ClinVar is a critical resource for clinical genomic interpretation by allowing global sharing of variant classifications and supporting evidence. As ClinVar has grown to over three million submissions over a 10 year period, there has been recognition that some entries in ClinVar are incorrect or out of date. This project will enable a subset of ClinGen biocurators, trained on our approaches, to review submissions in the ClinVar database. We will prioritize the review of conflicting entries in ClinVar, as well as submissions nominated by the community. Intralaboratory conflicts and P/LP vs VUS/LB/B conflicts will be prioritized over VUS vs LB/B conflicts. Curation activities may be focused on certain priority genes such as those for ClinGen Variant Curation Expert Panels to remove easy to resolve conflicts before the expert panel begins working on more challenging variants or variants that require internal data to resolve. 

A submitted record that is deemed outdated, incorrect or unsupported, based on a set of reasons listed below, will be curated by ClinGen as a candidate to be flagged in ClinVar, thereby no longer being included in the overall classification of the variant. Flagged records are still visible in ClinVar to allow users access to any usable evidence and to know that a given submitter may have observed the variant, but they do not contribute to the overall classification for the variant. The candidates for flagging will be sent to the ClinVar team, who will notify labs which records are candidates to be flagged. Submitters will be given 60 days to intervene by updating the record if they wish, before the records are flagged in ClinVar. Submitters are asked to reply if they disagree with any decisions to flag records and they are encouraged to update the record with their evidence and rationale for classification where sufficient evidence is not supplied. However, submitters are not required to update flagged records.

Common reasons for a record to be flagged include:

• Older submissions that are missing recent evidence compared to newer submissions. Note, age of the submission alone is insufficient to flag a record.

• Outlier submissions that conflict with most other submissions without providing evidence to support the conflicting claim. Note, absence of evidence alone is insufficient to flag a record.

• Submissions that appear to have intended to be updated by newer submissions from the same submitter.

• Submissions that cause a conflict based on interpretation for a condition that is not the primary or most relevant (e.g. pathogenic) disease association for the gene. See ClinGen’s guidance for evaluating multiple conditions for a single gene. 

CvC Variant and Gene Curation Discordance

ClinGen supports Gene Curation Expert Panels (GCEPs) that assess the validity of gene-disease relationships (GDRs). Crucially, the classification of a GDR informs the pathogenicity levels assignable to variants within that gene. The CvC discordance project focuses on P/LP variant classifications submitted to ClinVar for GDRs categorized as Limited, Disputed, or Refuted by a ClinGen GCEP. If a submission does not provide new evidence or internal data supporting the GDR, it will be deemed discordant and curated by ClinGen as a candidate to be flagged in ClinVar.