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Genet Med. 2019 Jun;21(6):1417-1424. doi: 10.1038/s41436-018-0353-5. Epub 2018 Nov 19.

Trajectory of exonic variant discovery in a large clinical population: implications for variant curation.

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Geisinger Clinic, Geisinger Health System, Danville, PA, USA.
Geisinger Clinic, Geisinger Health System, Danville, PA, USA.



Precision health initiatives and reduced sequencing costs are driving large-scale human genome analyses. Genetic variant curation is a bottleneck in clinical applications. The burden of variant curation can be high for newly discovered variants because they are less likely to have undergone previous clinical annotation; the rate of discovery of genetic variants in large clinical populations has not been empirically determined.


We determined the rate of accrual of unique sequence variants in 90,000 exome sequences. Separate analyses were done for 17,267 autosomal genes and a subset of 74 actionable genes; the effect of relatedness in the cohort was also determined.


Variant discovery showed a nonlinear growth pattern. The rate of unique variant accrual decreased as the database size increased; by 90,000 exomes 97% of all projected coding and splicing variants had been observed. Variants in 74 actionable genes showed a similar pattern. Family relatedness slightly reduced the rate of discovery of unique variants.


The heaviest burden of interpretation for genetic variants occurs early and diminishes as the database size increases. Our data provide a framework for scaling pathogenic genetic variant discovery and curation, a critical element of patient care in the era of precision health.


exome sequencing; genomic screening; secondary findings; sequence scaling; variant curation


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