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Diagnostics
Short report
Experience of reassessing FBN1 variants of uncertain significance by gene-specific guidelines
  1. Eungjun Yoon1,
  2. Jong Kwon Lee1,
  3. Taek Kyu Park2,
  4. Sung-A Chang2,
  5. June Huh3,
  6. Jong-Won Kim1,
  7. Duk-Kyung Kim2,4,
  8. Ja-Hyun Jang1
  1. 1 Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
  2. 2 Division of Cardiology, Department of Medicine, Heart Vascular Stroke Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
  3. 3 Division of Cardiology, Department of Pediatrics, Adult Congenital Heart Disease Clinic, Heart Vascular Stroke Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
  4. 4 Division of Cardiology, Department of Medicine, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, Republic of Korea
  1. Correspondence to Professor Ja-Hyun Jang, Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; jahyun.jang{at}gmail.com; Professor Duk-Kyung Kim, Division of Cardiology, Department of Medicine, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, Republic of Korea; dukkyung11.kim{at}samsung.com

Abstract

Background Despite the 2015 American College of Medical Genetics and Genomics (ACMG) and Association of Molecular Pathology (AMP) guideline, many variants of FBN1 gene remain inconclusive. In line with publication of the FBN1-specific variant interpretation guideline by ClinGen in 2022, we reassessed variants of uncertain significance (VUS) in FBN1 gene found in our institution.

Methods VUS found in the course of FBN1 sequencing between December 2015 and April 2022 were reassessed based on FBN1-specific variant interpretation guideline, review of updated literatures and additional genetic tests including family study and/or RNA study if available.

Results Out of 695 patients who underwent FBN1 sequencing, 61 VUS were found in 69 patients. Among them, 38 VUS in 43 patients (62.3%) were reclassified as pathogenic and likely pathogenic variant ((L)PV), including 20 novel (L)PV. Major causes of reclassification were: (1) gene-specific modification of ACMG/AMP criteria, (2) updated literatures and (3) additional genetic tests. The most important evidence for reclassification was clarification of critical amino acid residues.

Conclusions After reassessing FBN1 variants according to FBN1-specific guideline and up-to-date database, a significant number of VUS was reclassified. Clinical laboratories are encouraged to perform variant reassessment at regular intervals or when there is a major change in the principle of variant interpretation.

  • genetic variation
  • sequence analysis

https://doi.org/10.1136/jmg-2023-109433

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    Footnotes

    • EY and JKL contributed equally.

    • D-KK and J-HJ contributed equally.

    • Correction notice This article has been corrected since it was published Online First. One of the ORCID IDs has been amended.

    • Contributors Conceptualisation: J-WK, J-HJ, EY, JKL. Data curation: EY, JKL. Formal analysis: EY. Visualisation: EY. Writing—original draft: EY, JKL. Writing—review and editing: EY, JKL, TKP, S-AC, JH, D-KK, J-WK, J-HJ.

    • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.