The Frequency of Discordant Variant Classification in the Human Gene Mutation Database: A Comparison of the American College of Medical Genetics and Genomics Guidelines and ClinVar - PubMed

The Frequency of Discordant Variant Classification in the Human Gene Mutation Database: A Comparison of the American College of Medical Genetics and Genomics Guidelines and ClinVar - PubMed

The Frequency of Discordant Variant Classification in the Human Gene Mutation Database: A Comparison of the American College of Medical Genetics and Genomics Guidelines and ClinVar

Kyoung-Jin Park 1, Woochang Lee 2, Sail Chun 2, Won-Ki Min 2

Affiliations 

• PMID: 32926152
 
• DOI: 10.1093/labmed/lmaa072

Abstract

Objective: Discordant variant classifications among public databases is one of the well-documented limitations when interpreting the pathogenicity of variants. The aim of this study is to investigate the level of germline variant misannotation from the Human Gene Mutation Database (HGMD) and the annotation concordance between databases.

Methods: We used a total of 188,106 classified variants (disease-causing mutations [n = 179,454] and polymorphisms [n = 8652]) in 6466 genes from the HGMD. All variants were reanalyzed based on the American College of Medical Genetics and Genomics (ACMG) guidelines and compared to ClinVar database variants.

Results: When variants were classified based on the ACMG guidelines, misclassification was observed in 3.47% (2289/65,896) of variants. The overall concordance between HGMD and ClinVar was 97.62% (52,499/53,780) of variants studied.

Conclusion: Variants in databases must be used with caution when variant pathogenicity is interpreted. This study reveals the frequency of misannotation of the HGMD variants and annotation concordance between databases in depth.

Keywords: ClinVar; Human Gene Mutation Database; classification; database; pathogenicity; variant.

© American Society for Clinical Pathology 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Similar articles

• Clinical Variant Classification: A Comparison of Public Databases and a Commercial Testing Laboratory.

  Gradishar W, Johnson K, Brown K, Mundt E, Manley S.Oncologist. 2017 Jul;22(7):797-803. doi: 10.1634/theoncologist.2016-0431. Epub 2017 Apr 13.PMID: 28408614 Free PMC article.
• Reduced penetrance of pathogenic ACMG variants in a deeply phenotyped cohort study and evaluation of ClinVar classification over time.

  van Rooij J, Arp P, Broer L, Verlouw J, van Rooij F, Kraaij R, Uitterlinden A, Verkerk AJMH.Genet Med. 2020 Jul 15. doi: 10.1038/s41436-020-0900-8. Online ahead of print.PMID: 32665702
• Application of ACMG criteria to classify variants in the human gene mutation database.

  Qu HQ, Wang X, Tian L, Hakonarson H.J Hum Genet. 2019 Nov;64(11):1091-1095. doi: 10.1038/s10038-019-0663-8. Epub 2019 Aug 26.PMID: 31451714
• Mucopolysaccharidosis type VI (MPS VI) and molecular analysis: Review and classification of published variants in the ARSB gene.

  Tomanin R, Karageorgos L, Zanetti A, Al-Sayed M, Bailey M, Miller N, Sakuraba H, Hopwood JJ.Hum Mutat. 2018 Dec;39(12):1788-1802. doi: 10.1002/humu.23613. Epub 2018 Sep 17.PMID: 30118150 Free PMC article. Review.
• Difficulties in diagnosing Marfan syndrome using current FBN1 databases.

  Groth KA, Gaustadnes M, Thorsen K, Østergaard JR, Jensen UB, Gravholt CH, Andersen NH.Genet Med. 2016 Jan;18(1):98-102. doi: 10.1038/gim.2015.32. Epub 2015 Mar 26.PMID: 25812041 Review.