ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.1849T>C (p.Cys617Arg) (rs1060501017)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000816775 SCV000957300 pathogenic Marfan syndrome; Thoracic aortic aneurysm and aortic dissection 2018-12-04 criteria provided, single submitter clinical testing This sequence change replaces cysteine with arginine at codon 617 of the FBN1 protein (p.Cys617Arg). 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 observed in several individuals affected with Marfan syndrome (PMID: 29357934, Invitae). ClinVar contains an entry for this variant (Variation ID: 549054). This variant disrupts the p.Cys617 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (PMID: 21542060, 27906200), which suggests that this may be a clinically significant amino acid residue. 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 RCV000663504 SCV000786804 likely pathogenic Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing

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