ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.7487G>T (p.Cys2496Phe) (rs1555394245)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 2
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000696120 SCV000824668 likely pathogenic Marfan syndrome; Thoracic aortic aneurysm and aortic dissection 2018-06-21 criteria provided, single submitter clinical testing This sequence change replaces cysteine with phenylalanine at codon 2496 of the FBN1 protein (p.Cys2496Phe). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and phenylalanine. 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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). Variants that disrupt the p.Cys2496 amino acid residue in FBN1 have been observed in affected individuals (19839986, 24161884, 25644172). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. 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.
Center for Medical Genetics Ghent,University of Ghent RCV000663958 SCV000787335 likely pathogenic Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.