Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000474183 | SCV000553201 | uncertain significance | Congenital contractural arachnodactyly | 2019-09-24 | criteria provided, single submitter | clinical testing | In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. This variant affects a cysteine residue located within an epidermal growth factor (EGF)–like domain of the FBN2 protein. Cysteine residues in these domains are involved in the formation of disulfide bridges critical for protein structure and stability (PMID: 3495735, 4750422, 16677079). In addition, missense substitutions within the FBN2 EGF-like domains affecting cysteine residues are overrepresented in patients with congenital contractural arachnodactyly (PMID: 18767143). 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 is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a FBN2-related disease. This sequence change replaces cysteine with phenylalanine at codon 615 of the FBN2 protein (p.Cys615Phe). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and phenylalanine. |
| Ambry Genetics | RCV002313180 | SCV000738982 | uncertain significance | Familial thoracic aortic aneurysm and aortic dissection | 2016-09-08 | criteria provided, single submitter | clinical testing | The p.C615F variant (also known as c.1844G>T), located in coding exon 13 of the FBN2 gene, results from a G to T substitution at nucleotide position 1844. The cysteine at codon 615 is replaced by phenylalanine, an amino acid with highly dissimilar properties, and is located in the cb EGF-like # #06 domain. In one study, 13 of 14 reported FBN2 mutations were found in the middle region of the gene (exons 24-36), and 7 of these mutations were noted to alter or produce a cysteine residue (Callewaert BL et al. Hum Mutat. 2009;30(3):334-341). 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 6503 samples (13006 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 deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |