Abstract
Knowledge of variant pathogenicity is key to implementing genomic medicine. We describe variability between expert reviewers in assigning pathogenicity to sequence variants in LDLR, the causal gene in the majority of cases of familial hypercholesterolemia. LDLR was sequenced on the Illumina HiSeq platform (average read depth >200 × ) in 1013 Mayo Biobank participants recruited from 2012 to 2013. Variants with a minor allele frequency (MAF) <5% predicted to be functional or referenced in HGMD (Human Gene Mutation Database) or NCBI-ClinVar databases were reviewed. To assign pathogenicity, variant frequency in population data sets, computational predictions, reported observations and patient-level data including electronic health record-based post hoc phenotyping were leveraged. Of 178 LDLR variants passing quality control, 25 were selected for independent review using either an in-house protocol or a disease/gene-specific semi-quantitative framework based on the American College of Medical Genetics and Genomics-recommended lines of evidence. NCBI-ClinVar included interpretations for all queried variants with 74% (14/19) of variants with >1 submitter showing inconsistency in classification and 26% (5/19) appearing with conflicting clinical actionability. The discordance rate (one-step level of disagreement out of five classes in variant interpretation) between the reviewers was 40% (10/25). Two LDLR variants were independently deemed clinically actionable and returnable. Interpretation of LDLR variants was often discordant among ClinVar submitters and between expert reviewers. A quantitative approach based on strength of each predefined criterion in the context of specific genes and phenotypes may yield greater consistency between different reviewers.
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Acknowledgements
We thank the RIGHT Protocol and Mayo Clinic Biobank study investigators, field staff, and study participants. We thank Luanne F Wussow for assistance in preparation of the manuscript. We appreciate thoughtful comments on this contribution and valuable discussions with Xiao Fan PhD (Cardiovascular Biomarkers Research Laboratory, Mayo Clinic, Rochester, MN, USA). Dr Safarova is supported by AHA Postdoctoral Fellowship Award 16POST27280004. This study was funded as part of the National Human Genome Research Institute’s electronic Medical Records and Genomics Network grants to Mayo Clinic (HG04599 and HG006379), R01 GM28157, U01 HG005137, R01 CA138461, R01 AG034676 (The Rochester Epidemiology Project), and the Mayo Clinic Center for Individualized Medicine. The sequencing platform was developed by the next-generation sequencing centers of the Pharmacogenomics Research Network supported by NIH grants U19GM61388, U19HLO69757 and U01GMO97119. The National Human Genome Research Institute and American Heart Association had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review or approval of the manuscript, including the decision to submit the manuscript for publication. Discussion of this paper by Drs Kullo and Safarova is available in the Supplementary Video.
Web resources
NCBI-ClinVar database, http://www.ncbi.nlm.nih.gov/clinvar first assessed July 2015, last assessed August 2016, LDLR Leiden Open Variation, LOVD; versions 1.1.0 build 12, 2.0 build 36, and 3.0 build 13; http://www.ucl.ac.uk/ldlr/LOVDv.1.1.0/index.php?select_db=LDLR, http://www.ucl.ac.uk/ldlr, https://grenada.lumc.nl/LOVD2/UCL-Heart/home.php?select_db=LDLR, http://databases.lovd.nl/whole_genome/genes/LDLR assessed December 2015, NHLBI-Exome Variant Server, EVS; http://evs.gs.washington.edu/EVS/ assessed December 2015.
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Safarova, M., Klee, E., Baudhuin, L. et al. Variability in assigning pathogenicity to incidental findings: insights from LDLR sequence linked to the electronic health record in 1013 individuals. Eur J Hum Genet 25, 410–415 (2017). https://doi.org/10.1038/ejhg.2016.193
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DOI: https://doi.org/10.1038/ejhg.2016.193
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