ClinVar: public archive of interpretations of clinically relevant variants

Abstract

ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/) at the National Center for Biotechnology Information (NCBI) is a freely available archive for interpretations of clinical significance of variants for reported conditions. The database includes germline and somatic variants of any size, type or genomic location. Interpretations are submitted by clinical testing laboratories, research laboratories, locus-specific databases, OMIM®, GeneReviews™, UniProt, expert panels and practice guidelines. In NCBI's Variation submission portal, submitters upload batch submissions or use the Submission Wizard for single submissions. Each submitted interpretation is assigned an accession number prefixed with SCV. ClinVar staff review validation reports with data types such as HGVS (Human Genome Variation Society) expressions; however, clinical significance is reported directly from submitters. Interpretations are aggregated by variant-condition combination and assigned an accession number prefixed with RCV. Clinical significance is calculated for the aggregate record, indicating consensus or conflict in the submitted interpretations. ClinVar uses data standards, such as HGVS nomenclature for variants and MedGen identifiers for conditions. The data are available on the web as variant-specific views; the entire data set can be downloaded via ftp. Programmatic access for ClinVar records is available through NCBI's E-utilities. Future development includes providing a variant-centric XML archive and a web page for details of SCV submissions.

A framework for exhaustively mapping functional missense variants

“…To validate the utility of our maps in the context of human disease, we extracted known disease‐associated variants from ClinVar (Landrum et al , 2016), as well as rare and common polymorphisms observed independent of disease from GnomAD (Lek et al , 2016), and somatic variants previously observed in tumors from COSMIC (Forbes et al , 2001). …”

The landscape of human mutually exclusive splicing

“…To obtain a comprehensive overview of MXE‐mediated diseases, we annotated all MXEs with pathogenic SNPs from ClinVar (Landrum et al , 2016), resulting in 35 MXEs (eight newly predicted exons) with 82 pathogenic SNPs (Fig 4A, Dataset EV7). Disease‐associated MXEs show tight developmental and tissue‐specific expression with prominent selective expression in heart and brain, and cancer cell lines (Fig 4B and C, Dataset EV7).…”

“…To identify potentially pathogenic SNPs in MXEs, the MXEs were compared to the ClinVar SNP database (ClinVar VCF file downloaded on 11 Aug 2016, version updated at 30 Jun 2016, Landrum et al , 2016). The ClinVar variant summary file (VCF file) was converted into a BED file keeping all original information.…”

Adapting crowdsourced clinical cancer curation in CIViC to the ClinGen minimum variant level data community‐driven standards

“…Currently, there are multiple platforms and portals hosting cancer variant data with a clinical focus, including OncoKB, CanDL, My Cancer Genome, The Jackson Laboratories Clinical Knowledgebase, and ClinVar (Chakravarty et al., 2017; Damodaran et al., 2015; Landrum et al., 2016b; Patterson et al., 2016; Swanton, 2012). This speaks to the need for coordinated efforts such as that presented here to define and relate central data elements.…”

“…ClinGen is a global National Institutes of Health (NIH)‐funded effort to standardize gene and variant curation, for clinically relevant genetic information, aiding in rapid communication of this information between multiple end users including clinicians, research scientists, and the public. ClinGen works closely with ClinVar, a database of clinically relevant germline and somatic variants, to implement best‐practices in variant curation and presentation (Landrum et al., 2016a). The Somatic Working Group (WG) is in the Clinical Domain of ClinGen, and is composed of over 50 academic and industry stakeholders in cancer research.…”