ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.7531T>C (p.Cys2511Arg) (rs794728272)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Medical Genetics Ghent,University of Ghent RCV000663960 SCV000787337 likely pathogenic Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing
GeneDx RCV000181605 SCV000233908 likely pathogenic not provided 2016-12-14 criteria provided, single submitter clinical testing The C2511R variant has been reported in association with Marfan syndrome (reported as C1613R in one publication due to alternate nomenclature) (Kainulainen et al., 1994; Hayward et al., 1997; Baetens et al., 2011). This variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The C2511R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, the C2511R variant 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 Marfan syndrome (Collod-Beroud et al., 2003). A missense variants in the same residue (C2511Y) has been reported in the Human Gene Mutation Database in association with an FBN1-related disorder (Stenson et al., 2014); however, the pathogenicity of this variant has not been definitively determined.
Invitae RCV000470534 SCV000544960 pathogenic Marfan syndrome; Thoracic aortic aneurysm and aortic dissection 2017-06-20 criteria provided, single submitter clinical testing This sequence change replaces cysteine with arginine at codon 2511 of the FBN1 protein (p.Cys2511Arg). 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 (rs794728272, ExAC no frequency). This variant has been reported in several individuals affected with Marfan syndrome (PMID: 9401003, 10756346, 21542060). ClinVar contains an entry for this variant (Variation ID: 200115). 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.

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