The progression of the ClinGen gene clinical validity classification over time. Issue 11 (11th October 2018)

• Record Type: Journal Article
• Authors: McGlaughon, Jennifer L.; Goldstein, Jennifer L.; Thaxton, Courtney; Hemphill, Sarah E.; Berg, Jonathan S.
• Other Names: Rehm Heidi L. guestEditor.; Berg Jonathan S. guestEditor.; Plon Sharon E. guestEditor.
• Is Part Of: Human mutation. Volume 39:Issue 11(2018)
• Page Start: 1494
• Page End: 1504
• Publication Date: 2018-10-11
• Subjects: ClinGen -- Clinical Genome Resource -- clinical validity -- curation -- gene‐disease association -- reevaluation; Human chromosome abnormalities -- Periodicals; Mutation (Biology) -- Periodicals; 616.04205
• DOI: 10.1002/humu.23604
• Languages: English
• ISSNs: 1059-7794

Abstract

Abstract: In order for ClinGen to maintain up‐to‐date gene‐disease clinical validity classifications for use by clinicians and clinical laboratories, an appropriate timeline for reevaluating curated gene‐disease associations will need to be determined. To provide guidance on how often a gene‐disease association should be recurated, a retrospective analysis of 30 gene curations was performed. Curations were simulated at one‐year intervals starting with the year of the first publication to assert disease‐causing variants in the gene to observe trends in the classification over time, as well as factors that influenced changes in classification. On average, gene‐disease associations spent the least amount of time in the "Moderate" classification before progressing to "Strong" or "Definitive." In contrast, gene‐disease associations that spent five or more years in the "Limited" classification were most likely to remain "Limited" or become "Disputed/Refuted." Large population datasets contributed to the reclassification of several gene‐disease associations from "Limited" to "Disputed/Refuted." Finally, recent advancements in sequencing technology correlated with an increase in the quantity of case‐level evidence that was curated per paper. This study provided a number of key points to consider when determining how often to recurate a gene‐disease association. Abstract : Maintaining the most current ClinGen gene‐disease clinical validity classifications requires an appropriate timeline for re‐evaluating curated gene‐disease associations. In order to provide guidance on how often a gene‐disease association should be re‐evaluated, a retrospective analysis of 30 gene curations was performed at one‐year intervals to identify trends in the classification over time and factors that influenced changes in classification. This study provides key consideration points for determining the most effective timeline for re‐evaluating gene‐disease associations.