Using ClinVar as a Resource to Support Variant Interpretation

Steven M. Harrison1, Erin R. Riggs2, Donna R. Maglott3, Jennifer M. Lee3, Danielle R. Azzariti4, Annie Niehaus5, Erin M. Ramos5, Christa L. Martin2, Melissa J. Landrum6, Heidi L. Rehm6

1 Harvard Medical School, Boston, Massachusetts, 2 Geisinger Health System, Danville, Pennsylvania, 3 National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Rockville, Maryland, 4 Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, Cambridge, Massachusetts, 5 National Human Genome Research Institute, National Institutes of Health, Rockville, Maryland, 6 These authors contributed equally to this work
Publication Name:  Current Protocols in Human Genetics
Unit Number:  Unit 8.16
DOI:  10.1002/0471142905.hg0816s89
Online Posting Date:  April, 2016
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Abstract

ClinVar is a freely accessible, public archive of reports of the relationships among genomic variants and phenotypes. To facilitate evaluation of the clinical significance of each variant, ClinVar aggregates submissions of the same variant, displays supporting data from each submission, and determines if the submitted clinical interpretations are conflicting or concordant. The unit describes how to (1) identify sequence and structural variants of interest in ClinVar by multiple searching approaches, including Variation Viewer and (2) understand the display of submissions to ClinVar and the evidence supporting each interpretation. By following this protocol, ClinVar users will be able to learn how to incorporate the wealth of resources and knowledge in ClinVar into variant curation and interpretation. © 2016 by John Wiley & Sons, Inc.

Keywords: clinical genetics; variant interpretation; ClinVar; data sharing; databases

     
 
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Table of Contents

  • Introduction
  • Basic Protocol 1: Identifying Specific Variant Records in ClinVar
  • Alternate Protocol 1: Identifying All ClinVar Variants that Meet Specific Criteria
  • Alternate Protocol 2: Using Variation Viewer to Identify Variant Records in ClinVar
  • Support Protocol 1: Downloading ClinVar Variant Data
  • Basic Protocol 2: Using ClinVar as a Resource to Inform Variant Interpretation
  • Commentary
  • Literature Cited
  • Figures
  • Tables
     
 
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Materials

Basic Protocol 1: Identifying Specific Variant Records in ClinVar

  Necessary Resources
  • Up‐to‐date Web browser
  • Internet‐connected device

Alternate Protocol 1: Identifying All ClinVar Variants that Meet Specific Criteria

  Necessary Resources
  • Up‐to‐date Web browser
  • Internet‐connected device

Alternate Protocol 2: Using Variation Viewer to Identify Variant Records in ClinVar

  Necessary Resources
  • Up‐to‐date Web browser
  • Internet‐connected device

Support Protocol 1: Downloading ClinVar Variant Data

  Necessary Resources
  • Up‐to‐date Web browser
  • Internet‐connected device
  • Appropriate spreadsheet application
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Figures

Videos

Literature Cited

Literature Cited
  den Dunnen, J.T. and Antonarakis, S.E. 2001. Nomenclature for the description of human sequence variations. Hum. Genet. 109:121‐124. doi: 10.1007/s004390100505.
  Kearney, H.M., Thorland, E.C., Brown, K.K., Quintero‐Rivera, F., and South, S.T. 2011. American College of Medical Genetics standards and guidelines for interpretation and reporting of postnatal constitutional copy number variants. Genet. Med. 13:680‐685. doi: 10.1097/GIM.0b013e3182217a3a.
  Landrum, M.J., Lee, J.M., Riley, G.R., Jang, W., Rubinstein, W.S., Church, D.M., and Maglott, D.R. 2014. ClinVar: Public archive of relationships among sequence variation and human phenotype. Nucleic Acids Res. 42:D980‐D985. doi: 10.1093/nar/gkt1113.
  MacArthur, J.A., Morales, J., Tully, R.E., Astashyn, A., Gil, L., Bruford, E.A., Larsson, P., Flicek, P., Dalgleish, R., Maglott, D.R., and Cunningham, F. 2014. Locus reference genomic: Reference sequences for the reporting of clinically relevant sequence variants. Nucleic Acids Res. 42:D873‐D878. doi: 10.1093/nar/gkt1198.
  Pruitt, K.D., Brown, G.R., Hiatt, S.M., Thibaud‐Nissen, F., Astashyn, A., Ermolaeva, O., Farrell, C.M., Hart, J., Landrum, M.J., McGarvey, K.M., Murphy, M.R., O”Leary, N.A., Pujar, S., Rajput, B., Rangwala, S.H., Riddick, L.D., Shkeda, A., Sun, H., Tamez, P., Tully, R.E., Wallin, C., Webb, D., Weber, J., Wu, W., DiCuccio, M., Kitts, P., Maglott, D.R., Murphy, T.D., and Ostell, J.M. 2014. RefSeq: An update on mammalian reference sequences. Nucleic Acids Res. 42:D756‐D763. doi: 10.1093/nar/gkt1114.
  Richards, S., Aziz, N., Bale, S., Bick, D., Das, S., Gastier‐Foster, J., Grody, W.W., Hegde, M., Lyon, E., Spector, E., Voelkerding, K., and Rehm, H.L. 2015. 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. Genet. Med. 17:405‐424. doi: 10.1038/gim.2015.30.
  Riggs, E.R., Church, D.M., Hanson, K., Horner, V.L., Kaminsky, E.B., Kuhn, R.M., Wain, K.E., Williams, E.S., Aradhya, S., Kearney, H.M., Ledbetter, D.H., South, S.T., Thorland, E.C., and Martin, C.L. 2012. Towards an evidence‐based process for the clinical interpretation of copy number variation. Clin. Genet. 81:403‐412. doi: 10.1111/j.1399‐0004.2011.01818.x.
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