ClinVar Miner

Submissions for variant NM_000138.5(FBN1):c.6883T>C (p.Cys2295Arg)

dbSNP: rs1555394644
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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000688195 SCV000815797 pathogenic Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2020-02-07 criteria provided, single submitter clinical testing This variant has been observed in individuals affected with Marfan syndrome (PMID: 19659760, Invitae). For these reasons, this variant has been classified as Pathogenic. 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). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with arginine at codon 2295 of the FBN1 protein (p.Cys2295Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine.

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