Computational and Expert Manual Curation Led to Medically Significant Changes in Pathogenicity
To assess differences in variant interpretation between the DVD and ClinVar and HGMD, we compared the number of downgraded (from more severe to more benign) and upgraded (from more benign to more severe) classifications (Figures 2C–2F). Of the variants listed in the DVD, 7,056 are found in ClinVar (filtered to represent each variant by only its most pathogenic classification). Of these variants, 175 are unique to ClinVar (Figure 1B). There was classification agreement for 6,039 (85.6%) variants. Of the 1,017 (14.4%) discordant calls, classification discrepancies of one degree were most common (715 of 1,017 changes), with the DVD being more likely to downgrade a ClinVar classification (772 downgrades versus 245 upgrades) (Figure 2C). Major classification changes for deafness-related variants that resulted in medically significant differences (variants that were upgraded to or downgraded from P/LP) were identified for 72 variants. Of these variants, there were 53 up-classifications of a variant by the DVD to P/LP and 19 down-classifications of a variant from P/LP (Figure 2E).
A total of 7,845 DVD variants are found in HGMD. DVD and HGMD classifications were concordant in 7,458 (95%) cases. Of the 387 (5%) discordant calls, classification discrepancies of three degrees were most common (132 of the 387 changes), with DVD downgrades of HGMD calls more common than upgrades (312 downgrades versus 75 upgrades) (Figure 2D). There were 244 major classification changes that resulted in medically significant differences, with all except two representing downgrades by the DVD from an HGMD call of P/LP (Figure 2F).
Following computational and manual curation, variants in 101 genes were reclassified in the DVD. These reclassifications included major categorical changes representing medically significant changes (P/LP versus VUS/LB/B) for 300 variants in 52 genes (Table S3). Of the 20% of genes carrying the greatest number of medically significant differences, six are associated with the diagnosis of Usher syndrome (Figure 2G, Table S4). For both ClinVar and HGMD, the same five genes carry the greatest number of major categorical changes (USH2A [MIM: 608400], SLC26A4 [MIM: 605646], GJB2, MYO7A [MIM: 276903], CDH23 [MIM: 605516]) (Figure 2G, Table S4). The remaining frequently impacted genes are WFS1 (MIM: 606201) (DFNA6/14/38 [MIM: 600965] and Wolfram syndrome), USH1C (MIM: 605242) (DFNB18A [MIM: 602092] and USH1C [MIM: 276904]), ADGRV1 (MIM: 602851) (USH2C [MIM: 605472]), and MYO15A (MIM: 602666) (DFNB3 [MIM: 600316]).