www.iccg.org

U41 Grant Session

ISCA has evolved!Established in 2007, ISCA was originally focused on

copy number array data.

Realizing our goals are not unique to structural variation, in 2012 we evolved into ICCG to include

sequence-level variation efforts.

ICCG Membership• Over 190 member institutions• Over 2,400 individual members worldwide

GO Grant

U41 Grant Submitte

d

U41 Grant Resubmitte

d

2011 2012 2013ACMG Grant

20092007

ICCGLaunched

ISCALaunched

Timeline

CRVR Grant to be Awarded

Project GoalsTo raise the quality of patient care by:

• Standardizing testing platforms and data interpretation related to structural and sequence-level variation

• Creating a centralized database of clinically relevant variant annotations to share data for clinical and research purposes

• Implementing a QC and expert consensus process for curating data submitted across laboratories and developing evidence based classifications

Bioinformatics and IT WorkgroupJoyce Mitchell (co-chair) and Sandy Aronson (co-chair)

ARUP: David Crockett; Cartagenia: Steven Van Vooren; Emory: Virenkumar Patel; GeneDx: Rhonda Brandon; Mayo: Eric Klee; NCBI: Deanna Church, Donna Maglott; George Riley; Partners Healthcare: Eugene Clark, Larry Babb, Siva Gowrisanker,

Matt Varugheese, Tom Venman; University of Chicago Teja Nelakuditi; Utah: Karen Eilbeck

Sequence Variant Workgroup

Madhuri Hegde (co-chair, Emory)Sherri Bale (co-chair, GeneDx)

Soma Das (U Chicago)Matt Ferber (Mayo)

Birgit Funke (Harvard/Partners)Elaine Lyon (ARUP)

Heidi Rehm (Harvard/Partners)Avni Santani (CHOP)

Patrick Willems (Gendia)

Structural Variant Workgroup

Erik Thorland (co-chair, Mayo)Swaroop Aradhya (co-chair, GeneDx)

Deanna Church (NCBI)Hutton Kearney (Fullerton)

Charles Lee (Harvard/BWH)Christa Martin (Emory)Sarah South (ARUP)

Phenotyping Workgroup

David Miller (chair, Harvard)Ada Hamosh (Hopkins)

Mike Murray (Harvard/BWH) Robert Nussbaum (USCF)

Erin Riggs (Emory)Peter Robinson (Berlin)

Steven Van Vooren (Cartagenia) Patrick Willems (Gendia)

Engagement, Education and Access Workgroup

Andy Faucett (chair, Geisinger)Erin Riggs (Emory)

Danielle Metterville (Partners)Genetic Counselors from participating laboratories

ConsultantsLes Biesecker, Johan den Dunnen, Robert Green, Ada Hamosh, Laird Jackson, Stephen Kingsmore,

Jim Ostell, Sue Richards, Peter Robinson, Lisa Salberg, Joan Scott, Sharon Terry

U41 Principal Investigators and Workgroups

NIH U41 PIs: David Ledbetter (Geisinger), Christa Martin (Geisinger),

Joyce Mitchell (Utah), Robert Nussbaum (UCSF), Heidi Rehm (Harvard)

Structural Variant Workgroup

Co-Chairs: – Erik Thorland (Mayo) and Swaroop Aradhya (GeneDx)

Goals:1) Use evidence-based review to assess genes/regions

targeted on ISCA array design2) Develop a genome-wide dosage sensitivity map to

aid in clinical array interpretation and inform array design• Haploinsufficiency (loss) and/or Triplosensitivity (gain)

ISCA Participants

ARUPSarah SouthErica Andersen

Birmingham Women's NHS FoundationDominic McMullan

Emory UniversityChrista MartinErin KaminskyErin RiggsEli WilliamsVanessa Horner

GeneDxSwaroop AradhyaDaniel Pineda-Alvarez

Mayo ClinicErik ThorlandKaren WainLindsey Waltman

Mission HealthHutton Kearney

NCBIDeanna Church

Victorian Clinical Genetics ServicesDamien Bruno

DDG2PMatt HurlesHelen FirthDavid FitzPatrick

www.ncbi.nlm.nih.gov/projects/dbvar/ISCA

Sequence Variant Workgroup

Sequence Variant WorkgroupMadhuri Hegde (Co-Chair, Emory)Sherri Bale (Co-Chair, GeneDx)Soma Das (U Chicago)Matt Ferber (Mayo)Birgit Funke (Harvard/Partners)Elaine Lyon (ARUP)Heidi Rehm (Harvard/Partners)Avni Santani (CHOP)Patrick Willems (Gendia)TBN from NCBITBN from CRVR

