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What is ClinVar?

ClinVar is designed to provide a freely accessible, public archive of reports of the relationships among human variations and phenotypes, with supporting evidence. By so doing, ClinVar facilitates access to and communication about the relationships asserted between human variation and observed health status, and the history of that interpretation. ClinVar collects reports of variants found in patient samples, assertions made regarding their clinical significance, information about the submitter, and other supporting data. The alleles described in submissions are mapped to reference sequences, and reported according to the HGVS standard. ClinVar then presents the data for interactive users as well as those wishing to use ClinVar in daily workflows and other local applications. ClinVar works in collaboration with interested organizations to meet the needs of the medical genetics community as efficiently and effectively as possible. Information about using ClinVar is available here.

ClinVar supports submissions of differing levels of complexity. The submission may be as simple as a representation of an allele and its interpretation (sometimes termed variant-level), or as detailed as providing multiple types of structured observational (case-level)  or experimental evidence about the effect of  the variation on phenotype. A major goal is to support computational (re)evaluation, both of genotypes and assertions, and to enable the ongoing evolution and development of knowledge regarding variations and associated phenotypes. ClinVar archives and  versions submissions which means that when submitters update their records, the previous version is retained for review. Information about submitting data to ClinVar is available here.

The level of confidence in the accuracy of variation calls and assertions of clinical significance depends in large part on the supporting evidence, so this information, when available, is collected and visible to users. Since the availability of supporting evidence may vary, particularly in regard to retrospective data aggregated from published literature, the archive accepts submissions from multiple groups, and aggregates related information, to transparently reflect both consensus and conflicting assertions of clinical significance. A review status is also assigned to any assertion, to support communication about the trustworthiness of any assertion.

Accessions, of the format SCV000000000.0, are assigned to each record. Reports about sets of assertions about the same variation/phenotype relationship are aggregated within ClinVar's data flow and submitted as a reference accession of the format RCV000000000.0. Because of this model, one allele will be included in multiple RCV accessions whenever different phenotypes are reported for that allele. Groups wishing to evaluate a set of ClinVar records can also submit a review of a set of SCV or RCV records, with the result being the creation of a novel record assigned an RCV accession.

ClinVar archives submitted information, and reports additional data that may be available about a variant in other public resources, but ClinVar neither curates content nor modifies it independent of an explicit submission. If you have data that differs from what is current represented in ClinVar, we encourage you to submit your data and the evidence supporting your intepretation.

References

More information about ClinVar is available in these sources:

1. Nucleics Acid Research

Landrum MJ, Lee JM, Riley GR, Jang W, Rubinstein WS, Church DM, Maglott DR. ClinVar: public archive of relationships among sequence variation and human phenotype. Nucleic Acids Res. 2014 Jan 1;42(1):D980-5. doi: 10.1093/nar/gkt1113. PubMed PMID: 24234437

2. NCBI Handbook

Melissa Landrum, PhD, Jennifer Lee, PhD, George Riley, PhD, Wonhee Jang, PhD, Wendy Rubinstein, MD, PhD, Deanna Church, PhD, and Donna Maglott, PhD. ClinVar. http://www.ncbi.nlm.nih.gov/books/NBK174587/

Presentations

2013 National Society of Genetic Counselors Webinar - Save Yourself Some Time! Utilizing NCBI’s Resources for Phenotype (MedGen), Tests (GTR) and Variation (ClinVar)

The PowerPoint presentation is available for download.

Scope

ClinVar currently includes clinical assertions for variants identified through

method explanation term used in ClinVar's reports
clinical testing Clinical significance reported as part of the genetic testing process in CLIA certified  or ISO 1589 accredited laboratories. clinical testing
research General term for variations identified in humans as part of a research project. research
extraction from the literature Reporting of the effect variation on phenotype as extracted from the literature without modification of authors' statements. Used by third parties, not the authors of the paper being cited. literature only

ClinVar currently does not include uncurated sets of data from GWAS studies, although variants that were identified through GWAS and have been individually curated to provide an interpretation of clinical significance are in scope.

Represents medical phenotypes

ClinVar aggregates the names of medical conditions with a genetic basis from such sources as SNOMED CT, GeneReviews, Genetic Home Reference, Office of Rare Diseases, MeSH, and OMIM®. ClinVar also aggregates descriptions of associated traits from Human Phenotype Ontology (HPO), OMIM, and other sources. Each source of information is tracked, and can be used in queries.

