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).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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