Genetic sequencing technology has created a challenge in medicine: interpreting the vast number of human genetic variations and their connection to health. ClinVar is a publicly accessible resource designed to address this by creating a central database for information on the relationship between genetic variations and human health outcomes. This archive standardizes the interpretation of genetic variants, ensuring patients receive accurate and consistent genetic information. By collecting and organizing data from laboratories globally, ClinVar provides a uniform platform for understanding how changes in DNA might cause disease or affect drug response.
What is ClinVar and Why Was It Created
ClinVar is a freely accessible, public archive managed by the National Institutes of Health (NIH). It collects reports of human variations, their classifications for diseases or drug responses, and supporting evidence. This database was created to solve the problem of fragmentation and inconsistency in the interpretation of genetic variants across the medical and scientific communities. Before ClinVar, different laboratories often classified the same genetic change differently, leading to confusion and potential errors in patient care.
The purpose of ClinVar is to standardize the reporting and classification of genetic data, making it actionable for clinicians and researchers globally. Each submission is assigned a Submission to ClinVar (SCV) accession number, tracking the specific data provided by a single submitter. ClinVar aggregates these individual submissions into a single record for a given variant and condition, identified by a Variation to ClinVar (VCV) accession number. This structure allows users to see the entire history of interpretations for a variant and helps establish the overall clinical validity of a genetic change.
The Structure of a ClinVar Entry
Every entry in ClinVar links three essential pieces of information. The first component is the specific genetic variant itself, which can range from a single nucleotide change to a large structural variant, mapped to a reference sequence. The second component is the associated phenotype, which is the disease, trait, or drug response linked to the variant. These two elements define the variant-condition pair being reported.
The third component is the assertion of “clinical significance,” which is the submitter’s interpretation of the variant’s role in the associated condition. This classification informs clinicians and the public about the potential health impact. The categories typically follow a five-tier system: “pathogenic,” “likely pathogenic,” “benign,” “likely benign,” and “Variant of Uncertain Significance” (VUS). A VUS designation is common for rare variants where scientific evidence is insufficient to definitively determine clinical relevance.
The database aggregates all submitted interpretations for a variant to provide an overall consensus classification. This aggregate classification helps users quickly identify agreement or disagreement among submitting organizations. ClinVar also tracks the review status using a star rating system to indicate the level of scrutiny the classification has received. A higher star rating signifies that the interpretation has been reviewed by an expert panel or is based on established practice guidelines.
Ensuring Quality Through Data Submission and Review
The reliability of ClinVar is maintained through a multi-layered system of data submission and expert review. Data flows into the archive primarily from clinical testing laboratories, research groups, and individual physicians. Each submitter must provide their variant classification, the supporting evidence, and the criteria used to arrive at that interpretation.
The submission process is guided by established standards, such as those developed by the American College of Medical Genetics and Genomics (ACMG) for sequence variant interpretation. These standards provide a framework for evaluating different types of evidence, including population frequency, computational predictions, and functional studies. To encourage transparency, submitters must document their assertion criteria, which can be viewed by others to assess the rigor of the classification.
Conflicting interpretations are a consequence of pooling data from diverse sources, and ClinVar actively works to resolve these discrepancies. The database flags variants where different laboratories have provided conflicting interpretations, such as one calling a variant “pathogenic” while another calls it “benign.” The ClinGen project, a related NIH-funded resource, aids this resolution by convening Variant Curation Expert Panels (VCEPs). These VCEPs, composed of scientists and clinicians, perform a detailed, consensus-based review of the evidence. Their final classifications are submitted to ClinVar, often receiving the highest star rating, which promotes a unified understanding.
Transforming Diagnosis and Treatment
The centralized, standardized information within ClinVar affects the practical delivery of genomic medicine. Clinicians and genetic counselors use the database to interpret a patient’s genetic test results, which reduces the diagnostic turnaround time for individuals with rare or complex diseases. Instead of manually searching disparate literature, a doctor can quickly access a variant’s consensus classification and supporting evidence.
The collected data improves the accuracy of risk assessment for hereditary conditions, allowing physicians to provide precise counseling to families. A clear “pathogenic” classification, for instance, helps a family understand their risk and pursue appropriate preventative measures or surveillance. ClinVar also guides precision medicine decisions by providing context for how a variant might affect a patient’s response to a specific drug. The archive is continually updated, ensuring patient care is based on the most current scientific understanding.