Submitter

ClinVar represents submitters as both organizations and individuals. The infrastructure supporting this content is shared with the NIH Genetic Testing Registry (GTR), dbSNP, and dbVar. Submitters have the right to request anonymity, although to date no submitter has requested this option. Summary data about submissions are provided on the website (http://www.ncbi.nlm.nih.gov/clinvar/submitters/).

Variation

Variation is a key component of ClinVar’s data model, especially to be able to represent variation’s relationship to phenotype. Variation is thus represented both as the sequence at a particular location, or a combination of sequence changes. In other words, ClinVar can represent the interpretation of a single allele, compound heterozygotes, haplotypes, and combinations of alleles in different genes. Variation is modeled in the database as a set of varations, but currently most sets have only one member. The goal is to represent each variation on a reference sequence, but the data flow from some submitters is not amenable to establishing this immediately. Thus free text is accepted.

Variations submitted to ClinVar are compared to variations accessioned by dbSNP or dbVar. If known, ClinVar adds the rs# (dbSNP) or variant call identifier (dbVar) to the RCV record. If novel, the information is submitted to the appropriate variation database to be accessioned, so that the identifiers can be added to ClinVar. In other words, ClinVar does not create new identifiers for locations of variation. Also the archival databases do not note the number of submitters that have contributed information to ClinVar about a variation.That said, to support internal data flows and some public reports ClinVar does assign an internal unique identifier to the sequence change at each location, which is reported in the XML and tab-delimited exports as an integer identifier (Table 1).

Table 1.

Identifiers used by ClinVar

ClinVar reports multiple types of attributes for each variant. HGVS expressions are reported based on the current reference assembly, RefSeqGenes, cDNAs and proteins as appropriate. When there are multiple transcripts for a gene, ClinVar selects one HGVS expression to display as the preferred name. By default, this selection is based on the first reference standard transcript identified by the RefSeqGene/Locus Reference Genomic (LRG) collaboration, but can be overridden upon request.

Some of the data ClinVar reports related to variation are values added by NCBI. These are reported only as part of the RCV record (because the SCV accession is what the submitter provides), and can include alternate HGVS expressions, allele frequencies from the 1000 Genomes project or GO-ESP, identifiers from dbSNP or dbVar, molecular consequences (e.g., nonsense/missense/frameshift), location data (splice site, UTR’s, cytogenetic band, genes), and confidence in variation calls at that location.

Phenotype

ClinVar represents phenotype as concepts identified in MedGen. Similar to management of variation, these concepts can be single or sets of multiple values. Sets are used primarily to report a combination of clinical features; single values are used to represent diagnostic terms or indications. Submitters are encouraged to submit phenotypic information via identifier, e.g., MIM number, MeSH term, or identifier from the Human Phenotype Ontology (HPO). Free text is accepted and ClinVar staff will work with submitters to determine if that text can be mapped to current standardized concepts. If not, ClinVar establishes a new identifier to be represented in MedGen and adds that MedGen identifier to the RCV record.

Interpretation

All interpretations of the relationship between variation and phenotype in ClinVar are supplied by submitters. ClinVar reports clinical significance, the date that clinical significance was last interpreted by the submitter, and functional significance. To support interpretation, mode of inheritance of a variation relative to a disorder and qualification of severity of phenotype are also represented. Terms for clinical significance are those recommend by the American College of Medical Genetics (ACMG). If submitters disagree on the interpretation of the clinical significance of any variation, that record is marked in the aggregate report as having conflicts. If one submitter does not provide this information, and another does, that is not marked as conflicting.

Comparison of clinical signficiance provided by multiple submitters is computed by two methods. One is a strict interpretation, per RCV accession, of any difference. In other words, pathogenic and likely pathogenic are reported as being in conflict. The second is more relaxed, and based only on the variation and not the variation as related to a specific phenotype. In this mode, the conflicts are reported only at the extremes, i.e., differences between pathogenic/likely pathogenic, benign/likely benign, and uncertain significance.

Evidence

Evidence that supports an interpretation of the variation-phenotype relationship can be highly structured and/or a free-text summary discussing how the evidence was evaluated. When structured, content includes the description of how the variants were called and in what context (genetic testing, family studies, comparison of tumor/normal tissue, animal models, etc.) Based on that context, the results can be represented as number of independent observations per person or chromosome, number of segregations observed, number of times other rare variations were identified in the same gene or other genes, etc. At present, most structured data are reports of number of individuals in which non-somatic variation was observed, sometimes with indication of number of families.

