ClinVar

Description

The p.C1513G variant (also known as c.4537T>G), located in coding exon 36 of the FBN1 gene, results from a T to G substitution at nucleotide position 4537. The cysteine at codon 1513 is replaced by glycine, an amino acid with highly dissimilar properties, and is located in the cbEGF-like #22 domain. 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 particular alteration has been reported in one individual with classical Marfan syndrome (MFS) who was heterozygous for a second, nearby FBN1 variant (c.4536C>A p.D1512E) (Yoo EH et al. Clin. Genet. 2010;77:177-82). Two likely pathogenic alterations in the same codon (p.C1513R and p.C1513W) have also been associated with MFS (Kainulainen K et al. Nat. Genet. 1994;6:64-9; Ganesh A et al. Arch. Ophthalmol. 2006;124:205-9). Internal structural analysis indicates that this alteration disrupts a disulfide bond and is structurally destabilizing (Lee SS et al. Structure. 2004;12(4):717-29). 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.