Scope of Work
- Adapt ACMG classification criteria for genes associated with inherited cardiomyopathy
- Phase 1: MYH7 for Hypertrophic Cardiomyopathy (HCM), Dilated Cardiomyopathy (DCM), Restrictive Cardiomyopathy (RCM), and Left Ventricular Non-Compaction (LVNC).
- Phase 2: Evaluate applicability of the rules developed for MYH7 for all other HCM genes and adapt further if need be. The expectation is that most rules developed for MYH7 will apply without further modification to these genes.
- Note: Using the work of the cardiomyopathy gene-disease curation team, genes will be added as they are approved by this body as having definitive or strong evidence for association with disease. This working group is currently (2017) finalizing their review of HCM associated genes.
- Use modified rules to classify ALL variants in the public domain (ClinGen, HGMD, Locus Specific Databases).
- Phase 1: MYH7
- Phases 2 likely to follow the sequence above.
Development of modified ACMG/AMP framework for MYH7
The adaptation of the ACMG/AMP rules for MYH7 was carried out in three stages including (1) a systematic review of all rules and the development of proposed adjustments by the core task team and approved by the CMP-EP, (2) testing of the proposed draft rules using a representative set of 60 MYH7 variants and (3) refining rule adjustments as needed based on scenarios encountered during the testing phase. See Kelly et al. (in preparation) for further details.
Variants were selected to a) represent a realistic spectrum of variant types for MYH7, b) test as many rules as possible, c) cover a range of classifications and d) have discrepant ClinVar assertions.
- Representing the predominant pathogenic MYH7 variant type, 50/60 variants (83.3%) were missense changes with the remaining comprising small indels, silent, and intronic/splice variants.
- Variants were selected based upon available data including 53 (88.3%) that were listed in HGMD, (indicating that they were listed in at least 1 publication), 35 (58.3%) with segregation data of varying strengths, 11 (18.3%) with published functional evidence, and 8 (13.3%) that were reported de novo in at least once case.
- To represent a broad spectrum of classifications and evidence levels, the 60 variants included 21 pathogenic (42%), 9 likely pathogenic (18%), 24 VUS (28%), and 6 likely benign variants as classified at the time of selection by the LMM.
- Priority was given to variants with discordant classifications between labs with cardiovascular testing experience in ClinVar, including 22 (36.7%) pathogenic/likely pathogenic and VUS, 5 (8.3%) VUS and likely benign/benign, and 1 that was discordant between pathogenic/likely pathogenic and likely benign.