Represents  variations

Human variations are reported to the user as sequence changes relative to an mRNA, genomic and protein reference sequence (if appropriate), according to the HGVS standard. The defaults will be as ‘c.’ and any protein sequence change. Genomic sequences will be represented in RefSeqGene/LRG coordinates, as well as locations on chromosomes (as versioned accessions and per assembly name, such as NCBI36/hg18 and GRCh37/hg19). Novel variations will be accessioned in NCBI’s variation databases (dbSNP and dbVar).

Represents the relationships among phenotypes and variations

ClinVar is designed to support the evolution of our understanding of the relationship between genotypes and medically important phenotypes. By aggregating information about variations observed in individuals with or without a phenotype, ClinVar supports establishment of the clinical validity of human variation.

A ClinVar record will contain the following elements:

ClinVar Accession and version

  1. Accession number/version number separated by a decimal (SCV000000000.0) assigned to each record.
  2. Reference accession number/version separated by a decimal (RCV000000000.0) assigned to submitted sets of assertions about the same variation/phenotype

Identifiers for each variant allele or allele set

  1. HGVS expressions
  2. Published allele names
  3. Database identifiers

Attributes of each phenotype

  1. Name
  2. Descriptions
  3. Defining features
  4. Prevalence/population
  5. Database identifiers

Description of the genotype/phenotype relationship

  1. Review status of the asserted relationship
  2. Submitter of the assertion
  3. Clinical significance - see full documentation on clinical significance
  4. Summary of the evidence for clinical significance
    1. Number of observations of genotype/allele in those with the phenotype
    2. Number of observations of genotype/allele in those without the phenotype
    3. Family studies
    4. Description of the population sampled
    5. In vitro studies
    6. In silico studies
    7. Animal models
  5. Mode of inheritance
  6. Study design
  7. Citations, including URLs

Submission information

  1. Submitter description
  2. Dates submitted and updated
  3. Data added by NCBI computation

Detailed descriptions of the data elements are available in the ClinVar Data Dictionary.

Represents evidence for variations and assertions

Where submitted, evidence supporting the occurrence of a variation and the asserted association of a phenotype with a variation is archived for user review, to allow in-depth review of evidence by users and expert panels. In silico predictions of protein variation consequence using various algorithms may be calculated and reported.

Integrates data from multiple sources

The information aggregated in ClinVar is reported in the viewer in the most accessible presentation possible. Linking within ClinVar and links out are minimized where possible to sure that the greatest amount of information is visible with the fewest possible number of uninformative reference numbers.

Representative use cases

Location search

Clinicians, researchers and other users will search a DNA or protein location for what is known about the clinical significance of a sequence variation at the location.

Review evidence about a variation

Clinicians and researchers will review the evidence for/against a phenotype asserted to be associated with an allele, allowing determination or recalculation of a variant’s pathogenicity.  Any conflict or uncertainty will be reported explicitly. ClinVar will not compute conclusions, but only report conclusions from external data submitters.

Curation of assertions regarding a variation

Experts will review the evidence to assign appropriate levels of confidence to the assertions made in regard to alleles or sets of alleles and will be able to submit a reviewed record.

Integration into testers’ workflow

Clinical laboratories will integrate the information available from ClinVar into their workflow, both submitting variants and associated assertions of clinical significance and using the available information to identify the clinical significance of already documented variants.

Data sharing

The information archived in ClinVar is freely available to users and organizations to ensure the broadest utility to the medical genetics community. To that end, we are working with submitters and other archives to ensure that data structures are designed to facilitate data exchange so that data can be shared in both directions with willing organizations.

Attribution is important to identify the source of variants and assertions, to facilitate communication and to give due credit to submitters. Each submitter is explicitly acknowledged, with pointers to more detailed submitter contact information to facilitate communication and collaboration within the genetics community. Data sources can be used for queries.

It is a goal of ClinVar to be a cooperative effort so that the archive can represent the broadest range of high quality variation/phenotype information. It is in the community’s best interest not to duplicate efforts unnecessarily, but rather to integrate publicly where possible.

Phased implementation

A preliminary view of ClinVar was launched in 2012, with full public release in April 2013. The initial dataset included variations from OMIM, GeneReviews, some locus-specific databases (LSDB), contributing testing laboratories, and others, and ClinVar is accepting new submissions. Data extractions as XML and VCF are also provided for ftp transfer. We expect ClinVar to continue to evolve in response to the needs of the clinical genetics community.

We invite your response.

ClinVar is intended to meet the needs of the genetics community; we invite comments and responses to help make this resource as effective a tool as possible for all our user communities.

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Last updated: 2014-02-21T15:50:06-05:00