Copy number variant discrepancy resolution using the ClinGen dosage sensitivity map results in updated clinical interpretations in ClinVar

Erin R. Riggs, Tristan Nelson, Andrew Merz, Todd Ackley, Brian Bunke, Christin D. Collins, Morag N. Collinson, Yao Shan Fan, McKinsey L. Goodenberger, Denae M. Golden, Linda Haglund-Hazy, Danijela Krgovic, Allen N. Lamb, Zoe Lewis, Guang Li, Yajuan Liu, Jeanne Meck, Whitney Neufeld-Kaiser, Cassandra K. Runke, Jennifer N. SanmannDimitri J. Stavropoulos, Emma Strong, Meng Su, Marwan K. Tayeh, Nadja Kokalj Vokac, Erik C Thorland, Erica Andersen, Christa L. Martin

Research output: Contribution to journalArticle

6 Scopus citations


Conflict resolution in genomic variant interpretation is a critical step toward improving patient care. Evaluating interpretation discrepancies in copy number variants (CNVs) typically involves assessing overlapping genomic content with focus on genes/regions that may be subject to dosage sensitivity (haploinsufficiency (HI) and/or triplosensitivity (TS)). CNVs containing dosage sensitive genes/regions are generally interpreted as “likely pathogenic” (LP) or “pathogenic” (P), and CNVs involving the same known dosage sensitive gene(s) should receive the same clinical interpretation. We compared the Clinical Genome Resource (ClinGen) Dosage Map, a publicly available resource documenting known HI and TS genes/regions, against germline, clinical CNV interpretations within the ClinVar database. We identified 251 CNVs overlapping known dosage sensitive genes/regions but not classified as LP or P; these were sent back to their original submitting laboratories for re-evaluation. Of 246 CNVs re-evaluated, an updated clinical classification was warranted in 157 cases (63.8%); no change was made to the current classification in 79 cases (32.1%); and 10 cases (4.1%) resulted in other types of updates to ClinVar records. This effort will add curated interpretation data into the public domain and allow laboratories to focus attention on more complex discrepancies.

Original languageEnglish (US)
Pages (from-to)1650-1659
Number of pages10
JournalHuman Mutation
Issue number11
StatePublished - Nov 1 2018



  • ClinGen
  • ClinVar
  • CNV discrepancy
  • dosage sensitivity
  • variant interpretation

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

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., Haglund-Hazy, L., Krgovic, D., Lamb, A. N., Lewis, Z., Li, G., Liu, Y., Meck, J., Neufeld-Kaiser, W., Runke, C. K., ... Martin, C. L. (2018). Copy number variant discrepancy resolution using the ClinGen dosage sensitivity map results in updated clinical interpretations in ClinVar. Human Mutation, 39(11), 1650-1659.