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Hum Mutat. 2018 Nov;39(11):1494-1504. doi: 10.1002/humu.23604.

The progression of the ClinGen gene clinical validity classification over time.

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Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
Laboratory for Molecular Medicine, Partners Healthcare Personalized Medicine, Cambridge, Massachusetts.


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.


ClinGen; Clinical Genome Resource; clinical validity; curation; gene-disease association; reevaluation

[Available on 2019-11-01]

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