ClinVar: Getting the most from the reference assembly and reference materials

clinvar@ncbi.nlm.nih.gov

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