ClinVar

Description

Variant summary: The FBN1 c.2953G>A (p.Gly985Arg) missense variant involves the alteration of a conserved nucleotide and is predicted to be damaging by 4/4 in silico tools. This variant is located in TB domain and glycines in the FBN1 gene are implicated in correct domain-domain packing (Faive_2009). This variant is absent in 121470 control chromosomes (including ExAC). This variant has been reported in several MFS (classic as well as incomplete MFS) patients. In one family, this variant was found in three affected members with MFS or MFS-like syndrome but not in five unaffected members, indicating cosegregation with disease (Howarth_2007). In two other families, probands affected with classic MFS and two first-degree relatives in each family carried the variant; however affected status of the family members was not clearly indicated (Ware_2016). In contrast to the pathogenic outcome from these three families, a study reclassified this variant to benign from family segregation analysis (Yang_2016). However, genotypic and phenotypic details of family members were not provided, limiting independent evaluation of the evidences. Two clinical diagnostic laboratories (via ClinVar) have classified this variant as likely pathogenic (one has noted the finding of Yang_2016). Another missense change at the same residue G985E has also been reported in a patient with MFS, suggesting that Gly985 codon could be mutational hot-spot. Based on the currently available data, this variant is classified as likely pathogenic.