Human MutationVolume 39, Issue 11 p. 1517-1524 SPECIAL ARTICLE Recommendations for interpreting the loss of function PVS1 ACMG/AMP variant criterion Ahmad N. Abou Tayoun, Corresponding Author Ahmad N. Abou Tayoun Ahmad.Tayoun@ajch.ae orcid.org/0000-0002-9134-1673 The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania Current affiliation: Department of Genetics, Al Jalila Children's Specialty Hospital, Dubai, UAE. Correspondence Ahmad N. Abou Tayoun, Al Jalila Children's Specialty Hospital, Dubai, UAE. Email: Ahmad.Tayoun@ajch.aeSearch for more papers by this authorTina Pesaran, Tina Pesaran Ambry Genetics, Aliso Viejo, CaliforniaSearch for more papers by this authorMarina T. DiStefano, Marina T. DiStefano Laboratory for Molecular Medicine, Partners Healthcare Personalized Medicine, Cambridge, MassachusettsSearch for more papers by this authorAndrea Oza, Andrea Oza orcid.org/0000-0003-3125-7119 Laboratory for Molecular Medicine, Partners Healthcare Personalized Medicine, Cambridge, MassachusettsSearch for more papers by this authorHeidi L. Rehm, Heidi L. Rehm orcid.org/0000-0002-6025-0015 Laboratory for Molecular Medicine, Partners Healthcare Personalized Medicine, Cambridge, Massachusetts Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts The Broad Institute of MIT and Harvard, Cambridge, MassachusettsSearch for more papers by this authorLeslie G. Biesecker, Leslie G. Biesecker Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MarylandSearch for more papers by this authorSteven M. Harrison, Steven M. Harrison orcid.org/0000-0002-9614-9111 Laboratory for Molecular Medicine, Partners Healthcare Personalized Medicine, Cambridge, MassachusettsSearch for more papers by this authorClinGen Sequence Variant Interpretation Working Group (ClinGen SVI), ClinGen Sequence Variant Interpretation Working Group (ClinGen SVI)Search for more papers by this author Ahmad N. Abou Tayoun, Corresponding Author Ahmad N. Abou Tayoun Ahmad.Tayoun@ajch.ae orcid.org/0000-0002-9134-1673 The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania Current affiliation: Department of Genetics, Al Jalila Children's Specialty Hospital, Dubai, UAE. Correspondence Ahmad N. Abou Tayoun, Al Jalila Children's Specialty Hospital, Dubai, UAE. Email: Ahmad.Tayoun@ajch.aeSearch for more papers by this authorTina Pesaran, Tina Pesaran Ambry Genetics, Aliso Viejo, CaliforniaSearch for more papers by this authorMarina T. DiStefano, Marina T. DiStefano Laboratory for Molecular Medicine, Partners Healthcare Personalized Medicine, Cambridge, MassachusettsSearch for more papers by this authorAndrea Oza, Andrea Oza orcid.org/0000-0003-3125-7119 Laboratory for Molecular Medicine, Partners Healthcare Personalized Medicine, Cambridge, MassachusettsSearch for more papers by this authorHeidi L. Rehm, Heidi L. Rehm orcid.org/0000-0002-6025-0015 Laboratory for Molecular Medicine, Partners Healthcare Personalized Medicine, Cambridge, Massachusetts Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts The Broad Institute of MIT and Harvard, Cambridge, MassachusettsSearch for more papers by this authorLeslie G. Biesecker, Leslie G. Biesecker Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MarylandSearch for more papers by this authorSteven M. Harrison, Steven M. Harrison orcid.org/0000-0002-9614-9111 Laboratory for Molecular Medicine, Partners Healthcare Personalized Medicine, Cambridge, MassachusettsSearch for more papers by this authorClinGen Sequence Variant Interpretation Working Group (ClinGen SVI), ClinGen Sequence Variant Interpretation Working Group (ClinGen SVI)Search for more papers by this author First published: 07 September 2018 https://doi.org/10.1002/humu.23626Citations: 291 ClinGen Sequence Variant Interpretation Working Group Members: Ahmad Abou Tayoun, Al Jalila Children's Specialty Hospital, Dubai, UAE; Jonathan S. Berg, University of North Carolina, Chapel Hill, NC; Leslie G. Biesecker, co-chair, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD; Steven E. Brenner, University of California, Berkeley, Berkeley, CA; Garry Cutting, Johns Hopkins University School of Medicine, Baltimore, MD; Sian Ellard, University of Exeter Medical School, Exeter, UK; Marc Greenblatt, University of Vermont, Larner College of Medicine, Burlington, VT; Steven M. Harrison, co-chair, Broad Institute of MIT/Harvard, Cambridge, MA; Matt Hurles, Wellcome Trust Sanger Institute, Hinxton, UK; Hyunseok P. Kang, Counsyl, San Francisco, CA; Izabela Karbassi, Quest Diagnostics, Athena Diagnostics, Marlborough, MA; Rachel Karchin, Johns Hopkins University, Baltimore, MD; Jessica L. Mester, GeneDx, Inc., Gaithersburg, MD; Robert L. Nussbaum, Invitae, San Francisco, CA; Anne O'Donnell-Luria, Boston Children's Hospital, Boston, MA; Tina Pesaran, Ambry Genetics, Aliso Viejo, CA; Sharon Plon, Baylor College of Medicine, Houston, TX; Heidi Rehm, Massachusetts General Hospital, Boston, MA; Sean Tavtigian, University of Utah School of Medicine, Salt Lake City, UT; Scott Topper, Color Genomics, Burlingame, CA. For the ClinGen/ClinVar Special Issue Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Abstract The 2015 ACMG/AMP sequence variant interpretation guideline provided a framework for classifying variants based on several benign and pathogenic evidence criteria, including a pathogenic criterion (PVS1) for predicted loss of function variants. However, the guideline did not elaborate on specific considerations for the different types of loss of function variants, nor did it provide decision-making pathways assimilating information about variant type, its location, or any additional evidence for the likelihood of a true null effect. Furthermore, this guideline did not take into account the relative strengths for each evidence type and the final outcome of their combinations with respect to PVS1 strength. Finally, criteria specifying the genes for which PVS1 can be applied are still missing. Here, as part of the ClinGen Sequence Variant Interpretation (SVI) Workgroup's goal of refining ACMG/AMP criteria, we provide recommendations for applying the PVS1 criterion using detailed guidance addressing the above-mentioned gaps. Evaluation of the refined criterion by seven disease-specific groups using heterogeneous types of loss of function variants (n = 56) showed 89% agreement with the new recommendation, while discrepancies in six variants (11%) were appropriately due to disease-specific refinements. Our recommendations will facilitate consistent and accurate interpretation of predicted loss of function variants. Citing Literature Supporting Information Filename Description humu23626-sup-0001-tableS1.xlsx20.7 KB Supporting information Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. Volume39, Issue11Special Issue: ClinGen and ClinVar – Enabling Genomics in Precision MedicineNovember 2018Pages 1517-1524 This article also appears in:Editor's Choice Articles RelatedInformation