ClinVar

Description

The p.C1367Y variant (also known as c.4100G>A), located in coding exon 33 of the FBN1 gene, results from a G to A substitution at nucleotide position 4100. The cysteine at codon 1367 is replaced by tyrosine, an amino acid with highly dissimilar properties. This alteration has been reported in a Marfan syndrome cohort (Franken R et al. Eur Heart J, 2016 Nov;37:3285-3290). Based on internal structural assessment, this alteration eliminates a structurally critical disulfide bond in the structurally sensitive cbEGF domain #19. 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). Another alteration at the same codon, p.C1367R (c.4099T>C), has been reported in an individual with a clinical diagnosis of Marfan syndrome (Sakai H et al. Am J Med Genet A, 2006 Aug;140:1719-25). 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.