannenberg et al (2011) in an unrelated patient with HCM. Meyer quotes the Human Gene Mutation Database (Professional 2012.2) that states "The majority of MYBPC3 mutations found in HCM patients belong to the class of missense or nonsense mutations with nearly 250 different mutations identified so far, followed by small deletions (69 mutations) and splicing mutations (54 mutations)".
• PUBMED: 32973354
  Singer et al (2020) describe a 14kb partial deletion of MYBPC3 in a 43-year-old male patient with HCM by exome sequencing. The deletion removes the last 12 exons of the gene and overlaps an established haploinsufficiency locus that includes other exons in addition to the last exon. Therefore, nonsense-mediated decay is expected to occur. This deletion was previously classified as pathogenic per ACMG/ClinGen reporting criteria 2D-4 and 5G. He has no known family history of HCM, but also no parental samples were available for testing.
• PUBMED: 19574547
  Marston et al (2009) performed functional studies on ventricular muscle samples from affected patients undergoing myectomy versus donor hearts. Given that two-thirds of the 150+ mutations are predicted to result in a truncated protein product, haploinsufficiency has been postulated as the cause for disease, but truncated proteins have not been observed. They demonstrated markedly reduced protein content in the myectomy specimens which then led to impaired structural integrity of the contractile unit. The authors state their evidence supports haploinsufficiency as the mechanism of mutation.
• PUBMED: 7493025
  Watkins et al (1995) identified mutations in MYBPC3 in two families with familial hypertrophic cardiomyopathy in multiple generations. A splice donor mutation was found in one family and a duplication mutation in the other. Both variants led to a premature termination codon. In both families, the mutations segregated with disease in all affected family members as well as a presumed non-penetrant 16-year-old. And as expected, the mutations were not found in 200 chromosomes in control individuals.

• HI Evidence Comments: Numerous frameshift, splicing site, exonic deletion and nonsense mutations that all lead to premature termination support haploinsufficiency as a pathogenetic mechanism. Per Glazier et al (2019, PMID: 30456444): Over a span of 20+ years, numerous independent studies have not detected truncated mutated protein product in myocardial tissue of HCM patients (including longitudinal studies). This concludes that haploinsufficiency, not dominant negative, is the main mechanism leading to HCM for patients with MYBPC3 variants. Please also see PMID:32841044 for an additional review of evidence for haploinsufficiency.

Triplosensitivity (TS) Score Details

• TS Score: 0
• TS Evidence Strength: No Evidence for Triplosensitivity