MYH6

Inheritance Pattern: AD

Disease ID:MONDO:0013197

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0024573

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0013567

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0015470

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0013572

Submitter: Illumina

Inheritance Pattern: AD

Disease ID:MONDO:0005045

Submitter: ClinGen

MYH6 was first reported in association with autosomal dominant hypertrophic cardiomyopathy (HCM) in humans in 2002 (Niimura et al. 2002, PMID 11815426). MYH6 gene encodes alpha heavy chain subunit of cardiac myosin (MHC-α), which are actin-based molecular motors that convert chemical energy released from the hydrolysis of ATP. It has been associated with HCM in 3 probands in 2 publications. Four unique heterozygous missense variants have been reported in humans with limited evidence to support their pathogenicity (Niimura et al. 2002, PMID 11815426; Rubattu et al. 2016, PMID 27483260; Wang et al. 2020 PMID 33385793). Additional missense variants have been reported in humans, but were not scored because probands have variants in another HCM gene (Rubattu et al. 2016, PMID 27483260; Liu et al. 2021, PMID 34087240; Suzuki et al. 2022, PMID 35911064), or high frequency in the population (Carniel et al. 2005, PMID 15998695). The mechanism for disease remains unknown. The gene-disease association is supported by expression studies in the human heart (Gorza, et al. 1984, PMID 6234108) and biochemical function showing MHC-α interactions with ATP, actin and the light chains (Weiss et al. 1999, PMID 10388558). Additional studies on mice models of HCM using pre-engineered heterozygous, pathogenic MYH7 variant orthologous to the human p.R403Q allele into the mouse MYH6 were reviewed, but not scored because these mice models are not analogous to human MYH6 (Geisterfer-Lowrance et al. 1996, PMID 8614836; Jiang, et al. 2013 PMID 24092743). This classification was originally approved by the ClinGen Hypertrophic Cardiomyopathy Gene Curation Expert Panel on November 1, 2017, with a classification of “Limited”. It was reevaluated by the ClinGen Hereditary Cardiovascular Disease Gene Curation Expert Panel on July 12, 2023. As a result of this reevaluation, the classification was changed from “Limited” to “Disputed” due to absence of new compelling genetic and experimental evidence.

