Documents & Announcements

Adaptation and validation of the ACMG/AMP variant classification framework for MYH7-associated inherited cardiomyopathies: recommendations by ClinGen's Inherited Cardiomyopathy Expert Panel

Melissa A Kelly MS, Colleen Caleshu MS, Ana Morales MS, Jillian Buchan PhD, Zena Wolf PhD, Steven M Harrison PhD, Stuart Cook MD, Mitchell W Dillon MS, John Garcia PhD, Eden Haverfield PhD, Jan D H Jongbloed PhD, Daniela Macaya PhD, Arjun Manrai PhD, Kate Orland MS, Gabriele Richard MD, Katherine Spoonamore MS, Matthew Thomas MS, Kate Thomson BSc, Lisa M Vincent PhD, Roddy Walsh PhD, Hugh Watkins MD PhD, Nicola Whiffin PhD, Jodie Ingles PhD, J Peter van Tintelen MD PhD, Christopher Semsarian MBBS PhD, James S Ware PhD MRCP, Ray Hershberger MD & Birgit Funke PhD for the ClinGen Cardiovascular Clinical Domain Working Group

Abstract

Purpose
Integrating genomic sequencing in clinical care requires standardization of variant interpretation practices. The Clinical Genome Resource has established expert panels to adapt the American College of Medical Genetics and Genomics/Association for Molecular Pathology classification framework for specific genes and diseases. The Cardiomyopathy Expert Panel selected MYH7, a key contributor to inherited cardiomyopathies, as a pilot gene to develop a broadly applicable approach.

Methods
Expert revisions were tested with 60 variants using a structured double review by pairs of clinical and diagnostic laboratory experts. Final consensus rules were established via iterative discussions.

Results
Adjustments represented disease-/gene-informed specifications (12) or strength adjustments of existing rules (5). Nine rules were deemed not applicable. Key specifications included quantitative frameworks for minor allele frequency thresholds, the use of segregation data, and a semiquantitative approach to counting multiple independent variant occurrences where fully controlled case-control studies are lacking. Initial inter-expert classification concordance was 93%. Internal data from participating diagnostic laboratories changed the classification of 20% of the variants (n = 12), highlighting the critical importance of data sharing.

Conclusion
These adapted rules provide increased specificity for use in MYH7-associated disorders in combination with expert review and clinical judgment and serve as a stepping stone for genes and disorders with similar genetic and clinical characteristics.