Submissions for variant NM_000138.5(FBN1):c.2415T>G (p.Cys805Trp)

dbSNP: rs1597569551

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations	RCV000845291	SCV000986685	pathogenic	Marfan syndrome	2019-08-26	criteria provided, single submitter	clinical testing	The p.Cys805Trp variant was reported in 2 unrelated individuals with Ectopia Lentis (DOI: 10.1002/humu.21305; ESHG abstracts 2012 P02.086) and was absent from large population studies (ExAC no frequency). Other substitution at 805 codon (C805R) is known at patient with EL (PMID: 25053872). Cysteine is located in cbEGF-like domain and participating in Disulfide bonds 792-805. Substitutions at cysteine residues in EGF domains are a common mechanism for disease in FBN1 gene (PMID: 1301946, 12938084, 15161917). Computational results of PolyPhen2, Provean, SIFT, MutationMaster show deleterious effect. Based on this evidences p.Cys805Trp variant is classified as Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001233298	SCV001405885	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2024-12-29	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with tryptophan, which is neutral and slightly polar, at codon 805 of the FBN1 protein (p.Cys805Trp). 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: 17627385, 20564469). ClinVar contains an entry for this variant (Variation ID: 684779). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.Cys805 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (PMID: 25053872, 29848614), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.