title: Integration of 60,000 exomes and ACMG guidelines question the role of Catecholaminergic Polymorphic Ventricular Tachycardia-associated variants.
abstract: Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) is a highly lethal cardiac arrhythmia disease occurring during exercise or psychological stress. CPVT has an estimated prevalence of 1:10,000 and has mainly been associated with variants in calcium-regulating genes. Identification of potential false-positive pathogenic variants was conducted by searching the Exome Aggregation Consortium (ExAC) database (n = 60,706) for variants reported to be associated with CPVT. The pathogenicity of the interrogated variants was assessed using guidelines from the American College of Medical Genetics and Genomics (ACMG) and in silico prediction tools. Of 246 variants 38 (15%) variants previously associated with CPVT were identified in the ExAC database. We predicted the CPVT prevalence to be 1:132. The ACMG standards classified 29% of ExAC variants as pathogenic or likely pathogenic. The in silico predictions showed a reduced probability of disease-causing effect for the variants identified in the exome database (p < 0.001). We have observed a large overrepresentation of previously CPVT-associated variants in a large exome database. Based on the frequency of CPVT in the general population, it is less likely that the previously proposed variants are associated with a highly penetrant monogenic form of the disease.
authors.affiliation: Danish National Research Foundation Centre for Cardiac Arrhythmia, Department of Biomedical Sciences, University of Copenhagen, Denmark.|Laboratory for Molecular Cardiology, The Heart Centre, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: C
authors.identifier: 0000-0002-7724-544X
authors.initials: C
authors.lastname: Paludan-Müller
authors.affiliation: Danish National Research Foundation Centre for Cardiac Arrhythmia, Department of Biomedical Sciences, University of Copenhagen, Denmark.|Laboratory for Molecular Cardiology, The Heart Centre, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: G
authors.initials: G
authors.lastname: Ahlberg
authors.affiliation: Danish National Research Foundation Centre for Cardiac Arrhythmia, Department of Biomedical Sciences, University of Copenhagen, Denmark.|Laboratory for Molecular Cardiology, The Heart Centre, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: J
authors.initials: J
authors.lastname: Ghouse
authors.affiliation: Danish National Research Foundation Centre for Cardiac Arrhythmia, Department of Biomedical Sciences, University of Copenhagen, Denmark.|Laboratory for Molecular Cardiology, The Heart Centre, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: C
authors.initials: C
authors.lastname: Herfelt
authors.affiliation: Danish National Research Foundation Centre for Cardiac Arrhythmia, Department of Biomedical Sciences, University of Copenhagen, Denmark.|Laboratory for Molecular Cardiology, The Heart Centre, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.|Department of Clinical Medicine, Faculty of Health Sciences, Copenhagen, Denmark.
authors.forename: J H
authors.initials: JH
authors.lastname: Svendsen
authors.affiliation: Danish National Research Foundation Centre for Cardiac Arrhythmia, Department of Biomedical Sciences, University of Copenhagen, Denmark.|Laboratory for Molecular Cardiology, The Heart Centre, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.|Department of Clinical Medicine, Faculty of Health Sciences, Copenhagen, Denmark.
authors.forename: S
authors.initials: S
authors.lastname: Haunsø
authors.affiliation: Laboratory of Experimental Cardiology, Department of Biomedicine, University of Copenhagen, Copenhagen, Denmark.|Department of Cardiology, Herlev and Gentofte University Hospitals, Copenhagen, Denmark.
authors.forename: J K
authors.initials: JK
authors.lastname: Kanters
authors.affiliation: Danish National Research Foundation Centre for Cardiac Arrhythmia, Department of Biomedical Sciences, University of Copenhagen, Denmark.|Laboratory for Molecular Cardiology, The Heart Centre, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: M S
authors.initials: MS
authors.lastname: Olesen
mesh_terms: D000483:Alleles; D000574:American Medical Association; D030541:Databases, Genetic; D059472:Exome / Q000235:genetics*; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005826:Genetics, Medical; D023281:Genomics; D005838:Genotype; D017408:Guidelines as Topic; D006801:Humans; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D017180:Tachycardia, Ventricular / Q000235:genetics*; D014481:United States; D000098850:Polymorphic Catecholaminergic Ventricular Tachycardia
keywords: ACMG; CPVT; Catecholaminergic Polymorphic Ventricular Tachycardia; ExAC; Genetics; HGMD