Melissa J LandrumHVP6

June 2, 2016

ClinVar: Aggregating Data to Improve

Variant Interpretation

ClinVar www.ncbi.nlm.nih.gov/clinvar

Archive of interpretations of variants relative to conditionsVariant-level informationFully public and freely availableSubmission-driven database

Primary submissionsExpert-curated submissions

Curation support from NCBI staff

Data in ClinVar

Variation Condition

Interpretation Evidence

Data standardsContent 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 termsOMIM: disease-specific termsHuman phenotype ontology: clinical features

Clinical significance ACMG, CPIC?

Variant effects VAriO, Sequence ontology

Two levels of aggregation

VariantConditionSubmitter

BRCA2:c.9875C>T Familial cancer of breast

Lab ASCV000000010

Variant Condition

BRCA2:c.9875C>T Familial cancer of breast

RCV000000050

BRCA2:c.9875C>T Variant

BRCA2:c.9875C>TFamilial cancer of breast

Lab BSCV000000020

BRCA2:c.9875C>TBreast-ovarian cancer, familial 2

Lab CSCV000000030

BRCA2:c.9875C>T Breast-ovarian cancer, familial 2

RCV000000070

ClinVar Review Status

Practice guideline

Reviewed by expert panel

Multiple interpretations with assertion criteria that agree

One interpretation with assertion criteriaOR multiple interpretations with assertion criteria but conflictingNo interpretations with assertion criteria OR no interpretation provided

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

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

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

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

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

Attribution

Submission Portalhttps://submit.ncbi.nlm.nih.gov/clinvar/

• 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/

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

Updating submissions http://www.ncbi.nlm.nih.gov/clinvar/docs/submit/#update

Categories of interpretations

Clinical significance/pathogenicity for disease

Therapeutic effect

Functional/pharmacological effect

Categories of interpretations - proposal

AcknowledgementsMark BensonGarth BrownChao ChenShanmuga ChitipirallaBaoshan GuJennifer HartDouglas Hoffman Wonhee Jang Brandi KattmanKen Katz

Jennifer Lee Zenith MaddipatlaDonna Maglott Adriana Malheiro Michael Ovetsky George Riley Wendy Rubinstein Amanjeev Sethi Ray Tully Ricardo Villamarin

Steve SherryJim OstellDavid Lipman

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Send questions, comments, suggestions to clinvar@ncbi.nlm.nih.gov