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Grant Details

Grant Number: 5U41HG006834-05 Interpret this number
Primary Investigator: Rehm, Heidi
Organization: Brigham And Women'S Hospital
Project Title: Clinical Genome Resource
Fiscal Year: 2018
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Abstract

PROJECT SUMMARY Although knowledge in the field of human genetics has greatly increased since the time of the Human Genome Project, we still do not fully understand all of the ways in which genomic variation contributes to human health and disease. This proposal represents one of three linked U41 applications to continue support for the Clinical Genome Resource (ClinGen; www.clinicalgenome.org). The main goals of the ClinGen project are to support the deposition of genomic and health data into the public domain by all stakeholders, including patients, clinicians, laboratories, and researchers, develop methods and an informatics infrastructure to answer critical questions of the data (curation), and create a genomic knowledge base that makes this information available to the community for improved patient care. We have structured this proposal into five overarching aims to meet ClinGen's goals: 1) data sharing, 2) standardized approaches to interpretation of genes and variants, 3) software and informatics infrastructure to support and enhance interpretation, 4) community-driven efforts for curation and interpretation, and 5) outreach to maximize the impact of the ClinGen resource. To make high-quality genomic variant data available to the public, we will build upon the standards, experience and infrastructure we have developed during our first funding period. We will capitalize on our collaborative relationships with clinical laboratories to capture the clinical-grade interpretations of millions of genetic sequencing tests generated through the course of routine patient clinical care. All genomic variants and their interpretations will continue to be submitted to and made accessible through our partnership with the ClinVar database within NIH's National Center for Biotechnology Information (NCBI). We will also help to augment the genomic data with phenotype data collected through GenomeConnect, ClinGen's patient registry for individuals who have had genetic testing. ClinGen will use this shared genomic and health information to answer critical questions regarding relevance to human health and disease around clinical validity for gene/disease associations, variant pathogenicity and clinical actionability. Clinical Domain Working Groups (CDWG) and Expert Panels (EP) will enable disease experts to curate sets of genes and variants following approaches developed as part of the ClinGen project. Finally, we will make the ClinGen knowledge base widely available by developing ?clinician-friendly? user interfaces and supporting automatic EHR updates through the newly developed ClinGen EHR App to improve the quality of patient care through genomic medicine.

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Publications

Disease-targeted sequencing: a cornerstone in the clinic.
Authors: Rehm H.L. .
Source: Nature Reviews. Genetics, 2013 04; 14(4), p. 295-300.
EPub date: 2013-03-12 00:00:00.0.
PMID: 23478348
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A Case of HDR Syndrome and Ichthyosis: Dual Diagnosis by Whole-Genome Sequencing of Novel Mutations in GATA3 and STS Genes.
Authors: Goodwin G. , Hawley P.P. , Miller D.T. .
Source: The Journal Of Clinical Endocrinology And Metabolism, 2016 Mar; 101(3), p. 837-40.
EPub date: 2016-01-05 00:00:00.0.
PMID: 26731259
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Providing Access to Genomic Variant Knowledge in a Healthcare Setting: A Vision for the ClinGen Electronic Health Records Workgroup.
Authors: Overby C.L. , Heale B. , Aronson S. , Cherry J.M. , Dwight S. , Milosavljevic A. , Nelson T. , Niehaus A. , Weaver M.A. , Ramos E.M. , et al. .
Source: Clinical Pharmacology And Therapeutics, 2016 Feb; 99(2), p. 157-60.
EPub date: 2015-11-09 00:00:00.0.
PMID: 26418054
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The Changing Landscape of Molecular Diagnostic Testing: Implications for Academic Medical Centers.
Authors: Rehm H.L. , Hynes E. , Funke B.H. .
Source: Journal Of Personalized Medicine, 2016-01-27 00:00:00.0; 6(1), .
EPub date: 2016-01-27 00:00:00.0.
PMID: 26828522
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MSeqDR: A Centralized Knowledge Repository and Bioinformatics Web Resource to Facilitate Genomic Investigations in Mitochondrial Disease.
