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

Abstract

PurposeIntegrating 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.MethodsExpert 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.ResultsAdjustments 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.ConclusionThese 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.

Figure 1

Summary of ClinGen Inherited Cardiomyopathy Expert Panel (CMP-EP) involvement. Phase 1: Disease/gene and other specifications made to established American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) framework. Phase 2: Selection and review of 60 pilot variants by two independent reviewers. Classifications were then compared and discussed to resolve any conflicts. Phase 3: Additional adjustments to variant classifications. Final: Expert panel variant classifications submitted to ClinVar for public accessibility. Expert panel ratings in ClinVar are denoted with a three-star rating.

Figure 2

Derivation of allele frequency thresholds for rules BA1 and BS1. Disease prevalence = 1/200 individuals (1/400 chromosomes). Penetrance = 30%. % gene contribution = 10.6%. % maximum pathogenic variant contribution (max path. variant) = 2%.

Figure 3

Impact of data sharing on proband counts. Increased proband counts obtained from internal lab data changed the variant classification for eight variants. Hashed lines correspond to the thresholds for supporting (≥2, PS4_Supporting), moderate (≥6, PS4_Moderate), and strong (≥15, PS4). Publicly available data was collected from PubMed, Google, Human Gene Mutation Database Professional, ClinVar, and relevant locus-specific variant databases. Internal laboratory data was collected from the Partners HealthCare Laboratory for Molecular Medicine, Invitae, the Sarcomeric Human Cardiomyopathy Registry (https://theshareregistry.org/), the Australian Genetic Heart Disease Registry (http://www.heartregistry.org.au/), the National Institute for Health Research Cardiovascular Biomedical Research Unit at Royal Brompton Hospital and Imperial College London, and the National Heart Centre Singapore.