Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000556027 | SCV000630226 | likely pathogenic | Congenital contractural arachnodactyly | 2020-11-20 | criteria provided, single submitter | clinical testing | 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. Different missense substitutions at this codon (p.Cys1246Phe, p.Cys1246Gly) have been reported in individuals affected with congenital contractural arachnodactyly (PMID: 19006240, 22325249). This suggests that the cysteine residue is critical for FBN2 protein function and that other missense substitutions at this position may also be pathogenic. 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). This variant has not been reported in the literature in individuals with FBN2-related disease. It has been reported in individuals in the Universal Mutation Database (PMID: 18767143). ClinVar contains an entry for this variant (Variation ID: 458763). This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with arginine at codon 1246 of the FBN2 protein (p.Cys1246Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine. |
| Ambry Genetics | RCV002314952 | SCV000738963 | pathogenic | Familial thoracic aortic aneurysm and aortic dissection | 2016-04-13 | criteria provided, single submitter | clinical testing | The p.C1246R pathogenic mutation (also known as c.3736T>C), located in coding exon 29 of the FBN2 gene, results from a T to C substitution at nucleotide position 3736. The cysteine at codon 1246 is replaced by arginine, an amino acid with highly dissimilar properties, and is located in the cb EGF-like #16 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). Alterations involving the same amino acid position, p.C1246F (c.3737G>T) and p.C1246G (c.3736T>G), have been described in patients with congenital contractural arachnodactyly (CCA) (Callewaert BL et al. Hum Mutat. 2009;30(3):334-341; Paulson ML et al. Int J Tuberc Lung Dis. 2012;16(4):561-3). Based on the supporting evidence, p.C1246R is interpreted as a disease-causing mutation. |