The rate of variant discovery continues to surpass the rate of clinicalgrade interpretation. This is a challenge for precision medicine, because fast, reliable access to variant interpretations is necessary to provide well-informed and timely interpretations of test results to patients. ClinVar is a public repository for interpretations of clinical significance and functional effects of variants in any gene and for any disease. Interpretations are submitted by many sources, including clinical testing laboratories, research laboratories, locus-specific databases, expert panels, practice guidelines, as well as OMIM® and GeneReviews™. Collecting variant interpretations in ClinVar depends on integrating data from these different sources, which has several benefits. First, data integration requires standardizing the data from each source. This improves the quality of the data in ClinVar as well as in each of the individual datasets. ClinVar staff validate HGVS expressions as a routine part of ClinVar submission processing. Submitters are encouraged to use standard terms in MedGen for diseases and phenotypes. Standard terms for clinical significance are used in ClinVar when available; for example, ClinVar uses the terms recommended by ACMG to classify variants for Mendelian diseases. Secondly, ClinVar aggregates all data for a variant defined by its genomic location. Therefore, HGVS descriptions on different transcripts or on different genomic sequences can be recognized as the same variant. Thirdly, integrating data from multiple submitters allows the evidence from all sources to be pooled together. This larger collection of evidence aids the re-evaluation of variant classifications, and is especially valuable for rare variants and novel gene-disease relationships. Fourthly, data integration means that variant interpretations from different sources can be viewed together and compared. Thus a ClinVar user has access to interpretations outside any internal system and knows when there is consensus in the interpretation or not. Submitting laboratories use reports of conflicting interpretations in ClinVar to prioritize variants that they should re-evaluate. ClinVar receives data from many data providers, and therefore provides clear attribution to each contributing group, including links to records in LSDBs. Each source may update their submission to ClinVar at any time. For example, a record may be updated when a variant is re-classified or when additional evidence is available to support the interpretation. Submitters may consider providing regular updates to ClinVar to prevent their interpretations from becoming out of date. Submissions to ClinVar describe variants that range in complexity from simple alleles with explicit sequence locations through copy number changes and cytogenetic rearrangements with fuzzy boundaries.

1. Melissa J Landrum
HVP6
June 2, 2016

2.  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. Variation Condition
Interpretation Evidence

4. Content Authorities
Short variants HGVS
Structural variants ISCN (being developed)
Accessions for the variant location dbSNP, dbVar
Genes HGNC
Reference sequence Assembly: Genome Reference Consortium
(GRC)
Gene-specific: RefSeqGene/LRG
Type of variation, location in gene Sequence Ontology
Conditions Orphanet: group terms
OMIM: disease-specific terms
Human phenotype ontology: clinical features
Clinical significance ACMG, CPIC?
Variant effects VAriO, Sequence ontology

5. Variant
Condition
Submitter
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

8. 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
http://www.ncbi.nlm.nih.gov/clinvar/docs/assertion_criteria/

9. Country Submitters Submissions
United States 170 156201
United Kingdom 26 7423
Australia 17 2462
Finland 4 2121
Germany 34 1794
Canada 19 1607
France 24 1513
China 22 1345
Singapore 3 1102
Switzerland 5 970
Country Submitters Submissions
Netherlands 26 787
Estonia 1 761
Saudi Arabia 4 549
Sweden 9 459
Japan 10 388
Belgium 8 374
India 24 333
Brazil 10 243
Iran 9 121
Italy 15 81

10.  Submitters are acknowledged on web pages
 Links to the submitter’s website are provided, when
available
 The submitting organization owns its submissions (SCV)
 Only the submitter can update or delete a submission

11. • Register your organization
• Use the wizard to submit
single variant
interpretations
• Upload files of batch
submissions
http://www.ncbi.nlm.nih.gov/clinvar/
docs/submit/

12.  Updates are encouraged and expected
 Variant reclassification
 Refining the condition for the interpretation
 New evidence
 Updates must be provided by the submitter
 Clinical laboratories and LSDBs may consider regular
update cycles

14.  Clinical significance/pathogenicity for disease
 Therapeutic effect
 Functional/pharmacological effect

15. 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
Steve Sherry
Jim Ostell
David Lipman

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clinvar@ncbi.nlm.nih.gov