Submission Details

The MYBPC3 gene has been associated with autosomal dominant hypertrophic cardiomyopathy (HCM) using the ClinGen Clinical Validity Framework. This association was made using case-level data and case-control data. MYBPC3 was first associated with HCM in 1995 (Watkins et al, 1995, PMID 7493025). There are over 290 variants asserted as pathogenic for MYBPC3 for HCM in ClinVar, and mutations in MYBPC3 are reported in 40% of the reported cases of HCM (Cirino and Ho, 2014, GeneReviews, PMID 20301725). More evidence is available in the literature, but the maximum score for genetic evidence and/or experimental evidence (12 pts.) has been reached. Of note, MYBPC3 has been shown to cause HCM in an autosomal recessive fashion, with earlier and more severe presentation of phenotypes associated with HCM, and represents a semi-dominant condition. The molecular mechanism for HCM is loss of function (LOF), and missense, nonsense, frameshift and splice site mutations in MYBPC3 have been shown to be pathogenic for cardiomyopathy. Of note, this gene has been implicated in dilated cardiomyopathy and left ventricular noncompaction. This gene-disease relationship is supported by biochemical, expression, protein interaction, and animal models evidence. In summary, MYBPC3 is definitively associated with autosomal dominant HCM. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was originally approved by the ClinGen Hypertrophic Cardiomyopathy Expert Panel on September 5, 2017 using SOP version 5. This gene-disease relationship was reevaluated on October 6, 2021 by the Hereditary Cardiovascular Disorders GCEP. As a result of this reevaluation, the classification did not change.