Inheritance Pattern: AD

Disease ID:MONDO:0013198

Submitter: ClinGen

MYH6 was originally evaluated for DCM by the ClinGen DCM GCEP on 9/4/2020. Evidence of the association of this gene with DCM was re-evaluated using SOP v10 on 3/6/2025. 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. MYH6 was evaluated for autosomal dominant dilated cardiomyopathy (DCM). The MYH6 gene encodes the alpha heavy chain subunit of cardiac myosin (alpha-MHC), a fast ATPase primarily expressed in human atrial tissue. In addition to DCM, MYH6 has also been reported with congenital heart defects at the time of review. MYH6 has also been curated by the Congenital Heart Disease Gene Curation Expert Panel for MYH6-related congenital heart defects (definitive, May 2023) and by the Hereditary Cardiovascular Disease Gene Curation Expert Panel for hypertrophic cardiomyopathy (disputed, July, 2023). This was considered in accordance with ClinGen lumping and splitting criteria. Due to the distinct differences in phenotype for congenital heart disease versus DCM and due to disputed classification for HCM which also carries distinct phenotypic differences, the curation was split and curated for autosomal dominant DCM. Human genetic evidence supporting this gene-disease relationship includes case-level data. At time of this curation, there have been more than 60 unique variants (including majority missense (60/65), (2/65) nonsense, frameshift (1/65) and splice variants (2/65)) reported in humans with DCM across 11 primary publications. Given MYH6 has a high background of rare variation (approximate variation rate of 2%) with majority of reported variation being missense, additional supporting evidence was considered for case-level evidence for DCM including functional data, segregation data, or presence of additional, unrelated DCM cases harboring the same MYH6 variant. Functional evidence was reported in one primary publication. In brief, two MYH6 variants were functionally analyzed using adenovirus infected rat ventricular cardiomyocytes; however, evidence was not aberrant for the NM_002471.3(MYH6): c.2489C>T p.(Pro830Leu) variant and the other variant analyzed, NM_002471.3(MYH6): c.3010G>T p.Ala1004Ser, was not considered causative for DCM as due to high frequency in gnomAD (1769x in 1614160 reference alleles in version 4) and therefore were not scored for case-level evidence. At time of this curation, 6 of the primary publications had human genetic evidence for case level data for DCM detailing 6 unique missense variants with additional supporting evidence (PMID: 15998695, 20215591, 25163546, 28416588, 31983221, 34011823) and 3 unique, rare, predicted loss of function variants (PMID: 31983221, 34011823). For the missense variants observed in these cases, all supporting evidence was the presence of additional, unrelated DCM cases harboring a respective variant. Functional evidence was not available in scorable variants that supported pathogenicity. Additional experimental evidence supports this gene-disease association, including expression studies and animal models. Expression evidence in DCM literature is available across 3 primary publications. In brief, Lowes et al. 1997 detailed non-failing human ventricular myocardium expresses substantial amounts of alpha-myosin heavy chain mRNA (alpha-MHC, 23–34% of total) and in heart failure alpha-MHC is downregulated (by 67–84%) and beta-MHC gene expression is upregulated (PMID: 9410910). Similarly, Miyata et al. 2000, detailed alpha-MyHC protein was easily detectable in 12 nonfailing left ventricles. Alpha-MyHC protein represented only 7.3% of total MyHC protein (compared with ~35% of the MyHC mRNA), suggesting that translational regulation may be operative; in contrast, there was effectively no detectable alpha-MyHC protein in the left ventricles of 10 end-stage failing human hearts (PMID 10700442). Most recently Schiano et al. investigated transcriptomic profiles of 11 patients undergoing heart transplantation for familial DCM were compared versus controls utilizing a computational approach with quantitative real-time PCR validation. These results indicated downregulation of MYH6 in DCM-hearts compared to controls (PMID: 34946895). Animal model data was available from 1 primary publication. In brief, Carroll et al., 2016 investigated knockdown of Myh6 in postnatal mouse heart using Myh6 (promotor)-Cas9 mice intraperitoneally injected with AAV9 (adenovirus) encoded single guided RNA against Myh6 at postnatal day 10 quickly and efficiently induces massive cardiac dilation and heart failure, within 3 weeks of AAV delivery of sgRNA (Carroll et al, 2016, 26719419). However, limitations of this interpretation of this evidence are present as the major isoform in the adult mouse ventricle is alpha-Mhc, whereas in the human the major isoform is beta-MHC. In summary, there is limited evidence to support this gene-disease relationship. More evidence is needed to support the relationship of MYH6 with autosomal dominant DCM. This classification was approved by the ClinGen Dilated Cardiomyopathy Working Group on 3/6/2025 (SOP Version 10).

Inheritance Pattern: AD

Disease ID:MONDO:0013197

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

Inheritance Pattern: AD

Disease ID:MONDO:0016333

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0013197

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0800442

Submitter: ClinGen

MYH6 was first reported in relation to autosomal dominant congenital heart defects in 2005 (Ching et al. 2005, PMID: 15735645). The MYH6 gene encodes the alpha heavy chain subunit of cardiac myosin (alpha-MHC), a fast ATPase primarily expressed in human atrial tissue. Cardiac myosin is one of the major components of the cardiac sarcomere. Variants in MYH6 have been associated with multiple types of congenital heart disease including atrial septal defects (ASD), atrioventricular septal defects, conotruncal defects, tricuspid atresia and left sided obstructive lesions. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, Atrial Septal Defect 3 (OMIM:614089) is included in the curation with autosomal dominant MYH6 related congenital heart defects. The split curation for autosomal recessive MYH6 related congenital heart defects has been curated separately. The split curations for MYH6-dilated cardiomyopathy and MYH6 – hypertrophic cardiomyopathy have been previously reported. 21 variants including missense, nonsense, and splice site variants reported in 21 probands in 11 publications (PMIDs: 15735645, 22194935, 29969989, 31638415, 34481090, 29536580, 20656787, 22337856, 35863714, 27789736, 28991257) are included in this curation using an allele frequency threshold of 1x10-5. One case control study with 452 cases of atrial septal defect and 519 healthy controls found a nonsense variant in MYH6 that was significantly associated with ASD (PMID: 29505555). This gene-disease relationship is also supported by protein interaction studies, fetal expression in mice, animal models and functional alteration in patient cells (PMIDs: 15735645, 11247796, 15735645, 31129720, 19769958, 32656206). Additional experimental data are available but the maximum experimental score was reached. The mechanism of disease is unknown. In summary, there is definitive evidence supporting the relationship between MYH6 and autosomal dominant congenital heart defects. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Congenital Heart Disease GCEP on the meeting date May 9, 2023. (SOP Version 9).

Inheritance Pattern: AD

Disease ID:MONDO:0006664

Submitter: PanelApp Australia