ClinVar: A Central Repository for
Interpretations of Clinically Relevant Variants
Melissa LandrumHVP 2014
May 21, 2014
ClinVarwww.ncbi.nlm.nih.gov/clinvar/
ClinVar statswww.ncbi.nlm.nih.gov/clinvar/submitters/
Variation Phenotype
Interpretation Evidence
ClinVar integrates four domains of information
dbSNPdbVar
Gene
MedGen(HPO, OMIM)
PubMedACMG
Sequence Ontology
GTR
ClinVar – Standardized data607008.0001985A>G985A>G (K304E)985A>G (K329E)A985GACADM, LYS304GLUK304EK304E (985 A->G)K304E (K329E)K304E onlyK329EK329E(985A>G)LYS304GLUMutation c.985A>G (p.K304E)c.985A>Gc.985A>G (p.K304E)c.985A>G (p.Lys304Gluc985A>Gincludes: K304E (985A>G)p.K304Ep.Lys329Glupreviously known as p.Lys329GluAnalysis of ACADM 985A>G mutation
NC_000001.10:g.76226846A>G
NG_007045.1:g.41804A>G
NM_000016.4:c.985A>G
ACADM:c.985A>G
NP_000007.1:p.Lys329Glu
ClinVar aggregates by variant and phenotype
VariantPhenotypeSubmitter
SCV – submitted ClinVar record
FBN1:c.4786C>TMarfan syndrome
Lab ASCV000000010
FBN1:c.4786C>TMarfan syndrome
Lab BSCV000000020
Variant Phenotype
FBN1:c.4786C>TMarfan syndrome
RCV000000050
RCV – reference ClinVar record
Allele summary• Gene• Variant type• Genomic location• HGVS expressions*• Molecular consequence*• Links*• Frequency*
Phenotype summary• Names• Links*• Age of onset *• Prevalence *
Interpretation• Significance• Review status *• Accession.version *
* May be provided by NCBI
ClinVar web display
ClinVar web display
ClinVar web display
classified by single submitterclassified by multiple submittersconflicting data from submittersreviewed by expert panelreviewed by professional society
ClinVar Review Status
Expert panels – both medical and research experts with published criteria and process for evaluating variant pathogenicity
• CFTR2, InSiGHT
Professional society – groups that provide practice guidelines
• American College of Medical Genetics (ACMG)
ClinVar aggregates by variant
VariantPhenotypeSubmitter
PTPN11:c.205G>CNoonan syndrome
Lab ASCV000000010
PTPN11:c.205G>CNoonan syndrome
Lab BSCV000000020
Variant Phenotype
PTPN11:c.205G>CNoonan syndrome
RCV000000050
PTPN11:c.205G>CRasopathy
RCV000000050
PTPN11:c.205G>CVariant
PTPN11:c.205G>CRasopathy
Lab CSCV000000030
ClinVar – new web display
Accessing ClinVar data• Interactively on the web, updated weekly• Monthly full releases– Comprehensive XML extraction– VCF files– Tab-delimited summary files for genes, variants
• E-utilities as web service or via command line• Annotation on graphic sequence displays• Variation Viewer
www.ncbi.nlm.nih.gov/variation/view/
• Variation Reporter www.ncbi.nlm.nih.gov/variation/tools/reporter
Submitting data to ClinVar• Minimal or data-rich submissions are accepted• Multiple submission formats– Excel spreadsheet templates– tsv, csv files– XML
• Online documentationhttp://www.ncbi.nlm.nih.gov/clinvar/docs/submit/
And contact us with questions - [email protected]
AcknowledgementsClinVar/GTR/RefSeqGene/Gene/MedGen staff
dbSNP/dbVar/dbGaP
Alex AstashynChao Chen Shanmuga ChitipirallaBaoshan GuDouglas Hoffman Wonhee Jang Brandi KattmanKen KatzJennifer Lee Donna Maglott Adriana Malheiro Michael Ovetsky George Riley Wendy Rubinstein Amanjeev Sethi Ray Tully Ricardo Villamarin
Michael Feolo John GarnerTim HefferonBrad HolmesJohn LopezRama MaitiJose MenaLon PhanDavid ShaoMing Ward
All of NCBIJim OstellSteve Sherry
