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.
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.
摘要：
背景：尽管2015年美国医学遗传学和基因组学学院（ACMG）和分子病理学协会（AMP）指南，FBN1基因的许多变体仍然没有定论。根据ClinGen于2022年发布的FBN1特异性变异解释指南，我们重新评估了在我们机构中发现的FBN1基因中具有不确定意义的变异（VUS）。
方法：在2015年12月至2022年4月的FBN1测序过程中发现的VUS根据FBN1特异性变异解释指南进行了重新评估。审查最新文献和其他基因测试，包括家族研究和/或RNA研究（如果可用）。
结果：在695名接受FBN1测序的患者中，69例患者中发现61例VUS。其中,43例(62.3%)的38例VUS被重新分类为致病性和可能的致病性变异((L)PV)，包括20个新颖的(L)PV。重新分类的主要原因是：（1）ACMG/AMP标准的基因特异性修饰，(2)更新文献和(3)补充基因检测。重新分类的最重要证据是关键氨基酸残基的澄清。
结论：根据FBN1特定指南和最新数据库重新评估FBN1变异体后，大量的VUS被重新分类.鼓励临床实验室定期或在变体解释原理发生重大变化时进行变体重新评估。
方法：在2015年12月至2022年4月的FBN1测序过程中发现的VUS根据FBN1特异性变异解释指南进行了重新评估。审查最新文献和其他基因测试，包括家族研究和/或RNA研究（如果可用）。
结果：在695名接受FBN1测序的患者中，69例患者中发现61例VUS。其中,43例(62.3%)的38例VUS被重新分类为致病性和可能的致病性变异((L)PV)，包括20个新颖的(L)PV。重新分类的主要原因是：（1）ACMG/AMP标准的基因特异性修饰，(2)更新文献和(3)补充基因检测。重新分类的最重要证据是关键氨基酸残基的澄清。
结论：根据FBN1特定指南和最新数据库重新评估FBN1变异体后，大量的VUS被重新分类.鼓励临床实验室定期或在变体解释原理发生重大变化时进行变体重新评估。
