ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.7499G>A (p.Cys2500Tyr) (rs794728160)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181410 SCV000233712 likely pathogenic not provided 2017-04-13 criteria provided, single submitter clinical testing The C2500Y likely pathogenic variant in the FBN1 gene has been previously reported in one individual with Marfan syndrome who had a personal history of aortic dilation, ectopia lentis, mitral valve prolapse, and skeletal involvement (Arbustini et al., 2005). This variant has not been observed in large population cohorts (Lek et al., 2016; McVean et al., 2012; Exome Variant Server). Furthermore, C2500Y 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 also occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Moreover, C2500Y 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 (Collod-Beroud et al., 2003). Therefore, C2500Y in the FBN1 gene is interpreted as a likely pathogenic.
Blueprint Genetics RCV000181410 SCV000927229 likely pathogenic not provided 2017-04-13 criteria provided, single submitter clinical testing
Invitae RCV000795593 SCV000935061 pathogenic Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2018-12-18 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tyrosine at codon 2500 of the FBN1 protein (p.Cys2500Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals with clinical features of Marfan syndrome (PMID: 16222657, Invitae). ClinVar contains an entry for this variant (Variation ID: 199953). 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). This variant disrupts the p.Cys2500 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (PMID: 16222657, 11875032), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Mendelics RCV000989312 SCV001139588 benign Marfan syndrome 2019-05-28 criteria provided, single submitter clinical testing

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