Submissions for variant NM_000138.5(FBN1):c.5060G>T (p.Cys1687Phe)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV002287223	SCV002577446	likely pathogenic	Marfan syndrome	2022-09-22	criteria provided, single submitter	clinical testing	PM1, PM2, PM5, PP2, PP3
GeneDx	RCV002290864	SCV002578323	pathogenic	not provided	2022-04-07	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); 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); This variant is associated with the following publications: (PMID: 25652356)
Labcorp Genetics (formerly Invitae), Labcorp	RCV003774951	SCV004570904	likely pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-12-20	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 1687 of the FBN1 protein (p.Cys1687Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Marfan syndrome (PMID: 25652356). ClinVar contains an entry for this variant (Variation ID: 1708070). 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 with a positive predictive value of 95%. 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.Cys1687 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (PMID: 25652356; Invitae), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV002287223	SCV004848459	likely pathogenic	Marfan syndrome	2020-08-24	criteria provided, single submitter	clinical testing	The p.Cys1687Phe variant in FBN1 has been identified in 1 individual with Marfan syndrome (Baudhuin 2015 PubMed: 25652356) and was absent from large population studies. Two additional variants involving this codon (p.Cys1687Arg and p.Cys1687Tyr) have been reported (Groth 2017 PMID: 27906200; Takeda 2018 PMID: 29848614). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Furthermore, this variant affects a highly conserved cysteine residue in the EGF-like domains, which is a common finding in individuals with Marfan syndrome (Schrijver 1999). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant Marfan syndrome. ACMG/AMP Criteria applied: PM1; PM5_Supporting; PM2; PS4_Supporting; PP3.