Melissa J Landrum, Ph.D.Getting the Most from the Reference Assembly and
Reference MaterialsOct 18, 2016
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
ClinVar integrates four domains of information
Variation Condition
Interpretation Evidence
dbSNPdbVar
Gene
MedGen(HPO, OMIM)
PubMedACMG
Sequence Ontology
GTR
Submissions
170K
232K
596 submitters
5/1/201
3
7/6/201
3
9/10/2
013
11/15
/2013
1/20/2
014
3/27/2
014
6/1/201
4
8/6/201
4
10/11
/2014
12/16
/2014
2/20/2
015
4/27/2
015
7/2/201
5
9/6/20
15
11/11
/2015
1/16/2
016
3/22/2
016
5/27/2
016
8/1/201
60
50000
100000
150000
200000
250000
Submissions to ClinVar
020000400006000080000
100000120000140000160000180000
Variants in ClinVar
Submitters http://www.ncbi.nlm.nih.gov/clinvar/docs/submitter_list/
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
Standardize dataContent Authorities
Sequence variants HGVSStructural variants ISCN (being developed)Accessions for the variant location dbSNP, dbVarGenes HGNCConditions Orphanet: group terms
OMIM: disease-specific termsHuman phenotype ontology: clinical features
Reference sequence Assembly: Genome Reference Consortium (GRC)Gene-specific: RefSeqGene/LRG
Type of variation, location in gene Sequence ontologyVariant effects VAriO, Sequence ontologyClinical significance ACMG
Aggregate data
BRCA2:c.9875C>T Familial cancer of
breastLab A
SCV000000010
Variant Condition
BRCA2:c.9875C>T Familial cancer of breast
RCV000000050
BRCA2:c.9875C>T Variant
BRCA2:c.9875C>TFamilial cancer of
breastLab B
SCV000000020
BRCA2:c.9875C>TBreast-ovarian cancer,
familial 2Lab C
SCV000000030
BRCA2:c.9875C>T Breast-ovarian cancer, familial
2 RCV000000070
ClinVar review statusPractice 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
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
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
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
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