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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.

Author information

1
Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
2
Laboratory for Molecular Medicine, Partners Healthcare Personalized Medicine, Cambridge, Massachusetts.

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.

KEYWORDS:

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

PMID:
30311372
PMCID:
PMC6190678
[Available on 2019-11-01]
DOI:
10.1002/humu.23604

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