Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000465552 | SCV000544885 | likely pathogenic | Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection | 2019-06-11 | criteria provided, single submitter | clinical testing | This sequence change replaces cysteine with glycine at codon 2509 of the FBN1 protein (p.Cys2509Gly). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and glycine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a FBN1-related disease. This variant affects a cysteine residue located within an epidermal-growth-factor (EGF)–like domain of the FBN1 protein. Cysteine residues in these domains have been shown to be involved in the formation of disulfide bridges, which are critical for FBN1 protein structure and stability (PMID: 10486319, 3495735, 4750422, 16677079). In addition, missense substitutions within the FBN1 EGF-like domains affecting cysteine residues are significantly overrepresented among patients with Marfan syndrome (PMID: 16571647, 17701892). Other missense variants affecting this cysteine residue have been observed in individuals with Marfan syndrome (PMID: 19293843, 26787436). In summary, this variant is a novel missense change affecting a residue crucial for protein stability and function. Although additional genetic data will be necessary to further confirm pathogenicity for this variant, cysteine substitutions located in FBN1 EGF-like domains are likely deleterious. For these reasons, this variant has been classified as Likely Pathogenic. |
| Ambry Genetics | RCV002393094 | SCV002669124 | likely pathogenic | Familial thoracic aortic aneurysm and aortic dissection | 2018-04-12 | criteria provided, single submitter | clinical testing | The p.C2509G variant (also known as c.7525T>G), located in coding exon 60 of the FBN1 gene, results from a T to G substitution at nucleotide position 7525. The cysteine at codon 2509 is replaced by glycine, an amino acid with highly dissimilar properties. 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 internal structural assessment, this alteration eliminates a structurally critical disulfide in the structurally sensitive cbEGF domain #39. In addition, alterations affecting the same cysteine, p.C2509W and p.C2509Y, have been reported in individuals with Marfan syndrome (Franken R et al. Eur. Heart J., 2016 Nov;37:3285-3290; Stheneur C et al. Eur. J. Hum. Genet., 2009 Sep;17:1121-8). 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. |