ClinVar Miner

Submissions for variant NM_000138.5(FBN1):c.6650G>A (p.Cys2217Tyr)

dbSNP: rs794728254
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181573 SCV000233876 likely pathogenic not provided 2023-06-23 criteria provided, single submitter clinical testing Affects a cysteine residue within a calcium-binding EGF-like domain of the FBN1 gene, which may affect disulfide bonding and is predicted to alter the structure and function of the protein; cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with FBN1-related disorders (Schrijver et al., 1999; Collod-Beroud et al., 2003); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 10486319, 12938084, 26770496)
Invitae RCV001069452 SCV001234617 pathogenic Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2019-05-13 criteria provided, single submitter clinical testing Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. This variant has been observed in individuals with clinical features of Marfan syndrome (PMID: 26770496, Invitae). ClinVar contains an entry for this variant (Variation ID: 200090). This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with tyrosine at codon 2217 of the FBN1 protein (p.Cys2217Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine.

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