Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000248573 | SCV000319182 | likely pathogenic | Cardiovascular phenotype | 2013-10-30 | criteria provided, single submitter | clinical testing | The p.C734Y variant (also known as c.2201G>A) is located in coding exon 18 of the FBN1 gene. This alteration results from a G to A substitution at nucleotide position 2201. The cysteine at codon 734 is replaced by tyrosine, an amino acid with highly dissimilar properties. Another alteration of the same codon in the cbEGF 7 domain, p.C734F (c.2201G>T), was reported in a patient who required surgery at 15 years of age for significant aortic root dilatation, so the phenotype was defined as "atypically severe" (Katzke S et al. Hum Mutat. 2002;20(3):197-208). In general, cysteine substitutions that disrupt disulfide bridges that connect highly conserved cysteine residues in EGF-like domains are present in approximately 25% of all patients with Marfan syndrome (MFS) and in others not meeting MFS diagnostic criteria; a high frequency of ectopia lentis is associated with these types of mutations (Schrijver I et al. Am J Hum Genet. 1999;65(4):1007-1020).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. Based on protein sequence alignment, 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 available evidence to date, this variant is likely to be pathogenic. |
| Labcorp Genetics |
RCV000706264 | SCV000835304 | likely pathogenic | Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection | 2018-06-28 | criteria provided, single submitter | clinical testing | This sequence change replaces cysteine with tyrosine at codon 734 of the FBN1 protein (p.Cys734Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with FBN1-related disease. ClinVar contains an entry for this variant (Variation ID: 263790). 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). 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). A different missense substitution at this codon (p.Cys734Phe) has been reported in an individual affected with Marfan syndrome (PMID: 12203992). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |