ClinVar

Description

This variant affects a cysteine residue located within a calcium-binding EGF-like domain of the FBN1 protein. Cysteine residues in cbEGF-like domains are involved in the formation of disulfide bridges, which are critical for FBN1 protein structure and stability (PMID: 4750422, 16677079). Computational prediction also suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, this variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different missense variant disrupting the same cysteine residue, p.Cys1402Tyr, is considered to be disease-causing (ClinVar variation ID: 519799), suggesting that cysteine at this position is important for the protein function. Based on the available evidence, this variant is classified as Likely Pathogenic.