Authors: Shen L. , Diroma M.A. , Gonzalez M. , Navarro-Gomez D. , Leipzig J. , Lott M.T. , van Oven M. , Wallace D.C. , Muraresku C.C. , Zolkipli-Cunningham Z. , et al. .
Source: Human Mutation, 2016 06; 37(6), p. 540-548.
EPub date: 2016-03-21 00:00:00.0.
PMID: 26919060
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Personal Genomic Testing for Cancer Risk: Results From the Impact of Personal Genomics Study.
Authors: Gray S.W. , Gollust S.E. , Carere D.A. , Chen C.A. , Cronin A. , Kalia S.S. , Rana H.Q. , Ruffin M.T. , Wang C. , Roberts J.S. , et al. .
Source: Journal Of Clinical Oncology : Official Journal Of The American Society Of Clinical Oncology, 2017-02-20 00:00:00.0; 35(6), p. 636-644.
EPub date: 2016-12-12 00:00:00.0.
PMID: 27937091
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A taxonomy of medical uncertainties in clinical genome sequencing.
Authors: Han P.K. , Umstead K.L. , Bernhardt B.A. , Green R.C. , Joffe S. , Koenig B. , Krantz I. , Waterston L.B. , Biesecker L.G. , Biesecker B.B. .
Source: Genetics In Medicine : Official Journal Of The American College Of Medical Genetics, 2017-01-19 00:00:00.0; , .
EPub date: 2017-01-19 00:00:00.0.
PMID: 28102863
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Clingen Pathogenicity Calculator: A Configurable System For Assessing Pathogenicity Of Genetic Variants
Authors: Patel R.Y. , Shah N. , Jackson A.R. , Ghosh R. , Pawliczek P. , Paithankar S. , Baker A. , Riehle K. , Chen H. , Milosavljevic S. , et al. .
Source: Genome Medicine, 2017-01-12 00:00:00.0; 9(1), p. 3.
PMID: 28081714
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Aggregate penetrance of genomic variants for actionable disorders in European and African Americans.
Authors: Natarajan P. , Gold N.B. , Bick A.G. , McLaughlin H. , Kraft P. , Rehm H.L. , Peloso G.M. , Wilson J.G. , Correa A. , Seidman J.G. , et al. .
Source: Science Translational Medicine, 2016-11-09 00:00:00.0; 8(364), p. 364ra151.
PMID: 27831900
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Somatic Cancer Variant Curation And Harmonization Through Consensus Minimum Variant Level Data
Authors: Ritter D.I. , Roychowdhury S. , Roy A. , Rao S. , Landrum M.J. , Sonkin D. , Shekar M. , Davis C.F. , Hart R.K. , Micheel C. , et al. .
Source: Genome Medicine, 2016-11-04 00:00:00.0; 8(1), p. 117.
PMID: 27814769
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A Survey Of Current Practices For Genomic Sequencing Test Interpretation And Reporting Processes In Us Laboratories
Authors: O'Daniel J.M. , McLaughlin H.M. , Amendola L.M. , Bale S.J. , Berg J.S. , Bick D. , Bowling K.M. , Chao E.C. , Chung W.K. , Conlin L.K. , et al. .
Source: Genetics In Medicine : Official Journal Of The American College Of Medical Genetics, 2016-11-03 00:00:00.0; , .
PMID: 27811861
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Reassessment of Genomic Sequence Variation to Harmonize Interpretation for Personalized Medicine.
Authors: Garber K.B. , Vincent L.M. , Alexander J.J. , Bean L.J.H. , Bale S. , Hegde M. .
Source: American Journal Of Human Genetics, 2016-11-03 00:00:00.0; 99(5), p. 1140-1149.
EPub date: 2016-10-27 00:00:00.0.
PMID: 27843123
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Prescription Medication Changes Following Direct-to-consumer Personal Genomic Testing: Findings From The Impact Of Personal Genomics (pgen) Study
Authors: Carere D.A. , VanderWeele T.J. , Vassy J.L. , van der Wouden C.H. , Roberts J.S. , Kraft P. , Green R.C. .
