ClinVar

Description

Variant summary: FBN1 c.6410G>A (p.Cys2137Tyr) results in a non-conservative amino acid change. This variant lies in a conserved region within EGF-like #32. "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. The cysteine residues in the EGF-like motif may also be necessary for intermolecular interactions with other fibrillin molecules or with other proteins (Dietz_1992)." Therefore, alteration of cysteine in this domain could disrupt disulfide binding, affecting secondary or tertiary structure or possibly impairing fibrillin interactions. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 121012 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.6410G>A in individuals affected with Marfan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as a VUS - possibly pathogenic variant.