ClinVar Miner

Submissions for variant NM_000138.5(FBN1):c.2179T>A (p.Cys727Ser)

dbSNP: rs1064794025
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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 RCV001927184 SCV002160760 pathogenic Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2021-02-16 criteria provided, single submitter clinical testing This sequence change replaces cysteine with serine at codon 727 of the FBN1 protein (p.Cys727Ser). The cysteine residue is highly conserved and there is a moderate physicochemical difference between cysteine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of Marfan syndrome (Invitae). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FBN1 protein function. 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.

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