Send to

Choose Destination
J Med Genet. 2018 Aug;55(8):530-537. doi: 10.1136/jmedgenet-2017-105216. Epub 2018 Mar 29.

New workflow for classification of genetic variants' pathogenicity applied to hereditary recurrent fevers by the International Study Group for Systemic Autoinflammatory Diseases (INSAID).

Author information

Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
UOC Medical Genetics, Giannina Gaslini Institute, Genova, Italy.
Laboratory of FMF, Amyloidosis and Rare Autoinflammatory Diseases, Sheba Medical Center, Tel Hashomer, Israel.
Genomics Coordination Center, Department of Genetics, University Medical Center Groningen, Groningen, The Netherlands.
Department of Immunology, Hospital Clinic-IDIBAPS, Barcelona, Spain.
Laboratory of Rare and Autoinflammatory Diseases, CHU Montpellier, Montpellier University, INSERM U1183, Montpellier, France.
National Amyloidosis Centre, Division of Medicine, UCL, Royal Free Hospital, London, UK.
Great Ormond Street Institute of Child Health (ICH), University College London, London, UK.
Department of Medical Biology, Hacettepe University Faculty of Medicine, Ankara, Turkey.
Department of Pediatrics, University of California, San Diego, California, USA.
Contributed equally



Hereditary recurrent fevers (HRFs) are rare inflammatory diseases sharing similar clinical symptoms and effectively treated with anti-inflammatory biological drugs. Accurate diagnosis of HRF relies heavily on genetic testing.


This study aimed to obtain an experts' consensus on the clinical significance of gene variants in four well-known HRF genes: MEFV, TNFRSF1A, NLRP3 and MVK.


We configured a MOLGENIS web platform to share and analyse pathogenicity classifications of the variants and to manage a consensus-based classification process. Four experts in HRF genetics submitted independent classifications of 858 variants. Classifications were driven to consensus by recruiting four more expert opinions and by targeting discordant classifications in five iterative rounds.


Consensus classification was reached for 804/858 variants (94%). None of the unsolved variants (6%) remained with opposite classifications (eg, pathogenic vs benign). New mutational hotspots were found in all genes. We noted a lower pathogenic variant load and a higher fraction of variants with unknown or unsolved clinical significance in the MEFV gene.


Applying a consensus-driven process on the pathogenicity assessment of experts yielded rapid classification of almost all variants of four HRF genes. The high-throughput database will profoundly assist clinicians and geneticists in the diagnosis of HRFs. The configured MOLGENIS platform and consensus evolution protocol are usable for assembly of other variant pathogenicity databases. The MOLGENIS software is available for reuse at; the specific HRF configuration is available at The HRF pathogenicity classifications will be published on the INFEVERS database at


genetic diagnosis; hereditary recurrent fever; infevers; molgenis; pathogenicity classification

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center