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

BACKGROUND

Marfan syndrome (MFS) is caused by fibrillin-1 gene () variants. Mutational hotspots and/or well-established critical functional domains of 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) variant curation expert panel (VCEP), we re-evaluated germline variants reported as variants of uncertain significance (VUSs).

METHODS

We re-evaluated 26 VUSs in 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 COL3A1 variant (c.1988G>T, p.Gly633Val).

CONCLUSIONS

Considering the high penetrance of variants and clinical variability of MFS, the detection of pathogenic variants is important. The ClinGen 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 variants but also for distinguishing these variants from those that cause other connective tissue disorders with overlapping clinical features.