Functional Evidence for The Classification of Genetic Variants in Inherited Cardiomyopathies: A Systematic Review

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@article{1720206,
      author = {Abolaji Tawakalitu Durodoye},
      title = {Functional Evidence for The Classification of Genetic Variants in Inherited Cardiomyopathies: A Systematic Review},
      journal = {Iconic Research And Engineering Journals},
      year = {2026},
      volume = {10},
      number = {1},
      pages = {3776-3826},
      issn = {2456-8880},
      url = {https://www.irejournals.com/formatedpaper/1720206.pdf},
      abstract = {Inherited cardiomyopathies are genetically heterogeneous myocardial disorders associated with heart failure, arrhythmia and sudden cardiac death. Next-generation sequencing has increased the detection of rare variants, but many remain variants of uncertain significance because population, computational, segregation and clinical evidence alone may not establish pathogenicity. Functional studies can support classification through the ACMG/AMP PS3 and BS3 criteria, although their evidential value depends on biological relevance, assay validation, controls, replication and reproducibility.
Objective: This systematic review aims to evaluate the nature, methodological quality and classification impact of functional evidence reported for genetic variants associated with inherited cardiomyopathies.
Methods: A systematic search will be conducted in selected bibliographic databases from inception to the final search date. Peer-reviewed studies reporting variant-specific functional evaluation in inherited cardiomyopathy will be considered. Two-stage screening, structured data extraction, methodological appraisal and evidence synthesis will be performed according to a prespecified protocol. Experimental models, assay endpoints, controls, replication, statistical analysis, ACMG/AMP functional-criterion application and variant-reclassification outcomes will be examined. Reporting will follow PRISMA 2020.
Anticipated contribution: The review will identify functional approaches that provide robust evidence, clarify limitations that weaken PS3 or BS3 application, determine how functional results have influenced variant classification and identify priorities for assay validation and future research.
Conclusion: The final abstract will be updated after completion of searching, screening, quality assessment and synthesis to report the verified number of included studies, principal findings and evidence-based conclusions. No numerical result or reclassification outcome is asserted at the protocol stage.},
      keywords = {Inherited Cardiomyopathy, Functional Evidence, Genetic Variant, Variant of Uncertain Significance, ACMG/AMP, PS3, BS3, Systematic Review},
      month = {July},
      doi = {https://doi.org/10.64388/IREV10I1-1720206}
  }