ClinVar Miner

Submissions for variant NM_000138.5(FBN1):c.6952T>C (p.Cys2318Arg)

dbSNP: rs111588631
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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 RCV000663917 SCV002025428 pathogenic Marfan syndrome 2021-03-01 criteria provided, single submitter research PM2, PVS2, PP1, PP4
Invitae RCV003767936 SCV004570956 pathogenic Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2023-09-08 criteria provided, single submitter clinical testing This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 2318 of the FBN1 protein (p.Cys2318Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Marfan syndrome (PMID: 21542060). ClinVar contains an entry for this variant (Variation ID: 549381). 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. 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). For these reasons, this variant has been classified as Pathogenic.
Center for Medical Genetics Ghent, University of Ghent RCV000663917 SCV000787285 likely pathogenic Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing

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