ClinVar

Description

The p.C1895R variant (also known as c.5683T>C), located in coding exon 46 of the FBN1 gene, results from a T to C substitution at nucleotide position 5683. The cysteine at codon 1895 is replaced by arginine, an amino acid with highly dissimilar properties, and is located in the cb EGF-like #28 domain. This variant was reported in a patient with Marfan syndrome (Arbustini E et al, Hum Mutat. 2005 Nov; 26(5):494), as well as another individual with features of connective tissue disorder (Oh MR et al, Pediatr Int. 2000 Oct; 42(5):488-91). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6494 samples (12988 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be probably damaging and deleterious by PolyPhen and SIFT in silico analyses, respectively. Based on internal structural analysis, this variant results in a loss of the C1895-C1905 disulfide bond and is anticipated to result in a significant decrease in structural stability (Downing AK et al, Cell. 1996 May; 85(4):597-605). 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). Based on the majority of available evidence to date, this variant is likely to be pathogenic.