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dc.contributor.authorKelly, MAen_US
dc.contributor.authorCaleshu, Cen_US
dc.contributor.authorMorales, Aen_US
dc.contributor.authorBuchan, Jen_US
dc.contributor.authorWolf, Zen_US
dc.contributor.authorHarrison, SMen_US
dc.contributor.authorCook, Sen_US
dc.contributor.authorDillon, MWen_US
dc.contributor.authorGarcia, Jen_US
dc.contributor.authorHaverfield, Een_US
dc.contributor.authorJongbloed, JDHen_US
dc.contributor.authorMacaya, Den_US
dc.contributor.authorManrai, Aen_US
dc.contributor.authorOrland, Ken_US
dc.contributor.authorRichard, Gen_US
dc.contributor.authorSpoonamore, Ken_US
dc.contributor.authorThomas, Men_US
dc.contributor.authorThomson, Ken_US
dc.contributor.authorVincent, LMen_US
dc.contributor.authorWalsh, Ren_US
dc.contributor.authorWatkins, Hen_US
dc.contributor.authorWhiffin, Nen_US
dc.contributor.authorIngles, Jen_US
dc.contributor.authorvan Tintelen, JPen_US
dc.contributor.authorSemsarian, Cen_US
dc.contributor.authorWare, JSen_US
dc.contributor.authorHershberger, Ren_US
dc.contributor.authorFunke, Ben_US
dc.coverage.spatialUnited Statesen_US
dc.date.accessioned2019-02-27T10:05:00Z
dc.date.issued2018-03en_US
dc.identifierhttps://www.ncbi.nlm.nih.gov/pubmed/29300372en_US
dc.identifiergim2017218en_US
dc.identifier.citationGenet Med, 2018, 20 (3), pp. 351 - 359en_US
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3104
dc.identifier.eissn1530-0366en_US
dc.identifier.doi10.1038/gim.2017.218en_US
dc.description.abstractPurposeIntegrating 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.en_US
dc.format.extent351 - 359en_US
dc.languageengen_US
dc.language.isoengen_US
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en_US
dc.subjectAllelesen_US
dc.subjectCardiac Myosinsen_US
dc.subjectCardiomyopathiesen_US
dc.subjectClinical Decision-Makingen_US
dc.subjectExpert Testimonyen_US
dc.subjectGene Frequencyen_US
dc.subjectGenetic Diseases, Inbornen_US
dc.subjectGenetic Testingen_US
dc.subjectGenetic Variationen_US
dc.subjectHumansen_US
dc.subjectMyosin Heavy Chainsen_US
dc.subjectPhenotypeen_US
dc.subjectReproducibility of Resultsen_US
dc.titleAdaptation and validation of the ACMG/AMP variant classification framework for MYH7-associated inherited cardiomyopathies: recommendations by ClinGen's Inherited Cardiomyopathy Expert Panel.en_US
dc.typeJournal Article
dcterms.dateAccepted2017-10-24en_US
rioxxterms.versionofrecord10.1038/gim.2017.218en_US
rioxxterms.licenseref.startdate2018-03en_US
rioxxterms.typeJournal Article/Reviewen_US
dc.relation.isPartOfGenet Meden_US
pubs.issue3en_US
pubs.notesNot knownen_US
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Genetics and Epidemiology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Genetics and Epidemiology/Molecular & Population Genetics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Molecular & Population Genetics
pubs.publication-statusPublisheden_US
pubs.volume20en_US
pubs.embargo.termsNot knownen_US
icr.researchteamMolecular & Population Geneticsen_US
dc.contributor.icrauthorWhiffin, Nicolaen_US


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