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

5.
Submitters
http://www.ncbi.nlm.nih.gov/clinvar/docs/submitter_list/

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

9.
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

10.
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

11.
 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

12.
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

13.
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