With the advent of precision and genomic medicine, a critical issue is whether a disease gene variant is pathogenic or benign. Such is the case for the three autosomal dominant acute hepatic porphyrias (AHPs), including acute intermittent porphyria, hereditary coproporphyria, and variegate porphyria, each resulting from the half-normal enzymatic activities of hydroxymethylbilane synthase, coproporphyrinogen oxidase, and protoporphyrinogen oxidase, respectively. To date, there is no public database that documents the likely pathogenicity of variants causing the porphyrias, and more specifically, the AHPs with biochemically and clinically verified information. Therefore, an international collaborative with the European Porphyria Network and the National Institutes of Health/National Center for Advancing Translational Sciences/National Institute of Diabetes and Digestive and Kidney Diseases (NIH/NCATS/NIDDK)-sponsored Porphyrias Consortium of porphyria diagnostic experts is establishing an online database that will collate biochemical and clinical evidence verifying the pathogenicity of the published and newly identified variants in the AHP-causing genes. The overall goal of the International Porphyria Molecular Diagnostic Collaborative is to determine the pathogenic and benign variants for all eight porphyrias. Here we describe the overall objectives and the initial efforts to validate pathogenic and benign variants in the respective heme biosynthetic genes causing the AHPs.

1st Faculty of Medicine Charles University Prague Prague Czech Republic

Biochemistry and Molecular Genetics Department Hospital Clínic IDIBAPS University of Barcelona Barcelona Spain

Centre Français des Porphyries Hôpital Louis Mourier Assistance Publique Hôpitaux de Paris Colombes and Centre de Recherche sur l'Inflammation UMR1149 INSERM Université Paris Diderot Paris France

Department of Genetics and Genomic Sciences Icahn School of Medicine at Mount Sinai New York NY USA

Department of Internal Medicine University of Utah Salt Lake City UT USA

Department of Medical Biochemistry and Immunology University Hospital of Wales Cardiff UK

Department of Medicine University of California San Francisco CA USA

Department of Medicine Wake Forest University Winston Salem NC USA

Department of Preventive Medicine and Community Health University of Texas Medical Branch Galveston TX USA

Dipartimento di Medicina Interna Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico Università degli Studi di Milano Milan Italy

Institute of Medical Genetics University Hospital of Wales Cardiff UK

Norwegian Porphyria Centre Department of Medical Biochemistry and Pharmacology Haukeland University Hospital Bergen Norway

Norwegian Porphyria Centre Department of Medical Biochemistry and Pharmacology Haukeland University Hospital Bergen Norway The Norwegian Quality Improvement of Laboratory Examinations Haraldsplass Deaconness Hospital Bergen Medical Faculty University of Bergen Bergen Norway

Porphyria Center Rotterdam Center for Lysosomal and Metabolic Disorders Department of Internal Medicine Erasmus MC University Medical Center Rotterdam The Netherlands

Porphyria Centre Sweden Centre for Inherited Metabolic Diseases Karolinska Institutet Karolinska University Hospital Stockholm Sweden

Porphyria Research Unit Department of Medicine University Central Hospital of Helsinki Helsinki Finland

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