ClinVar

Description

The p.C734S variant (also known as c.2200T>A), located in coding exon 18 of the FBN1 gene, results from a T to A substitution at nucleotide position 2200. The cysteine at codon 734 is replaced by serine, an amino acid with dissimilar properties, and is located in the cbEGF-like #07 domain. Two other alterations at the same codon, p.C734F (c.2201G>T) and p.C734Y (c.2201G>A), have been reported in individuals with a clinical diagnosis of Marfan syndrome (Katzke S et al. Hum Mutat, 2002 Sep;20:197-208; Ogawa N et al. Am J Cardiol, 2011 Dec;108:1801-7; Ambry internal data). Based on internal structural assessment, this alteration eliminates a structurally critical disulfide bond in the structurally sensitive cbEGF domain #07. The majority of FBN1 mutations identified to date have involved the substitution or generation of cysteine residues within cbEGF domains (Vollbrandt T et al. J Biol Chem. 2004;279(31):32924-32931). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.