ClinVar Miner

Submissions for variant NM_000138.5(FBN1):c.7447T>C (p.Cys2483Arg)

dbSNP: rs1555394391
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Centre of Medical Genetics, University of Antwerp RCV000663954 SCV002025447 pathogenic Marfan syndrome 2021-03-01 criteria provided, single submitter research PM2, PVS2, PP4
Invitae RCV002530616 SCV003222261 likely pathogenic Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2022-07-19 criteria provided, single submitter clinical testing 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: 549410). This variant has not been reported in the literature in individuals affected with FBN1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 2483 of the FBN1 protein (p.Cys2483Arg). 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 RCV000663954 SCV000787331 likely pathogenic Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing

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