Experience of reassessing FBN1 variants of uncertain significance by gene-specific guidelines

• Published in: Journal of medical genetics Vol. 61; no. 1; pp. 57 - 60
• Main Authors: Yoon, Eungjun, Lee, Jong Kwon, Park, Taek Kyu, Chang, Sung-A, Huh, June, Kim, Jong-Won, Kim, Duk-Kyung, Jang, Ja-Hyun
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group Ltd 01.01.2024; BMJ Publishing Group LTD
• Subjects: Adipokines - genetics; Amino acids; Connective tissue; Diagnostics; Epidermal growth factor; Fibrillin; Fibrillin-1 - genetics; Genes; Genetic screening; Genetic Testing; genetic variation; Genetic Variation - genetics; Genomics; Genotype & phenotype; High-Throughput Nucleotide Sequencing; Humans; Leukocytes; Medicine; Mutation; Patients; Reclassification; sequence analysis; Sequence Analysis, DNA; Standard scores; United States > US; South Korea; genetic variation; sequence analysis
• ISSN: 0022-2593; 1468-6244; 1468-6244
• DOI: 10.1136/jmg-2023-109433

AbstractBackgroundDespite 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.MethodsVUS 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.ResultsOut 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.ConclusionsAfter 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.