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

Jiale Xiang,Haiyan Yang,Jiyun Yang,Qiang Chen,Zhiyu Peng,Qing Zhou,Lisha Chen,Chengcheng Sun

doi:10.1038/s41598-019-57335-5

Abstract

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.

Highlights

High-frequency disease-causing alleles exist, but their number is rather small
Whiffin et al curated 43 variants classified in ClinVar as pathogenic (P)/likely pathogenic (LP) that were insufficiently rare in at least one ExAC population and found that 42 of them should be reclassified as variant of uncertain significance (VUS)[6]
We focused on P and LP variants found in ClinVar without conflicting interpretations and which were common, defined here as having an allele frequency greater than 0.5% in at least one ancestry in The Genome Aggregation Database[7]

Summary

Introduction

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. ClinVar is a freely available, public archive of interpretations of clinically relevant variants which has received an increasing number of submissions globally[1] It provides a site for data sharing among researchers, laboratories, expert groups, and patients, improving the accuracy of variant interpretation[2]. The accurate interpretation of these variants has a significant impact in clinical and research settings Their pathogenicity affects the gene-specific allele frequency thresholds used as evidence for pathogenic or benign variant interpretation[4]. We focused on P and LP variants found in ClinVar without conflicting interpretations and which were common, defined here as having an allele frequency greater than 0.5% in at least one ancestry in The Genome Aggregation Database (gnomAD)[7]. 83 Variants were not compatible with ACMG/AMP criteria 18 were classified as “risk factors”, “protective”, or “other” 11 were somatic 54 were inconsistent with Mendelian disease*

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