1. Develop standards for variant classification in conjunction with ACMG, CAP, AMP

2. Guide ClinVar Development

3. Define the Medical Exome

4. Solicit and support labs to submitting data

5. Develop process for expert consensus - 8 pilot projects

Phenotyping WorkgroupDavid Miller (chair, Harvard/BCH)Ada Hamosh (Hopkins)Mike Murray (Harvard/BWH) Robert Nussbaum (USCF)Erin Riggs (Emory)Peter Robinson (Germany)Steven Van Vooren (Cartagenia) Patrick Willems (Gendia)

Phenotyping Workgroup

1. Develop approaches to improve the collection of phenotypic data for association with genotypes

2. Ensure the use of consistent and compatible terminologies and ontologies across interconnected phenotype resources

Education, Engagement and Access Working Group

• Chair: Andy Faucett (Geisinger)• Members: Genetic counselors and ICCG project

managers• Educate stakeholders on ICCG efforts

– Publications, webinars, booths at meetings, website• Engage groups to encourage submission of data

– Labs, clinicians, researchers, patient advocacy groups• Ensure access to data and resources is

appropriately managed

Bioinformatics and IT Workgroup

Co-Chairs: Joyce Mitchell and Sandy Aronson

ARUP/Utah: David Crockett, Karen Eilbeck

Cartagenia: Steven Van Vooren

Emory: Stuart Tinker, Viren Patel

GeneDx: Rhonda Brandon

Mayo Clinic: Eric Klee

NCBI: Deanna Church, Donna Maglott; George Riley

Partners Healthcare: Eugene Clark, Larry Babb, Siva Gowrisanker, Matt Varugheese, Tom Venman

Univ of Chicago: Teja Nelakuditi

1. Facilitate communication between laboratories, vendors and NCBI

2. Develop submission standards for ClinVar

3. Evaluate how labs are using ClinVar and recommend enhancements

4. Support activities of other workgroups

• NCBI (ClinVar, dbSNP, dbVar, dbGaP, GTR) and EBI

• Regulatory and Standards: ACMG, CAP, CDC, FDA, ASHG, AMP, CMGS

• NHGRI (CRVR, eMERGE, CSER, ROR)

• IRDiRC

• Locus Specific Databases (LSDBs – LOVD and non-LOVD)

• InSiGHT, PharmGKB, MSeqDB, CFTR2, ENIGMA, etc

• Human Variome Project, HGVS and LOVD

• PhenoDB (Ada Hamosh) and Human Phenotype Ontology (Peter Robinson)

• OMIM (Ada Hamosh) and GeneReviews (Bonnie Pagon)

• Patient Advocacy Groups (Patient CrossRoads, Genetic Alliance, UNIQUE, Disease Specific Groups)

• Commercial Efforts

Working with Existing Efforts

Proposed U01/U41 Governance StructureNote: pending funding decisions

PopulationGeneticsPrenatalGWAS

Non-coding

Standards/Data Collection Workgroups Clinical Domain Workgroups Bioinformatics & IT Workgroups

Steering Committee U41, UNC/Geisinger/ACMG,

Stanford/Baylor, NHGRI, NCBI

External StakeholderCommittee

Scientific Advisory Board

UNC/Geisinger/ACMG Executive Committee

Stanford/Baylor Executive Committee

U41 Executive Committee

Phenotyping WG

Medical Exome

Cardio WGActionabilityWG

Informatics WG

Curation Tools WG

ClinVarWG

AnalysisWG

JIRA CNV

EHRWGCardio WGClinical Domain

WGs

PGxPGxWG

Sequence Variant WG Informatics WGBioinformatics and IT WG

Education, Engagement, Access WG ELSI and Genetic Counseling WGData & Tool Dissemination WG

Epigenetics

Disease Area WGs

StructuralVariant WG

Sequence Variant WG

StructuralVariant WG

Sequence Variant WG

StructuralVariant WG

CoreDBDisease Area Curation Tool

ClinVar/CRVR System InteractionsNote: pending funding decisions

OMIM

Patient Registries

EHR Interface

Expert Curation of Genes and Variants by Clinical Domain and Disease Area Workgroups

dbGaP

LSDBs

LabsLabs

Labs(Genotypes & Phenotypes)

Gene Resource

(Medical Exome, Actionability)

CNV Curation Tool

(JIRA)

Application Interface

External Informatics Activities Enabled

ExpertCuratedVariants

Case-level Data

Variant-level Data

ClinVar

Disease WGs

Clinical Domain WGs

Data

Crowd-sourced Curation

Controlled Access

Public Access

Private

PharmGKB

Machine Learning Algorithms

PopulationDatasets

MedicalLit

Portal for the Public

1. Tell us you are interested

2. Send us your data!

• Send sample export of what you have

3. Are you interested in curating?

• Medical exome project

• Disease area variant curation groups

4. Help support the project by engaging with stakeholders

Opportunities to get involved