ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000011.9) (NC_000011.10)
Evidence for haploinsufficiency phenotype
PubMed ID Description
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.
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 mutations 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.
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.

Haploinsufficiency phenotype comments:

Numerous frameshift, splicing site, exonic deletion and nonsense mutations that all lead to premature termination support haploinsufficiency as a pathogenetic mechanism. Complete deletion of MYBPC3 in patients with large CNV has not been reported with cardiomyopathy phenotype.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity