Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000692304 | SCV000820118 | uncertain significance | Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection | 2018-01-29 | criteria provided, single submitter | clinical testing | This sequence change replaces tyrosine with cysteine at codon 2588 of the FBN1 protein (p.Tyr2588Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with FBN1-related disease. This variant is not present in population databases (ExAC no frequency). This variant generates a cysteine residue in 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: 4750422, 16677079). Cysteine creating variants in these domains have been shown to affect protein stability and are overrepresented among individuals with Marfan syndrome (PMID: 15161917, 16571647, 17701892). |
| Ambry Genetics | RCV002406569 | SCV002672195 | likely pathogenic | Familial thoracic aortic aneurysm and aortic dissection | 2018-04-30 | criteria provided, single submitter | clinical testing | The p.Y2588C variant (also known as c.7763A>G), located in coding exon 62 of the FBN1 gene, results from an A to G substitution at nucleotide position 7763. The tyrosine at codon 2588 is replaced by cysteine, an amino acid with highly dissimilar properties, and is located in the cbEGF-like #41 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 amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Furthermore, based on internal structural assessment, this alteration disrupts proper disulfide-mediated folding of cbEGF domain 41 (Jensen SA et al. Structure, 2009 May;17:759-68). Based on the majority of available evidence to date, this variant is likely to be pathogenic. |