Initial records

The major data flows for ClinVar are diagrammed in Figure 1. Direct submissions are validated, converted to XML, and accessioned. If any content does not validate, submitters are contacted and corrections are requested. When valid, the records are assigned accessions (SCV) and processed. Submitters are provided reports including the accessions assigned to their data and indications as to whether any of their data conflicted with current public submissions.

Figure 1.

Overview of the flow of information through ClinVar. ClinVar validates content and looks for differences relative to previous submissions and returns reports to the submitter before the data are released to the public.

Data that NCBI processes from OMIM or GeneReviews are managed slightly differently. Data from OMIM are updated daily from automatic feeds, and bypass the validation assigned to direct submissions. If possible, novel variations are converted to sequence coordinates by testing possible reference sequences and determining if the data in the text of OMIM’s description of the allele are consistent with reported sequence changes. As resources permit, NCBI staff reviews recent records from OMIM that cannot be processed automatically. Data from GeneReviews are extracted from the tables embedded in the GeneReview, as well as attached tables provided by the submitter. Any questions that arise in processing data from GeneReviews are reported to GeneReviews staff for review.

Updates

Submitters may update their submissions at any time. With an update, the accession is assigned a new version. Thus if a unit record in a submission were assigned the accession SCV000000001, with an update the version would be incremented, in this case to 2 (SCV000000001.2).

RCV-specific processing

Data associated with an RCV accession can change in one of two ways. One is represented by an increment of a version. Again, if there are multiple submissions about the same variation-phenotype relationship, these are aggregated into one RCV accession and versioned. The version of an RCV accession is incremented if a new submission is received for the same variation-phenotype relationship (i.e., a new SCV accession is added to the set represented by the RCV accession), or if any SCV accession in the set is itself updated and assigned a new version.

The content of an RCV accession can also change without that being reflected in a new version. If a genomic assembly changes, if genomic coordinates are established for a variation for the first time, if database identifiers such as rs#, nsv#, or PubMed ids are added, if preferred terms are redefined, then the content will be updated without assigning a new version, but with a new unique identifier. These snapshots of content are calculated weekly, and the unique integer identifer is detected when accessing ClinVar via E-Utilities.

Web

ClinVar’s website, http://www.ncbi.nlm.nih.gov/clinvar, is part of NCBI’s Entrez system and thus is searchable with the standard query interface and Advanced query options. ClinVar supports retrieval by any text in the RCV record, including descriptions of variation (HGVS expression, rs, nsv, nssv, OMIM allelic variant identifier, identifier used in a locus-specific database or LSDB), genes (symbol or full name), disease (names and identifiers), submitter names, and clinical significance. To facilitate a common search strategy, a query that is detected to be a human gene symbol displays a link to make it easier to limit your query results by that symbol. The default result set is a table of 20 rows, but that can be altered using Display Settings (Figure 2). When multiple results are returned from a query, filters are provided at the left that reflect the content of the retrieval set (values and counts of each). Clicking on one of those options removes all but the selection from the display, a restriction that can be reversed by using the Clear option.

Figure 2.

Tabular results of a ClinVar search.

The full record is accessed by clicking on See details in the first column of the tabular display, or the title row if the summary display option is used. At present, the detailed display corresponds to content of an RCV accession (Figure 3). The Clinical significance, Allele description, Condition(s) sections, and the Genome view report aggregate data; the Clinical Assertions are submitter-specific, and the Evidence (not shown) is provided both in aggregate and submitter-specific sections.

Figure 3.

Detailed display of an RCV record. This is currently the default display.

Before the end of 2013, a new display will be provided via See details, quite similar to the RCV report but aggregated per single variation rather than variation-phenotype combination. This new display allows users to see all data for a variation even when submitters’ representation of phenotype differs.

Data in ClinVar can also be discovered via other NCBI databases, based on the links that are built when content is shared. Examples include dbSNP, dbVar, Gene, MedGen, Nucleotide, and PubMed. Locations of variation represented in ClinVar are annotated on RefSeqs and are visible in the graphical sequence displays (e.g., http://www.ncbi.nlm.nih.gov/nuccore/125662814?report=graph), and browsers such as 1000 Genomes (http://www.ncbi.nlm.nih.gov/variation/tools/1000genomes/). ClinVar also provides specialized pages for certain types of access. One is the list of genes and disorders for which ACMG recommends that incidental findings be reported (1) (http://www.ncbi.nlm.nih.gov/clinvar/docs/acmg/); another is the listing of submitters and all their submissions (http://www.ncbi.nlm.nih.gov/clinvar/submitters/).