ClinVar: Getting the most from the reference assembly and reference materials
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Talk by Melissa Landrum at GRC/GIAB ASHG2016 workshop.
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ClinVar: Getting the most from the reference assembly and reference materials
- 1. clinvar@ncbi.nlm.nih.gov Melissa J Landrum, Ph.D. Getting the Most from the Reference Assembly and Reference Materials Oct 18, 2016
- 2. ClinVar www.ncbi.nlm.nih.gov/clinvar Archive of interpretations of variants relative to conditions Variant-level information Fully public and freely available Submission-driven database Primary submissions Expert-curated submissions Curation support from NCBI staff
- 3. ClinVar integrates four domains of information Variation Condition Interpretation Evidence dbSNP dbVar Gene MedGen (HPO, OMIM) PubMedACMG Sequence Ontology GTR
- 4. Submissions 170K 232K 596 submitters 0 50000 100000 150000 200000 250000 5/1/2013 5/1/2014 5/1/2015 5/1/2016 Submissions to ClinVar 0 20000 40000 60000 80000 100000 120000 140000 160000 180000 4/5/2013 4/5/2014 4/5/2015 4/5/2016 Variants in ClinVar
- 6. Archive submitted interpretations All submissions are accessioned and versioned ClinVar maintains a history of changes to interpretations History is currently available in XML Planned development: provide web access to record history
- 7. Standardize data Content Authorities Sequence variants HGVS Structural variants ISCN (being developed) Accessions for the variant location dbSNP, dbVar Genes HGNC Conditions Orphanet: group terms OMIM: disease-specific terms Human phenotype ontology: clinical features Reference sequence Assembly: Genome Reference Consortium (GRC) Gene-specific: RefSeqGene/LRG Type of variation, location in gene Sequence ontology Variant effects VAriO, Sequence ontology Clinical significance ACMG
- 8. Aggregate data BRCA2:c.9875C>T Familial cancer of breast Lab A SCV000000010 Variant Condition BRCA2:c.9875C>T Familial cancer of breast RCV000000050 BRCA2:c.9875C>TVariant BRCA2:c.9875C>T Familial cancer of breast Lab B SCV000000020 BRCA2:c.9875C>T Breast-ovarian cancer, familial 2 Lab C SCV000000030 BRCA2:c.9875C>T Breast-ovarian cancer, familial 2 RCV000000070
- 13. ClinVar review status Practice guideline Reviewed by expert panel Multiple interpretations with assertion criteria that agree • One interpretation with assertion criteria • OR multiple interpretations with assertion criteria but conflicting • No interpretations with assertion criteria • OR no interpretation provided
- 14. Data access • Monthly full releases – Comprehensive XML extraction – VCF files – Tab-delimited summary files, e.g. genes, variants, conflicts • E-utilities • Variation Viewer, Sequence Viewer • Website – Subset of data – Updated weekly
- 15. Assembly used to call the variant Definition of variant Condition Clinical significance Method used to collect the data Allele origin Affected status Required fields for submission
- 16. Making the move to GRCh38 Most or all clinical laboratories that submit to ClinVar still report on GRCh37 Lack of tools to analyze GRCh38 Lack of reference materials for GRCh38 ClinVar maps variants between GRCh37 and GRCh38 and reports both locations XML VCF website
- 17. Acknowledgements Mark Benson Garth Brown Chao Chen Shanmuga Chitipiralla Baoshan Gu Jennifer Hart Douglas Hoffman Wonhee Jang Brandi Kattman Ken Katz Jennifer Lee Zenith Maddipatla Donna Maglott Adriana Malheiro Michael Ovetsky George Riley Wendy Rubinstein Amanjeev Sethi Ray Tully Ricardo Villamarin George Zhou Steve Sherry Jim Ostell David Lipman