ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.1462T>C (p.Cys488Arg) (rs1555400373)

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
Center for Medical Genetics Ghent,University of Ghent RCV000663458 SCV000786751 likely pathogenic Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763359 SCV000894049 likely pathogenic Ectopia lentis, isolated, autosomal dominant; Marfan syndrome; MASS syndrome; Stiff skin syndrome; Weill-Marchesani syndrome 2; Acromicric dysplasia; Geleophysic dysplasia 2; Marfan lipodystrophy syndrome 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000547735 SCV000627839 pathogenic Marfan syndrome; Thoracic aortic aneurysm and aortic dissection 2018-07-17 criteria provided, single submitter clinical testing This sequence change replaces cysteine with arginine at codon 488 of the FBN1 protein (p.Cys488Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in individuals affected with Marfan syndrome and ectopia lentis (PMID: 18435798, Invitae). This variant affects a cysteine residue located within 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: 10486319, 3495735, 4750422, 16677079). In addition, missense substitutions within the FBN1 EGF-like domains affecting cysteine residues are significantly overrepresented among patients with Marfan syndrome (PMID: 16571647, 17701892). A different missense substitution at this codon (p.Cys488Phe) has been determined to be pathogenic (PMID: 15241795). This suggests that the cysteine residue is critical for FBN1 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as 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.