ClinVar Miner

Submissions for variant NM_000138.5(FBN1):c.1496G>A (p.Cys499Tyr)

dbSNP: rs587782944
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001201373 SCV000544931 pathogenic Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2022-08-27 criteria provided, single submitter clinical testing This missense change has been observed in individuals with Marfan syndrome (PMID: 10486319, 18471089, 21542060, 21932315). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 499 of the FBN1 protein (p.Cys499Tyr). ClinVar contains an entry for this variant (Variation ID: 155791). 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). Experimental studies have shown that this missense change affects FBN1 function (PMID: 10486319). 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.
Centre of Medical Genetics, University of Antwerp RCV000143890 SCV002025488 pathogenic Marfan syndrome 2021-03-01 criteria provided, single submitter research PM2, PVS2, PP4
Blueprint Genetics RCV000143890 SCV000188759 pathogenic Marfan syndrome 2014-02-04 no assertion criteria provided clinical testing
Center for Medical Genetics Ghent, University of Ghent RCV000143890 SCV000786758 likely pathogenic Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing

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