Source: Genetics In Medicine : Official Journal Of The American College Of Medical Genetics, 2016-09-22 00:00:00.0; , .
PMID: 27657683
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The impact of personal genomics on risk perceptions and medical decision-making.
Authors: Krieger J.L. , Murray F. , Roberts J.S. , Green R.C. .
Source: Nature Biotechnology, 2016-09-08 00:00:00.0; 34(9), p. 912-8.
PMID: 27606453
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Clinical Sequencing Exploratory Research Consortium: Accelerating Evidence-Based Practice of Genomic Medicine.
Authors: Green R.C. , Goddard K.A. , Jarvik G.P. , Amendola L.M. , Appelbaum P.S. , Berg J.S. , Bernhardt B.A. , Biesecker L.G. , Biswas S. , Blout C.L. , et al. .
Source: American Journal Of Human Genetics, 2016-06-02 00:00:00.0; 98(6), p. 1051-66.
EPub date: 2016-06-02 00:00:00.0.
PMID: 27181682
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Performance of ACMG-AMP Variant-Interpretation Guidelines among Nine Laboratories in the Clinical Sequencing Exploratory Research Consortium.
Authors: Amendola L.M. , Jarvik G.P. , Leo M.C. , McLaughlin H.M. , Akkari Y. , Amaral M.D. , Berg J.S. , Biswas S. , Bowling K.M. , Conlin L.K. , et al. .
Source: American Journal Of Human Genetics, 2016-06-02 00:00:00.0; 98(6), p. 1067-76.
EPub date: 2016-06-02 00:00:00.0.
PMID: 27181684
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Using ClinVar as a Resource to Support Variant Interpretation.
Authors: Harrison S.M. , Riggs E.R. , Maglott D.R. , Lee J.M. , Azzariti D.R. , Niehaus A. , Ramos E.M. , Martin C.L. , Landrum M.J. , Rehm H.L. .
Source: Current Protocols In Human Genetics, 2016-04-01 00:00:00.0; 89, p. 8.16.1-8.16.23.
EPub date: 2016-04-01 00:00:00.0.
PMID: 27037489
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Personal Genome Sequencing in Ostensibly Healthy Individuals and the PeopleSeq Consortium.
Authors: Linderman M.D. , Nielsen D.E. , Green R.C. .
Source: Journal Of Personalized Medicine, 2016-03-25 00:00:00.0; 6(2), .
EPub date: 2016-03-25 00:00:00.0.
PMID: 27023617
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Toward clinical genomics in everyday medicine: perspectives and recommendations.
Authors: Delaney S.K. , Hultner M.L. , Jacob H.J. , Ledbetter D.H. , McCarthy J.J. , Ball M. , Beckman K.B. , Belmont J.W. , Bloss C.S. , Christman M.F. , et al. .
Source: Expert Review Of Molecular Diagnostics, 2016; 16(5), p. 521-32.
EPub date: 2016-02-24 00:00:00.0.
PMID: 26810587
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Building the foundation for genomics in precision medicine.
Authors: Aronson S.J. , Rehm H.L. .
Source: Nature, 2015-10-15 00:00:00.0; 526(7573), p. 336-42.
PMID: 26469044
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Innovative genomic collaboration using the GENESIS (GEM.app) platform.
Authors: Gonzalez M. , Falk M.J. , Gai X. , Postrel R. , Schüle R. , Zuchner S. .
Source: Human Mutation, 2015 Oct; 36(10), p. 950-6.
EPub date: 2015-08-12 00:00:00.0.
PMID: 26173844
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GenomeConnect: matchmaking between patients, clinical laboratories, and researchers to improve genomic knowledge.
Authors: Kirkpatrick B.E. , Riggs E.R. , Azzariti D.R. , Miller V.R. , Ledbetter D.H. , Miller D.T. , Rehm H. , Martin C.L. , Faucett W.A. , ClinGen Resource .
Source: Human Mutation, 2015 Oct; 36(10), p. 974-8.
EPub date: 2015-08-06 00:00:00.0.
PMID: 26178529
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The Matchmaker Exchange: a platform for rare disease gene discovery.
Authors: Philippakis A.A. , Azzariti D.R. , Beltran S. , Brookes A.J. , Brownstein C.A. , Brudno M. , Brunner H.G. , Buske O.J. , Carey K. , Doll C. , et al. .
Source: Human Mutation, 2015 Oct; 36(10), p. 915-21.
PMID: 26295439
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Maternal Hypercalcemia Due to Failure of 1,25-Dihydroxyvitamin-D3 Catabolism in a Patient With CYP24A1 Mutations.
Authors: Shah A.D. , Hsiao E.C. , O'Donnell B. , Salmeen K. , Nussbaum R. , Krebs M. , Baumgartner-Parzer S. , Kaufmann M. , Jones G. , Bikle D.D. , et al. .
Source: The Journal Of Clinical Endocrinology And Metabolism, 2015 Aug; 100(8), p. 2832-6.
EPub date: 2015-06-22 00:00:00.0.
PMID: 26097993
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Summarizing polygenic risks for complex diseases in a clinical whole-genome report.
Authors: Kong S.W. , Lee I.H. , Leshchiner I. , Krier J. , Kraft P. , Rehm H.L. , Green R.C. , Kohane I.S. , MacRae C.A. , MedSeq Project .
Source: Genetics In Medicine : Official Journal Of The American College Of Medical Genetics, 2015 Jul; 17(7), p. 536-44.
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PMID: 25341114
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Good laboratory practice for clinical next-generation sequencing informatics pipelines.
Authors: Gargis A.S. , Kalman L. , Bick D.P. , da Silva C. , Dimmock D.P. , Funke B.H. , Gowrisankar S. , Hegde M.R. , Kulkarni S. , Mason C.E. , et al. .
Source: Nature Biotechnology, 2015 Jul; 33(7), p. 689-93.
PMID: 26154004
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ClinGen--the Clinical Genome Resource.
Authors: Rehm H.L. , Berg J.S. , Brooks L.D. , Bustamante C.D. , Evans J.P. , Landrum M.J. , Ledbetter D.H. , Maglott D.R. , Martin C.L. , Nussbaum R.L. , et al. .
Source: The New England Journal Of Medicine, 2015-06-04 00:00:00.0; 372(23), p. 2235-42.
EPub date: 2015-05-27 00:00:00.0.
PMID: 26014595
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Copy number variants, aneuploidies, and human disease.
Authors: Martin C.L. , Kirkpatrick B.E. , Ledbetter D.H. .
Source: Clinics In Perinatology, 2015 Jun; 42(2), p. 227-42, vii.
EPub date: 2015-04-01 00:00:00.0.
PMID: 26042902
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Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
Authors: Richards S. , Aziz N. , Bale S. , Bick D. , Das S. , Gastier-Foster J. , Grody W.W. , Hegde M. , Lyon E. , Spector E. , et al. .
Source: Genetics In Medicine : Official Journal Of The American College Of Medical Genetics, 2015 May; 17(5), p. 405-24.
EPub date: 2015-03-05 00:00:00.0.
PMID: 25741868
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Phy-Mer: a novel alignment-free and reference-independent mitochondrial haplogroup classifier.
Authors: Navarro-Gomez D. , Leipzig J. , Shen L. , Lott M. , Stassen A.P. , Wallace D.C. , Wiggs J.L. , Falk M.J. , van Oven M. , Gai X. .
Source: Bioinformatics (oxford, England), 2015-04-15 00:00:00.0; 31(8), p. 1310-2.
EPub date: 2014-12-12 00:00:00.0.
PMID: 25505086
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Mitochondrial Disease Sequence Data Resource (MSeqDR): a global grass-roots consortium to facilitate deposition, curation, annotation, and integrated analysis of genomic data for the mitochondrial disease clinical and research communities.
