Submission Details

MYBPC3 was originally evaluated for DCM by the ClinGen DCM GCEP on 22 April 2020. Evidence of the association of this gene with DCM was re-evaluated using SOP v10 on 16th May 2025. As a result, the classification did not change. A summary of the information contributing to the classification of this gene at the time of re-evaluation is summarized herein. MYBPC3 was first reported in relation to autosomal dominant DCM in 2002 (Daehmlow et al, 2002 PMID: 12379228). More than 120 MYBPC3 variants have been reported in humans. The majority these variants are missense variants classified as variants of uncertain significance, though there is an increasing number of truncating variants identified in DCM patients. There were no reports of variants segregating with disease in large families. Ehlermann et al (2008, PMID: 18957093) reported segregation of a splicing variant in a family where two individuals had DCM, but the remainder had HCM. This gene-disease relationship has been studied in one large case-control study at the aggregate variant level (Mazzarotto et al, 2020, PMID: 31983221). There was no enrichment of MYBPC3 truncating or nontruncating variants in two DCM cohorts vs. ExAC derived controls. Case-control assessment conducted by the DCM GCEP of truncating variants identified in Escobar-Lopez L et al (2021, PMID 34674813) suggested enrichment of MYBPC3 truncating variants in DCM vs. gnomAD derived control, though this was not scored as the analysis was not published. This gene-disease association is supported by expression studies and animal model data. However, expression studies are difficult to interpret given the strong association with HCM (Fougerousse, et al, 1998, PMID: 9440712; Gautel M et al, 1995, PMID: 7744002; Freiburg A et al, 1996, PMID: 8631348; Shaffer et al, 2009, PMID: 19269976). MYBPC3 animal models producing DCM have a mixed phenotype with concurrent left ventricular hypertrophy and are homozygote only. Heterozygote models produce HCM. Therefore, these animal models have not been scored. MYBPC3 has also been implicated in hypertrophic cardiomyopathy (definitive, October 7, 2021), arrhythmogenic right ventricular cardiomyopathy (limited, August 6, 2019), and congenital heart disease (limited, July 8, 2024) and has been assessed separately. In summary, there is limited evidence to support this gene-disease relationship. More evidence is needed to support the relationship of MYBPC3 with DCM. The DCM GCEP made the decision to downgrade this classification to limited due to the genetic evidence being driven predominantly by VUSs from cohort studies with no strong pedigree data and limited experimental evidence. This classification was approved by the ClinGen Dilated Cardiomyopathy Working Group on 16th May 2025 (SOP Version 10).