Variability in assigning pathogenicity to incidental findings: insights from LDLR sequence linked to the electronic health record in 1013 individuals
| Autor: | Michelle L. Kluge, Suzette J. Bielinski, Eric W. Klee, Janet E. Olson, Erin M. Winkler, Iftikhar J. Kullo, Linnea M. Baudhuin, Maya S. Safarova |
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| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine Context (language use) Biology Article Hyperlipoproteinemia Type II 03 medical and health sciences Gene Frequency Polymorphism (computer science) Databases Genetic Genetics medicine Electronic Health Records Humans Genetic Testing Allele frequency Genetics (clinical) Aged Sequence (medicine) Genetic testing Observer Variation Incidental Findings Polymorphism Genetic medicine.diagnostic_test Middle Aged Biobank Minor allele frequency 030104 developmental biology Receptors LDL LDL receptor Female |
| Zdroj: | European Journal of Human Genetics. 25:410-415 |
| ISSN: | 1476-5438 1018-4813 |
| DOI: | 10.1038/ejhg.2016.193 |
| Popis: | 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) 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. |
| Databáze: | OpenAIRE |
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