Using BMHC abundance to predict cardiomyopathy risk of MYH7 variants in the S1 domain at scale AHA Conference Repository

American Heart Association

Final ID: Mon029

Using BMHC abundance to predict cardiomyopathy risk of MYH7 variants in the S1 domain at scale

Abstract Body:
Hypertrophic cardiomyopathy (HCM) is a common heritable heart disease responsible for heart failure and sudden cardiac death. The majority of HCM is caused by mutations in sarcomeric protein coding genes, 40% of which are autosomal dominant missense variants of myosin heavy chain 7 (MYH7) that encode beta myosin heavy chain protein (BMHC). However, an accurate diagnosis and treatment for familial HCM is hindered by the fact that the most of the currently reported missense variants are classified as variants of uncertain significance (VUS), a classification that is not clinically useful. Our lab has been trying to address the thousands of VUS in the MYH7 gene by generating experimental data that determines the effect of each MYH7 variant on cardiomyocyte biology. By developing a deep mutational scan that measures bMHC protein abundance in gene edited human iPSCs (hiPSC-CM) expressing MYH7 variants, we found that BMHC abundance can successfully discriminate pathogenic (low BMHC abundance) from benign (normal BMHC abundance) variants within the coil-coil rod domain of BMHC protein. To determine if bMHC protein abundance can discriminate pathogenic and benign variants in the motor head domain of the bMHC protein, we created a hiPSC library of 416 single nucleotide variants (SNV) in the motor domain. After differentiating the hiPSC library to cardiomyocytes, we measured bMHC protein abundance in all variant cardiomyocytes and found that bMHC abundance can identify 7 out of 7 known pathogenic variants and 27 out of 31 known benign variants, in addition to providing data for the other 378 variants. The overall accuracy of the assay was 87%, and the strength of this assay as assessed by OddsPath was moderate, which can assist with the formal reclassification of 90 VUS and variants of conflicting classifications by following the variant interpretation framework recommended by the American College of Medical Genetics and Genomics. In summary, we have developed a scalable method to generate and functionally annotate MYH7 variants in cardiomyocytes that enables accurate variant classification. This strategy can help reclassify VUS at scale and provide functional evidence for the classification that have yet to be encountered.

Kim, Hoyon ( University of Washington , Seattle , Washington , United States )
Lee, Yeongji ( University of Washington , Seattle , Washington , United States )
Loiben, Alexander ( University of Washington , Seattle , Washington , United States )
Chien, Wei-ming ( University of Washington , Seattle , Washington , United States )
Yang, Daniel ( University of Washington , Seattle , Washington , United States )

Author Disclosures:

Meeting Info:

Basic Cardiovascular Sciences 2026

2026

Boston, Massachusetts

Session Info:

Poster Session 1

Monday, 07/13/2026 , 04:30PM - 07:00PM

Poster Session and Reception

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