What Is the ClinVar Database and How Is It Used?

The ClinVar database is a public resource that catalogs the relationships between human genetic variations and health. Managed by the National Center for Biotechnology Information (NCBI), this freely accessible archive serves as a global repository for information on how specific changes in our DNA are connected to diseases. Its primary purpose is to aggregate these findings from various sources, making them available to clinicians, researchers, and the public. By centralizing this information, ClinVar helps advance our understanding of genetic health and provides a foundational tool for genetic testing.

The information housed within ClinVar is not generated by the NCBI itself, but rather collected from a global community of contributors. This collaborative approach creates a bridge between genetics and clinical medicine and ensures a continuously updated resource.

The Core Data within ClinVar

At the heart of ClinVar’s data structure is the relationship between a “genetic variant” and a “phenotype.” A genetic variant is a specific alteration in the DNA sequence. While many variants are harmless, some can affect how a gene functions, leading to a particular health outcome, which is known as the phenotype.

ClinVar’s role is to document the asserted link between a variant and its associated phenotype. For each entry, the database includes the evidence provided by the submitter to support this connection. This evidence can come from population studies, functional analyses of the gene, or patient case studies.

A well-known example is the connection between variants in the BRCA1 gene and an increased risk for hereditary breast and ovarian cancer. A specific variant, such as c.181T>G, is documented in ClinVar alongside its associated phenotype. The database then displays the submitted evidence that supports this link, providing a transparent view of the data. This documentation allows users to see the scientific basis for a conclusion. ClinVar archives both germline (inherited) variants and somatic (acquired) variants, which are often associated with cancer.

Sources of Information and Submission Process

The data within ClinVar is contributed by external organizations, making it a collaborative effort. The main contributors are clinical diagnostic laboratories that perform genetic testing for patients, identifying variants and interpreting their potential health implications in a real-world clinical context. Research laboratories also submit data from studies focused on understanding the genetic underpinnings of specific diseases. Expert panels, which are groups of specialists who review evidence for particular genes or diseases, also contribute their consensus interpretations to the database.

The submission process is designed to capture the interpretation of the variant from the contributing group. Submitters provide their analysis of a variant’s significance based on the evidence they have gathered. This information is uploaded to ClinVar, where it is standardized and made publicly available. This model means that ClinVar serves as an aggregator of interpretations, faithfully representing the assertions made by its contributors.

Understanding Clinical Significance Classifications

To make sense of the submitted data, ClinVar uses a standardized five-tier system to classify the clinical significance of genetic variants. This framework helps users understand the likelihood that a particular variant is associated with a disease.

The classifications are:

• Pathogenic: Strong evidence to support a variant’s role in causing disease.
• Likely Pathogenic: A high likelihood of the variant being disease-causing, but with slightly less evidence than for a pathogenic variant.
• Benign: Strong evidence that the variant is harmless.
• Likely Benign: A high probability of it being harmless.
• Variant of Uncertain Significance (VUS): Not enough evidence to definitively classify it as either pathogenic or benign.

The VUS category is for variants where the available evidence is insufficient to reach a conclusive verdict. A VUS is not necessarily a cause for alarm, but rather a reflection of the current limits of scientific knowledge.

These classifications are not static and can be updated over time as new scientific evidence becomes available. A variant initially classified as a VUS may be reclassified as pathogenic or benign as more research is conducted and more data is submitted to ClinVar.

Addressing Conflicting Interpretations

Because ClinVar aggregates data from many different sources, it is not uncommon for conflicting interpretations of the same variant to exist. For example, one laboratory might classify a variant as a VUS, while another, with access to different evidence, may classify it as “Likely Pathogenic.” ClinVar does not resolve these conflicts but instead displays all submitted interpretations transparently.

To help users navigate these discrepancies, ClinVar has implemented a “review status” system, often represented by stars. This system provides a measure of the level of confidence and consensus behind a classification, offering a quick visual guide to the strength of the evidence.

• A one-star rating indicates that a submission has met basic criteria, but the evidence has not been extensively reviewed.
• A two-star rating is given when multiple submitters provide the same interpretation, suggesting a degree of consensus.
• A three-star rating is reserved for interpretations reviewed and approved by an expert panel.
• The highest level, a four-star rating, is given to variants whose interpretations are included in clinical practice guidelines.

This star system is a tool for users to assess the weight of the evidence for a particular variant classification. It allows them to understand not only what has been reported but also the level of scrutiny and agreement behind that report.