Submissions for variant NM_000138.5(FBN1):c.7217G>A (p.Cys2406Tyr)

dbSNP: rs1131691479

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000492809	SCV000582202	likely pathogenic	not provided	2017-05-17	criteria provided, single submitter	clinical testing	The C2406Y likely pathogenic variant in the FBN1 gene has been reported previously in at least two unrelated individuals with Marfan syndrome, however no additional segregation information is available (Loeys et al., 2001; Baetens et al., 2011). The C2406Y 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 C2406Y 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. Additionally, this substitution occurs at a position that is conserved across species. Consequently, in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, the C2406Y 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). Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded
Centre of Medical Genetics, University of Antwerp	RCV000663939	SCV002025439	pathogenic	Marfan syndrome	2021-03-01	criteria provided, single submitter	research	PM2, PVS2, PP4
Invitae	RCV001851355	SCV002242161	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2021-05-31	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys2406 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (Invitae), which suggests that this may be a clinically significant amino acid residue. 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). 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 has been observed in individual(s) with Marfan syndrome or its clinical features (PMID: 11700157, Invitae). ClinVar contains an entry for this variant (Variation ID: 429595). This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with tyrosine at codon 2406 of the FBN1 protein (p.Cys2406Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine.
Center for Medical Genetics Ghent, University of Ghent	RCV000663939	SCV000787314	likely pathogenic	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing