ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.2722T>C (p.Cys908Arg) (rs1060501021)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000791419 SCV000544827 pathogenic Marfan syndrome; Thoracic aortic aneurysm and aortic dissection 2018-12-27 criteria provided, single submitter clinical testing This sequence change replaces cysteine with arginine at codon 908 of the FBN1 protein (p.Cys908Arg). 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 several individuals affected with FBN1-related conditions (PMID: 12203992, 24698609, 19353630, 28941062, Invitae). Different missense variants at the same codon (p.Cys908Tyr, Cys908Gly) have also been reported in individuals with FBN1-related conditions (PMID: 11170092, 18471089, 25656438). This variant has been reported to affect FBN1 protein function (PMID: 16905551, 26281765). 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 RCV000460579 SCV000786885 likely pathogenic Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing

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