Authors: Falk M.J. , Shen L. , Gonzalez M. , Leipzig J. , Lott M.T. , Stassen A.P. , Diroma M.A. , Navarro-Gomez D. , Yeske P. , Bai R. , et al. .
Source: Molecular Genetics And Metabolism, 2015 Mar; 114(3), p. 388-96.
EPub date: 2014-12-04 00:00:00.0.
PMID: 25542617
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Actionable exomic incidental findings in 6503 participants: challenges of variant classification.
Authors: Amendola L.M. , Dorschner M.O. , Robertson P.D. , Salama J.S. , Hart R. , Shirts B.H. , Murray M.L. , Tokita M.J. , Gallego C.J. , Kim D.S. , et al. .
Source: Genome Research, 2015 Mar; 25(3), p. 305-15.
PMID: 25637381
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A one-page summary report of genome sequencing for the healthy adult.
Authors: Vassy J.L. , McLaughlin H.M. , McLaughlin H.L. , MacRae C.A. , Seidman C.E. , Lautenbach D. , Krier J.B. , Lane W.J. , Kohane I.S. , Murray M.F. , et al. .
Source: Public Health Genomics, 2015; 18(2), p. 123-9.
EPub date: 2015-01-21 00:00:00.0.
PMID: 25612602
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Detection of Chromosomal Aberrations in Clinical Practice: From Karyotype to Genome Sequence.
Authors: Martin C.L. , Warburton D. .
Source: Annual Review Of Genomics And Human Genetics, 2015; 16, p. 309-26.
EPub date: 2015-05-06 00:00:00.0.
PMID: 26077817
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A systematic approach to the reporting of medically relevant findings from whole genome sequencing.
Authors: McLaughlin H.M. , Ceyhan-Birsoy O. , Christensen K.D. , Kohane I.S. , Krier J. , Lane W.J. , Lautenbach D. , Lebo M.S. , Machini K. , MacRae C.A. , et al. .
Source: Bmc Medical Genetics, 2014-12-14 00:00:00.0; 15, p. 134.
EPub date: 2014-12-14 00:00:00.0.
PMID: 25714468
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Genomic Variation: Lessons Learned from Whole-Genome CNV Analysis.
Authors: Riggs E.R. , Ledbetter D.H. , Martin C.L. .
Source: Current Genetic Medicine Reports, 2014; 2, p. 146-150.
EPub date: 2014-07-18 00:00:00.0.
PMID: 25152847
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A systematic approach to assessing the clinical significance of genetic variants.
Authors: Duzkale H. , Shen J. , McLaughlin H. , Alfares A. , Kelly M.A. , Pugh T.J. , Funke B.H. , Rehm H.L. , Lebo M.S. .
Source: Clinical Genetics, 2013 Nov; 84(5), p. 453-63.
PMID: 24033266
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A standardized, evidence-based protocol to assess clinical actionability of genetic disorders associated with genomic variation.
Authors: Hunter J.E. , Irving S.A. , Biesecker L.G. , Buchanan A. , Jensen B. , Lee K. , Martin C.L. , Milko L. , Muessig K. , Niehaus A.D. , et al. .
Source: Genetics In Medicine : Official Journal Of The American College Of Medical Genetics, 2016 12; 18(12), p. 1258-1268.
EPub date: 2016-04-28 00:00:00.0.
PMID: 27124788
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A Clinician's perspective on clinical exome sequencing.
Authors: O'Donnell-Luria A.H. , Miller D.T. .
Source: Human Genetics, 2016 06; 135(6), p. 643-54.
EPub date: 2016-04-28 00:00:00.0.
PMID: 27126233
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BRAT1 mutations present with a spectrum of clinical severity.
Authors: Srivastava S. , Olson H.E. , Cohen J.S. , Gubbels C.S. , Lincoln S. , Davis B.T. , Shahmirzadi L. , Gupta S. , Picker J. , Yu T.W. , et al. .
Source: American Journal Of Medical Genetics. Part A, 2016 09; 170(9), p. 2265-73.
EPub date: 2016-06-09 00:00:00.0.
