Fig. 2

Variant reclassification in ClinVar and HGMD. A Reclassification paths of P/LP screened IEM ClinVar variants from 2014 (or first submission thereafter) to 2020, visualized in a Sankey plot in which line width represents the number of reclassified variants. Blue lines indicate increasing pathogenicity or review stars, orange lines indicate increasing benignity or reduced confidence of pathogenicity, and gray lines indicate no change. Numbers in parentheses provide variant counts of initial and final classifications for each category. B Reclassification paths of DM and DM? HGMD variants from 2014 to 2020. Disease-associated polymorphism (DP) and disease-associated polymorphism with additional functional evidence (DFP) are used to classify variants associated with disease but not necessarily disease-causing. Variants are retired (R) when they are found to no longer be associated with disease. C Reclassification paths of ClinVar variants from P/LP or B/LB to VUS or Conflicting. We plot only variants that could be assigned to a principal ancestry. Variant paths are colored by ancestry as in D. D Rate of reclassification of variants shown in C when normalized by the historical ancestry composition of variants in ClinVar. E Reclassification paths of ClinVar variants from VUS or Conflicting to P/LP or B/LB. F Rate of reclassification of variants shown in E when normalized by historical ancestry composition of variants in ClinVar