Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV002311111 | SCV000320020 | likely pathogenic | Familial thoracic aortic aneurysm and aortic dissection | 2017-04-05 | criteria provided, single submitter | clinical testing | The p.C2302S variant (also known as c.6904T>A), located in coding exon 56 of the FBN1 gene, results from a T to A substitution at nucleotide position 6904. The cysteine at codon 2302 is replaced by serine, an amino acid with dissimilar properties. This amino acid position is located in calcium-binding EGF-like domain 40. This variant occurred de novo in an internal affected proband whose parents were clinically asymptomatic. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Another alteration at the same codon, C2302Y, has been reported in a 19 year-old with some features of Marfan syndrome, including major cardiovascular involvement and minor involvement of the skeletal system, skin, and integument, but who did not fulfill Gent clinical diagnostic criteria (Comeglio P et al. Hum. Mutat. 2007 Sep;28(9):928). Moreover, 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. |
| Gene |
RCV000489245 | SCV000576715 | pathogenic | not provided | 2017-04-20 | criteria provided, single submitter | clinical testing | The C2302S variant in the FBN1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The C2302S variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The C2302S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. A missense variant in the same residue (C2302Y) has been reported in an individual with features of either Marfan syndrome or a Marfan-related disorder (Comeglio et al., 2007), supporting the functional importance of this region of the protein. We interpret C2302S as a pathogenic variant. |