Pathogenic and Uncertain Genetic Variants Have Clinical Cardiac Correlates in Diverse Biobank Participants

Tess D. Pottinger, Megan J. Puckelwartz*, Lorenzo L. Pesce, Avery Robinson, Samuel Kearns, Jennifer A. Pacheco, Laura J. Rasmussen-Torvik, Maureen E. Smith, Rex Chisholm, Elizabeth M. McNally

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

18 Scopus citations


Background: Genome sequencing coupled with electronic heath record data can uncover medically important genetic variation. Interpretation of rare genetic variation and its role in mediating cardiovascular phenotypes is confounded by variants of uncertain significance. Methods and Results: We analyzed the whole genome sequence of 900 racially and ethnically diverse biobank participants selected from a single US center. Participants were equally divided among European, African, Hispanic, and mixed races/ethnicities. We evaluated the American College of Medical Genetics and Genomics medically actionable list of 59 genes, focusing on the cardiac genes. Variation was interpreted using the most recent reports in ClinVar, a database of medically relevant human variation. We identified 19 individuals with pathogenic or likely pathogenic variants in cardiac actionable genes (2%) and found evidence of related clinical correlates in the electronic health record. Participants of African ancestry, compared with those of European ancestry, had more variants of uncertain significance in the medically actionable genes including the 30 cardiac actionable genes, even when normalized to total variant count per person. Longitudinal measures of left ventricle size from ≈400 biobank participants (1723 patient-years) were correlated with genetic findings. The presence of ≥1 uncertain variant in the actionable cardiac genes and a cardiomyopathy diagnosis correlated with increased left ventricular internal diameter in diastole and in systole. In particular, MYBPC3 was identified as a gene with excess variants of uncertain significance. Conclusions: These data indicate that a subset of uncertain genetic variants may confer risk and should not be considered benign.

Original languageEnglish (US)
Article numbere013808
JournalJournal of the American Heart Association
Issue number3
StatePublished - Feb 4 2020


  • biobank
  • cardiomyopathy
  • left ventricle
  • medically actionable genes
  • variants of uncertain significance

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine


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