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.

Targeted panel sequencing in pediatric primary cardiomyopathy supports a critical role of TNNI3

“…Seven MYH7 missense variants were classified as pathogenic or probably pathogenic. All of these seven missense variants localize within the HCM cluster region MYH7_167‐931 supporting their pathogenic character . Moreover, the high detection rate of already known missense variants (only three novel MYH7 variants out of 12) solicits reliable MYH7 disease variant identification as well as classification .…”

CardioVAI: An automatic implementation of ACMG-AMP variant interpretation guidelines in the diagnosis of cardiovascular diseases

“…CMP‐EP reports the same variant as VUS, since it is reported at a lower allele frequency in ExAC only (0.0074%). Interestingly, another variant (p.Arg787His) has been classified as LB by CardioVAI since it is reported in ExAC with frequency 0.022% (thus activating the BS1), however the same variant has been interpreted as VUS by the CMP‐EP and BS1 was not triggered in this case (Kelly et al., ). The third case is an LP variant that CardioVAI classifies as VUS (p.Arg1045Cys).…”

“…We further validated CardioVAI by comparing its ACMG–AMP‐based classification on 60 MYH7‐related variants assessed by ClinGen's Inherited Cardiomyopathy Expert Panel (CMP‐EP) (Kelly et al., ). In this work, ACMG–AMP guidelines have been applied to MYH7 gene, providing a set of adjusted criteria and final classification rules.…”

“…Notably, we defined and added a new supporting benign criterion (BP8, see ). Moreover, we have incorporated recent adaptation of ACMG–AMP guidelines for MYH7‐related variants (Kelly et al., ) proposed by the ClinGen Cardiomyopathy Expert Panel (CMP‐EP). As a consequence, MYH7 variants will be classified according to CMP‐EP recommendations.…”

Rapid communication of efforts to resolve differences or update variant interpretations in ClinVar through case-level data sharing

“…This rapid exchange also led the family to continue the pregnancy without concern for an adverse outcome. Recent publications from ClinGen have also demonstrated the benefit of sharing unpublished data from clinical laboratories to resolve discrepancies or reclassify VUSs (Gelb et al 2018; Kelly et al 2018). The Editors of Cold Spring Harbor Molecular Case Studies encourage these interlaboratory exchanges and have generated an article type to allow this work to be recognized and more rapidly captured in a documented form that the community can access.…”