Download Exploring ClinVar

Exploring ClinVar:
What's There and How Do I Use It?
Melissa Landrum
ICCG
June 12, 2014
What is ClinVar?
• Archive of assertions of clinical significance
for variants relative to phenotypes
• Fully public and freely available
• Submission-driven database
• Currently accepting variant/aggregate-level
data; case-level support under development
• Curation support from NCBI staff
What is the difference between
ClinVar and ClinGen?
ClinGen
ClinVar
• An archival database at • The Clinical Genome
Project – multiple
NCBI
institutions
• Supported by NIH
• Submit data to ClinVar
intramural funding
• Perform analysis on data
extracted from ClinVar
• Perform expert curation of
variants and submit to ClinVar
• Funded by grants from
NHGRI
ClinVar
www.ncbi.nlm.nih.gov/clinvar/
ClinVar stats
www.ncbi.nlm.nih.gov/clinvar/submitters/
ClinVar integrates four
domains of information
dbSNP
dbVar
Variation
Phenotype
MedGen
(HPO, OMIM)
Gene
PubMed
ACMG
Interpretation
Sequence
Ontology
Evidence
GTR
ClinVar aggregates by variant and
phenotype
Variant
Phenotype
Variant
Phenotype
Submitter
FBN1:c.4786C>T
Marfan syndrome
RCV000000050
FBN1:c.4786C>T
Marfan syndrome
Lab A
SCV000000010
FBN1:c.4786C>T
Marfan syndrome
Lab B
SCV000000020
RCV – reference
ClinVar record
SCV – submitted
ClinVar record
ClinVar web display
Clinical significance
Benign
Likely benign
Uncertain significance
Likely pathogenic
Pathogenic
Drug response
Confers sensitivity
Risk factor
Association
Protective
Has conflicts
ClinVar web display
Review Status
classified by single
submitter
classified by multiple
submitters
conflicting data from
submitters
not classified by
submitter
reviewed by expert panel
reviewed by professional
society
ClinVar web display
Accession
• All records are accessioned
and versioned
• Supports search
Allele summary
• Track changes to the
• Gene
clinicaltype
interpretation over
• Variant
time location
• Genomic
•
•
•
•
HGVS expressions*
Molecular consequence*
Links*
Frequency*
Phenotype summary
• Names
• Links*
• Age of onset *
• Prevalence *
* May be provided by NCBI
ClinVar web display
ClinVar web display
ClinVar aggregates by variant
Variant
Variant
Phenotype
Variant
Phenotype
Submitter
BRCA2:c.5946del
BRCA2:c.5946del
Familiar cancer of breast
RCV000000050
BRCA2:c.5946del
Familial cancer of breast
Lab A
SCV000000010
BRCA2:c.5946del
Familial cancer of breast
Lab B
SCV000000020
BRCA2:c.5946del
Pancreatic cancer 2
RCV000000070
BRCA2:c.5946del
Pancreatic cancer 2
Lab C
SCV000000030
Variation-centric web display
Variation-centric web display
Variation-centric web display
Searching ClinVar
•
•
•
•
•
Gene symbols
HGVS expressions
Protein changes
Phenotypes
Submitter
Searching uses exact words
and is not field-specific!
Search by gene symbol
Upcoming improvements
to ClinVar searching
• HGVS sensor – to restrict the query to variant
name
• Protein change sensor – to detect a partial
protein change query, e.g. Arg911
• Phenotype query – to detect a phenotype term
as query and provide the option to search for
related terms
Refining your search results
Refining your search results
Searching by genomic location
- Variation Viewer
www.ncbi.nlm.nih.gov/variation/view/
Accessing ClinVar data
• Interactively on the web; updated weekly
• Monthly full releases
– Comprehensive XML extraction
– VCF files
– Tab-delimited summary files for genes, variants
• E-utilities as web service or via command line
• Annotation on graphic sequence displays
• Variation Viewer
www.ncbi.nlm.nih.gov/variation/view/
• Variation Reporter
www.ncbi.nlm.nih.gov/variation/tools/reporter
Acknowledgements
Alex Astashyn
Garth Brown
Chao Chen
Shanmuga Chitipiralla
Arkadi Doubintchik
Brad Holmes
John Garner
Anna Glodek
Baoshan Gu
Tim Hefferon
Douglas Hoffman
Wonhee Jang
Brandi Kattman
Ken Katz
Jennifer Lee
Donna Maglott
Adriana Malheiro
Michael Ovetsky
Lon Phan
George Riley
Wendy Rubinstein
Amanjeev Sethi
Ray Tully
Ricardo Villamarin
Ming Ward
Jim Ostell
Steve Sherry
Contact us at [email protected]