ClinVar

What is ClinVar?

ClinVar is a public archive maintained by the NCBI (National Center for Biotechnology Information), part of the US National Institutes of Health (NIH). It gathers, free and openly, the assertions that clinical laboratories, research groups and expert panels submit about the clinical significance of human genetic variants. Landrum and colleagues described the resource in Nucleic Acids Research, in a paper published online in late 2013.

ClinVar does not produce its own classifications. It aggregates those of its submitters and shows whether they agree.

How it works

Each submission links a variant to a condition or phenotype and a classification, usually in the five tiers of the ACMG criteria: pathogenic, likely pathogenic, uncertain significance (VUS), likely benign and benign.

For each variant, ClinVar shows:

• An aggregate classification summarising all submissions. Where they disagree, it is labelled “conflicting interpretations of pathogenicity”.
• Review status (0 to 4 stars), indicating how well supported the classification is. A variant with a single submitter and no assertion criteria scores low; the top levels (3 and 4 stars) go to variants reviewed by a recognised expert panel or included in a practice guideline.
• The evidence and date of each submission, which matters because classifications change over time.

Using it with care

• A low-star or older classification may be out of date.
• Conflicts most often involve variants of uncertain significance.
• Pathogenicity is asserted for a specific condition; the same variant may carry different weight in another context.
• ClinVar is one source of evidence among several, not a diagnostic report.

Example

A clinical genetics laboratory finds a missense variant in a cardiomyopathy gene in a patient’s exome. ClinVar lists two submissions: one calls it a VUS, the other likely pathogenic, with a one-star review status. The clinical scientist reviews each submitter’s evidence, applies the ACMG criteria using the patient’s and family’s data, and reports the variant as a VUS with a recommendation for family segregation studies.

ClinVar at Xenogene

Two different things share almost the same name. ClinVar is the NCBI’s public database described here. Clinvar is also the name of Xenogene’s genetic variant interpretation platform, a separate service that is independent of the public database.

According to its product page, Xenogene’s Clinvar platform classifies variants according to ACMG/AMP criteria and is updated against pathogenicity databases: the sources it draws on include the NCBI’s ClinVar itself, dbSNP, gnomAD, HGMD and OMIM, together with annotation tools and predictive algorithms. In other words, the public database is one of the sources the platform consults, not the product itself. The final interpretation of each variant rests with the professional who requested the analysis.