Ann Lab Med.  2024 May;44(3):271-278. 10.3343/alm.2023.0152.

Re-evaluation of a Fibrillin-1 Gene Variant of Uncertain Significance Using the ClinGen Guidelines

• Kim SW
• Kim B
• Kim Y
• Lee KA

• KMID: 2555698
• DOI: http://doi.org/10.3343/alm.2023.0152

Abstract

Background
Marfan syndrome (MFS) is caused by fibrillin-1 gene (FBN1) variants. Mutational hotspots and/or well-established critical functional domains of FBN1 include cysteine residues, calcium-binding consensus sequences, and amino acids related to interdomain packaging. Previous guidelines for variant interpretation do not reflect the features of genes or related diseases. Using the Clinical Genome Resource (ClinGen) FBN1 variant curation expert panel (VCEP), we re-evaluated FBN1 germline variants reported as variants of uncertain significance (VUSs).
Methods
We re-evaluated 26 VUSs in FBN1 reported in 161 patients with MFS. We checked the variants in the Human Genome Mutation Database, ClinVar, and VarSome databases and assessed their allele frequencies using the gnomAD database. Patients’ clinical information was reviewed.
Results
Four missense variants affecting cysteines (c.460T > C, c.1006T > C, c.5330G > C, and c.8020T > C) were reclassified as likely pathogenic and were assigned PM1_strong or PM1. Two intronic variants were reclassified as benign by granting BA1 (stand-alone). Four missense variants were reclassified as likely benign. BP5 criteria were applied in cases with an alternate molecular basis for disease, one of which (c.7231G > A) was discovered alongside a pathogenic de novo COL3A1 variant (c.1988G > T, p.Gly633Val).
Conclusions
Considering the high penetrance of FBN1 variants and clinical variability of MFS, the detection of pathogenic variants is important. The ClinGen FBN1 VCEP encompasses mutational hotspots and/or well-established critical functional domains and adjusts the criteria specifically for MFS; therefore, it is beneficial not only for identifying pathogenic FBN1 variants but also for distinguishing these variants from those that cause other connective tissue disorders with overlapping clinical features.

Keyword

ClinGen; Connective tissue; Fibrillin-1; Gene frequency; Marfan syndrome; Penetrance

Figure

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  Fig. 1 Classification of reported FBN1 variants according to the ACMG/AMP guidelines. In this study, 161 patients diagnosed as having MFS, suspected of having MFS (presenting marfanoid features), or with aortic aneurysm/dissection were enrolled. Seventy-three FBN1 variants were identified in 69 of these patients. The ACMG/AMP guidelines were used to classify the 73 variants as PV, LPV, VUS, LBV, or BV. Among 26 VUSs, 24 different types were reported in 26 patients. Abbreviations: ACMG/AMP, American College of Medical Genetics and Association for Molecular Pathology; MFS, marfan syndrome; PV, pathogenic variant; LPV, likely pathogenic variant; VUS, variant of uncertain significance; LBV, likely benign variant; BV, benign variant.

Reference

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