数据库Clinvar简介

Clinvar 数据库变异展示格式：

What is ClinVar?

ClinVar is a freely accessible, public archive（公共档案馆） of reports of the relationships among human variations and phenotypes, with supporting evidence. ClinVar thus facilitates （促使、帮助、有利于）access to and communication about the relationships asserted（宣称、判断、断言） between human variation and observed health status, and the history of that interpretation. ClinVar processes submissions reporting 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. Read more about using ClinVar.

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 a variant-level submission), 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 is an active partner of the ClinGen project, providing data for evaluation and archiving （评估与归档）the results of interpretation by recognized expert panels（专家小组） and providers of practice guidelines（实践指南）. ClinVar archives and versions submissions which means that when submitters update their records, the previous version is retained for review（回顾、审查）. Read more about submitting data to ClinVar.

The level of confidence in the accuracy of variation calls and assertions of clinical significance （临床意义的断定）depends in large part on the supporting evidence, so this information, when available, is collected and visible to users. Because the availability of supporting evidence may vary, particularly in regard to retrospective data （回顾性数据）aggregated from published literature, the archive accepts submissions from multiple groups, and aggregates related information, to reflect transparently both consensus and conflicting assertions of clinical significance. A review status is also assigned to any assertion, to support communication about the trustworthiness（可信度） of any assertion（任何断言）. Domain experts are encouraged to apply for recognition as an expert panel.

Accessions, with the format SCV000000000.0, are assigned to each submitted record. If there are multiple submitted records about the same variation/condition pair, they are aggregated within ClinVar's data flow and reported as a reference accession with the format RCV000000000.0. Because of this model, one variant will be included in multiple RCV accessions whenever different conditions are reported for that variant. Submitted records for the same variation are also aggregated and reported as an accession with the format VCV000000000.0. This aggregation lets a user review all submitted data for a variant, regardless of the condition for which it was interpreted.

 

 

ClinVar archives submitted information, and adds identifiers and other other data that may be available about a variant or condition from other public resources. However ClinVar neither curates content（管理内容） nor modifies interpretations independent of an explicit submission. If you have data that differs from what is currently represented in ClinVar, we encourage you to submit your data and the evidence supporting your interpretation. There is a submission wizard to guide you through that process.

If you are submitting variants that were interpreted as part of work funded by the NIH, please consult your program officer about expectations（期望） for submissions to ClinVar.

References

More information about ClinVar is available in these sources:

1. Human Mutation Landrum MJ, Kattman BL. ClinVar at five years: Delivering on the promise. Hum Mutat. 2018 Nov;39(11):1623-1630. doi: 10.1002/humu.23641. [PubMed PMID:30311387]

2. Nucleic Acids Research Landrum MJ, Lee JM, Benson M, Brown GR, Chao C, Chitipiralla S, Gu B, Hart J, Hoffman D, Jang W, Karapetyan K, Katz K, Liu C, Maddipatla Z, Malheiro A, McDaniel K, Ovetsky M, Riley G, Zhou G, Holmes JB, Kattman BL, Maglott DR. ClinVar: improving access to variant interpretations and supporting evidence. Nucleic Acids Res. 2018 Jan 4;46(D1):D1062-D1067. doi: 10.1093/nar/gkx1153. [PubMed PMID:29165669]

3. Nucleic Acids Research Landrum MJ, Lee JM, Benson M, Brown G, Chao C, Chitipiralla S, Gu B, Hart J, Hoffman D, Hoover J, Jang W, Katz K, Ovetsky M, Riley G, Sethi A, Tully R, Villamarin-Salomon R, Rubinstein W, Maglott DR. ClinVar: public archive of interpretations of clinically relevant variants. Nucleic Acids Res. 2016 Jan 4;44(D1):D862-8. doi: 10.1093/nar/gkv122. [PubMed PMID:26582918]

4. Nucleic Acids 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]

5. 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. [Bookshelf ID: NBK174587]

Scope

ClinVar accepts variants in any part of the genome and interpreted for any type of condition.

ClinVar currently includes clinical assertions for variants identified through several methods of data collection, including clinical testing, research, and reports from the literature (literature only). See our documentation on submitting collection method for more details.

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（范围、视野）.

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 are as ‘c.’ and any protein sequence change. Genomic sequences are 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 are 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（临床有效性/效应） of human variation.

 

 

A ClinVar record contains the following elements:

ClinVar Accession and version

1. Submission accession number/version number separated by a decimal (SCV000000000.0) assigned to each submitted record.
2. Reference accession number/version separated by a decimal (RCV000000000.0) assigned to sets of submitted records about the same variation/condition pair.
3. Variation accession number/version separated by a decimal (VCV000000000.0) assigned to sets of submitted records about the same variation.

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. 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 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 review the evidence for/against a phenotype asserted to be associated with a variant, allowing determination or reassessment of a variant’s pathogenicity. Any conflict or uncertainty is reported explicitly. ClinVar does not compute conclusions, but only report conclusions from external data submitters.

Curation（管理） of assertions regarding a variation

Experts review the evidence to assign appropriate levels of confidence to the assertions made in regard to a variant or sets of variants and submit expert-reviewed records.

Integration into testers’ workflow

Clinical laboratories 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 work 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.

Implementation

A preliminary view of ClinVar was launched in 2012, with the first full public release in April 2013. The initial dataset included variations from OMIM, GeneReviews, some locus-specific databases (LSDB), contributing testing laboratories, and others. ClinVar is an active participant in the ClinGen project, leading to improved content and representation of that content. ClinVar continues to evolve in response to the needs of the clinical genetics community.