Reinterpretation of common pathogenic variants in ClinVar revealed a high proportion of downgrades

High-frequency disease-causing alleles exist, but their number is rather small. This study aimed to interpret and reclassify common pathogenic (P) and likely pathogenic (LP) variants in ClinVar and to identify indicators linked with reclassification. We analyzed P/LP variants without conflicting interpretations in ClinVar. Only variants with an allele frequency exceeding 0.5% in at least one ancestry in gnomAD were included. Variants were manually interpreted according to the guidelines of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Of 326 variants retrieved, 217 variants in 173 genes were selected for curation. Overall, 87 (40%) variants were downgraded to benign, likely benign or variant of uncertain significance. Five variants (2%) were found to be more likely to be risk factors. Most of the reclassifications were of variants with a low rank, an older classification, a higher allele frequency, or which were collected through methods other than clinical testing. ClinVar provides a universal platform for users who intend to share the classification variants, resulting in the improved concordance of variant interpretation. P/LP variants with a high allele frequency should be used with caution. Ongoing improvements would further improve the practicability of ClinVar database.