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.

Expanded carrier screening (ECS) has been demonstrated to increase the detection rate of carriers compared with traditional tests. The aim of this study was to assess the potential value of ECS for clinical application in Southern China, a region with high prevalence of thalassemia and with diverse ethnic groups, and to provide a reference for future implementations in areas with similar population characteristics. A total of 10,476 prenatal/preconception couples from 34 self-reported ethnic groups were simultaneously tested and analyzed anonymously for 11 Mendelian disorders using targeted next-generation sequencing. Overall, 27.49% of individuals without self-reported family history of disorders were found to be carriers of at least 1 of the 11 conditions, and the carrier frequency varied greatly between ethnic groups, ranging from 4.15% to 81.35%. Furthermore, 255 couples (2.43%) were identified as carrier couples at an elevated risk having an affected baby, sixty-five of which would not have been identified through the existing screening strategy, which only detects thalassemia. The modeled risk of fetuses being affected by any of the selected disorders was 531 per 100,000 (95% CI, 497–567 per 100,000). Our data demonstrate the feasibility of ECS, and provide evidence that ECS is a promising alternative to traditional one-condition screening strategies. The lessons learned from this experience should be applicable for other countries or regions with diverse ethnic groups.