PMID: 27282546
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Commentary: 2016 Clinical Epilepsia Prize.
Authors: Miller D.T. .
Source: Epilepsia, 2016 09; 57(9), p. 1345-6.
EPub date: 2016-08-14 00:00:00.0.
PMID: 27522563
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Genomic sequencing in clinical practice: applications, challenges, and opportunities.
Authors: Krier J.B. , Kalia S.S. , Green R.C. .
Source: Dialogues In Clinical Neuroscience, 2016 09; 18(3), p. 299-312.
PMID: 27757064
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A curated gene list for reporting results of newborn genomic sequencing.
Authors: Ceyhan-Birsoy O. , Machini K. , Lebo M.S. , Yu T.W. , Agrawal P.B. , Parad R.B. , Holm I.A. , McGuire A. , Green R.C. , Beggs A.H. , et al. .
Source: Genetics In Medicine : Official Journal Of The American College Of Medical Genetics, 2017 07; 19(7), p. 809-818.
EPub date: 2017-01-12 00:00:00.0.
PMID: 28079900
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Evolving health care through personal genomics.
Authors: Rehm H.L. .
Source: Nature Reviews. Genetics, 2017 04; 18(4), p. 259-267.
EPub date: 2017-01-31 00:00:00.0.
PMID: 28138143
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The current state of clinical interpretation of sequence variants.
Authors: Hoskinson D.C. , Dubuc A.M. , Mason-Suares H. .
Source: Current Opinion In Genetics & Development, 2017 Feb; 42, p. 33-39.
EPub date: 2017-01-31 00:00:00.0.
PMID: 28157586
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Clinical laboratories collaborate to resolve differences in variant interpretations submitted to ClinVar.
Authors: Harrison S.M. , Dolinsky J.S. , Knight Johnson A.E. , Pesaran T. , Azzariti D.R. , Bale S. , Chao E.C. , Das S. , Vincent L. , Rehm H.L. .
Source: Genetics In Medicine : Official Journal Of The American College Of Medical Genetics, 2017 10; 19(10), p. 1096-1104.
EPub date: 2017-03-16 00:00:00.0.
PMID: 28301460
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Copy number variant discrepancy resolution using the ClinGen dosage sensitivity map results in updated clinical interpretations in ClinVar.
Authors: Riggs E.R. , Nelson T. , Merz A. , Ackley T. , Bunke B. , Collins C.D. , Collinson M.N. , Fan Y.S. , Goodenberger M.L. , Golden D.M. , et al. .
Source: Human Mutation, 2018 Nov; 39(11), p. 1650-1659.
PMID: 30095202
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Curating Clinically Relevant Transcripts for the Interpretation of Sequence Variants.
Authors: DiStefano M.T. , Hemphill S.E. , Cushman B.J. , Bowser M.J. , Hynes E. , Grant A.R. , Siegert R.K. , Oza A.M. , Gonzalez M.A. , Amr S.S. , et al. .
Source: The Journal Of Molecular Diagnostics : Jmd, 2018 Nov; 20(6), p. 789-801.
EPub date: 2018-08-08 00:00:00.0.
PMID: 30096381
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Effectiveness of a Web-Based Personalized Rheumatoid Arthritis Risk Tool With or Without a Health Educator for Knowledge of Rheumatoid Arthritis Risk Factors.
Authors: Prado M.G. , Iversen M.D. , Yu Z. , Miller Kroouze R. , Triedman N.A. , Kalia S.S. , Lu B. , Green R.C. , Karlson E.W. , Sparks J.A. .
Source: Arthritis Care & Research, 2018 Oct; 70(10), p. 1421-1430.
PMID: 29316383
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A Commentary on Opportunities for the Genetic Counseling Profession through Genomic Variant Interpretation: Reflections from an Ex-Lab Rat.
Authors: Wain K. .
Source: Journal Of Genetic Counseling, 2018 Aug; 27(4), p. 747-750.
EPub date: 2018-03-10 00:00:00.0.
PMID: 29525931
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