ClinVar Miner

Submissions for variant NM_000138.5(FBN1):c.7448G>A (p.Cys2483Tyr)

dbSNP: rs1555394390
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Department of Vascular Biology, Beijing Anzhen Hospital RCV001374813 SCV001439514 likely pathogenic Isolated thoracic aortic aneurysm 2018-09-01 criteria provided, single submitter research
Invitae RCV001880027 SCV002238214 pathogenic Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2021-10-04 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This variant affects a cysteine residue in the EGF-like, TGFBP or hybrid motif domains of FBN1. Cysteine residues are believed to be involved in intramolecular disulfide bridges and have been shown to be important for FBN1 protein structure (PMID: 16905551, 19349279). In addition, missense substitutions affecting cysteine residues within these domains are significantly overrepresented among patients with Marfan syndrome (PMID: 16571647, 17701892). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FBN1 protein function. ClinVar contains an entry for this variant (Variation ID: 982347). This variant is also known as C2452Y. This missense change has been observed in individual(s) with Marfan syndrome (PMID: 11170092). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with tyrosine at codon 2483 of the FBN1 protein (p.Cys2483Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine.
Ambry Genetics RCV002379964 SCV002672600 likely pathogenic Familial thoracic aortic aneurysm and aortic dissection 2021-03-22 criteria provided, single submitter clinical testing The p.C2483Y variant (also known as c.7448G>A), located in coding exon 59 of the FBN1 gene, results from a G to A substitution at nucleotide position 7448. The cysteine at codon 2483 is replaced by tyrosine, an amino acid with highly dissimilar properties, and is located in the cbEGF-like #38 domain. 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 (referred to as p.C2452Y, c.7355G>A), segregated with disease in several members of a family reported to have Marfan syndrome (Judge DP et al. Am J Med Genet, 2001 Feb;99:39-47). Based on internal structural assessment, this alteration eliminates a structurally critical disulfide bond in the structurally sensitive cbEGF domain #38. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). 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 the majority of available evidence to date, this variant is likely to be pathogenic.

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.