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

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

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Item Type: Article
Status: Published
Official URL: https://doi.org/10.1038/gim.2017.218
Journal or Publication Title: Genetics in Medicine
Volume: 20
Number: 3
Page Range: pp. 351-359
Date: 2018
Divisions: Molecular Cardiology
Depositing User: General Admin
Identification Number: 10.1038/gim.2017.218
ISSN: 1098-3600
Date Deposited: 03 Jan 2021 22:49
Abstract:

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.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.

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Kelly, Melissa A
UNSPECIFIED
Caleshu, Colleen
UNSPECIFIED
Morales, Ana
UNSPECIFIED
Buchan, Jillian
UNSPECIFIED
Wolf, Zena
UNSPECIFIED
Harrison, Steven M
UNSPECIFIED
Cook, Stuart
UNSPECIFIED
Dillon, Mitchell W
UNSPECIFIED
Garcia, John
UNSPECIFIED
Haverfield, Eden
UNSPECIFIED
Jongbloed, Jan D H
UNSPECIFIED
Macaya, Daniela
UNSPECIFIED
Manrai, Arjun
UNSPECIFIED
Orland, Kate
UNSPECIFIED
Richard, Gabriele
UNSPECIFIED
Spoonamore, Katherine
UNSPECIFIED
Thomas, Matthew
UNSPECIFIED
Thomson, Kate
UNSPECIFIED
Vincent, Lisa M
UNSPECIFIED
Walsh, Roddy
UNSPECIFIED
Watkins, Hugh
UNSPECIFIED
Whiffin, Nicola
UNSPECIFIED
Ingles, Jodie
UNSPECIFIED
van Tintelen, J Peter
UNSPECIFIED
Semsarian, Christopher
UNSPECIFIED
Ware, James S
UNSPECIFIED
Hershberger, Ray
UNSPECIFIED
Funke, Birgit
UNSPECIFIED
Last Modified: 03 Jan 2021 22:49
URI: https://eprints.centenary.org.au/id/eprint/518

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