Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV002345247 | SCV002621243 | likely pathogenic | Familial thoracic aortic aneurysm and aortic dissection | 2016-01-28 | criteria provided, single submitter | clinical testing | The p.C1249S variant (also known as c.3746G>C), located in coding exon 30 of the FBN1 gene, results from a G to C substitution at nucleotide position 3746. The cysteine at codon 1249 is replaced by serine, an amino acid with 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). This variant was first reported in a patient described to have classic manifestations of Marfan syndrome, including ectopia lentis and aortic root dilation (Dietz HC et al. Hum Mutat. 1992;1(5):366-74). In separate functional in vitro analyses using fibroblasts, this variant demonstrated significantly reduced fibrillin deposition suggesting inhibited fibrillin assembly from a dominant-negative effect (Aoyama T et al. J Clin Invest. 1994;94(1):130-7; Schrijver I et al. Am J Hum Genet. 1999;65(4):1007-20). This variant was previously reported in the SNPDatabase as rs137854458. It was not reported in population based cohorts in the following databases: NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project. In the ESP, this variant was not observed in 6494 samples (12988 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 probably damaging and deleterious by PolyPhen and SIFT in silico analyses, respectively. Based on the majority of available evidence to date, this alteration is likely to be pathogenic. |
| OMIM | RCV000017887 | SCV000038166 | pathogenic | Marfan syndrome | 2023-08-11 | no assertion criteria provided | literature only |