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Evaluating Pathogenicity of TPM1 Variants of Unknown Significance Using In-silico and In-vitro Models.

Saiti S Halder1, Jenette G Bellitto1, Michael J Rynkiewicz2

  • 1Department of Biomedical Engineering, Yale University.

Journal of Precision Medicine (Amsterdam, Netherlands)
|June 4, 2026
PubMed
Summary

Computational methods can classify TPM1 variants of unknown significance (VUS) in inherited cardiomyopathies. This study demonstrates that in silico predictions correlate with in vitro functional changes, aiding genetic screening.

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Last Updated: Jun 5, 2026

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Published on: August 20, 2019

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Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation
07:15

Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation

Published on: January 16, 2019

Area of Science:

  • Cardiovascular Genetics
  • Molecular Cardiology
  • Computational Biology

Background:

  • Variants of unknown significance (VUS) hinder genetic screening for inherited cardiomyopathies.
  • Accurate classification of TPM1 VUS is crucial for family cascade screening.

Purpose of the Study:

  • To evaluate scalable computational methods for assessing the pathogenicity of TPM1 VUS.
  • To validate computational predictions with in vitro functional data.

Main Methods:

  • Atomistic modeling and molecular dynamics simulations of 20 TPM1 VUS.
  • Assessment of tropomyosin flexibility and electrostatic interactions with actin.
  • In vitro functional studies including motility assays, engineered heart tissues (EHTs), and iPSC-derived cardiomyocyte morphology.

Main Results:

  • Four TPM1 variants (A102D, D258E, K233N, A239T) exhibited significantly altered contractile function.
  • A102D increased Ca2+ sensitivity and contraction force, while D258E slowed relaxation.
  • K233N and A239T reduced motility and contraction force, increasing cardiomyocyte aspect ratio.

Conclusions:

  • Computational predictions of molecular aberrations in TPM1 variants correlate with functional changes.
  • A scalable computational pipeline shows feasibility for TPM1 VUS classification.
  • This approach supports improved genetic screening for inherited cardiomyopathies.