ClinVar

Description

Variant summary: The FBN1 c.2939G>T (p.Cys980Phe) variant causes a missense change involving the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). The variant of interest lies in a conserved region within a TGF-beta binding (TB) domain. Many manifestations of Marfan syndrome relate to excess activation and signaling by the growth factor TGF-beta (Dietz_2005). This variant leads to the substitution of cysteine with phenylalanine. The sulfhydryl group of cysteine is unique in its ability to participate in disulfide covalent cross-linkage. In fact, two thirds of fibrillin cysteine residues exist in the half-cystinyl form, suggesting their participation in intramolecular disulfide linkage. Therefore, alteration of cysteine in this domain could disrupt disulfide binding, affecting secondary or tertiary structure or possibly impairing fibrillin interactions. Further supporting the critical function of Cys980, p.Cys980Ser and p.Cys980Tyr have been reported to associate with MFS in HGMD. The variant of interest is absent in a large, broad control population, ExAC in 121332 control chromosomes. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as likely pathogenic.