ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.1496G>A (p.Cys499Tyr) (rs587782944)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000143890 SCV000544931 pathogenic Marfan syndrome 2016-07-18 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tyrosine at codon 499 of the FBN1 protein (p.Cys499Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with Marfan syndrome (PMID: 10486319, 18471089, 21542060, 21932315). ClinVar contains an entry for this variant (Variation ID: 155791). Experimental studies using fibroblasts collected from an affected individual indicate that this missense change leads to a defect in fibrillin matrix deposition (PMID: 10486319). Furthermore, other missense substitutions at this codon (p.Cys499Ser, p.Cys499Arg) have also been determined to be pathogenic (PMID: 10486319, 18471089, 22772377). Further indicating that this cysteine residue is critical for FBN1 protein function. 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). For these reasons, this variant has been classified as Pathogenic.
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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