MYBPC3

Inheritance Pattern: AD

Disease ID:MONDO:0005021

Submitter: ClinGen

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).

Inheritance Pattern: AD

Disease ID:MONDO:0015470

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0016587

Submitter: ClinGen

MYBPC3: Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) HGNC: 7551 http://purl.obolibrary.org/obo/MONDO_0016587 Mode of Inheritance: Autosomal dominant inheritance (HP:0000006) Expert Panel: Arrhythmogenic Right Ventricular Cardiomyopathy SOP: Gene Clinical Validity Standard Operating Procedures (SOP), Version 6 Calculated Classification (date) Limited 22/02/2019 Evidence Summary: There is limited evidence that MYBPC3 is associated with ARVC. Screening of ARVC patient cohorts for MYBPC3 mutations has been performed in two studies (29709087, 27194543). In these studies, a total of 151 ARVC patients were investigated and three individuals were reported carrying MYBPC3 missense variants. However, the significance of these variants in the context of ARVC is unclear as they were either VUS (e.g. p.Arg238Cys) or MYBPC3 variant carriers were also double heterozygotes for variants in other genes associated with cardiomyopathies (29709087, 27194543). In one ARVC pedigree the identified MYBPC3 p.Phe305Profs variant did not segregate with ARVC in the family (28699631). A recent publication presented a single ARVC case with a missense variant (p.Glu1179Lys) in MYBPC3 (28843747). In summary, there is limited evidence to support this gene-disease association. There is no clear evidence that the identified MYBPC3 variants contribute to the ARVC phenotype and there is no known disease mechanism that would link MYBPC3 with ARVC.

Inheritance Pattern: AD

Disease ID:MONDO:0016587

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0005021

Submitter: ClinGen

MYBPC3 was originally evaluated for autosomal recessive DCM by the ClinGen DCM GCEP on 16 May 2025. MYBPC3 was first reported in relation to autosomal recessive DCM in 2019 (Kolokotronis K, et al., PMID: 30924982). Human genetic evidence supporting this gene-disease relationship includes case-level data. Two probands with DCM have been reported in two publications (Kolokotronis et al, PMID: 30924982; Blagova et al, PMID: 33101033). One probands was homozygous for a small in-frame deletion and the other compound heterozygous for a whole gene MYBPC3 deletion and an MYBPC3 missense variant. This gene-disease association is supported by multiple animal models (mouse), expression studies, and rescue studies in two mouse models. MYBPC3 has not been assessed in any other autosomal recessive conditions but has been assessed separately for autosomal dominant dilated cardiomyopathy (limited, May 16, 2025), hypertrophic cardiomyopathy (definitive, October 7, 2021), arrhythmogenic right ventricular cardiomyopathy (limited, August 6, 2019), and congenital heart disease (limited, July 8, 2024). In summary, there is limited evidence to support this gene-disease relationship. More evidence is needed to support the relationship of MYBPC3 with autosomal recessive DCM. This classification was approved by the ClinGen Dilated Cardiomyopathy Working Group on 16th May 2025 (SOP Version 10).

Inheritance Pattern: AD

Disease ID:MONDO:0004981

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0014163

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0007268

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0014163

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0007268

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0016333

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0007268

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0007268

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0014163

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0005045

Submitter: ClinGen

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.

Inheritance Pattern: AD

Disease ID:MONDO:0005453

Submitter: ClinGen

*MYBPC3* was first reported in relation to autosomal dominant congenital heart disease in 2011 (Posch et al., PMID: 22194935). Nine variants (missense, nonsense, splice acceptor) that have been reported in 10 probands with CHD in eight publications (PMIDs: 22194935, 27418595, 28991257, 31440271, 33209723, 35146008, 34670123, 35885957) are included in this curation, but only three variants were scored, as the other variants were present in unaffected family members and/or too frequent in population databases. The mechanism of pathogenicity appears to be loss-of-function. This gene-disease relationship is also supported by experimental evidence (expression data; PMID: 28315668). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the Congenital Heart Disease GCEP on July 8th, 2024 (SOP Version 10)