Submissions for variant NM_000138.5(FBN1):c.6772T>C (p.Cys2258Arg)

dbSNP: rs1057520617

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000443127	SCV000516603	pathogenic	not provided	2015-04-17	criteria provided, single submitter	clinical testing	The C2258R variant in the FBN1 gene has been previously reported in one individual with features ofMarfan syndrome, including ocular, skeletal, and cardiovascular features (Hayward C et al., 1997). Thissubstitution was absent from 120 control alleles without features of Marfan and identified in the proband's otheraffected relatives (Hayward et al., 1997). Furthermore, the C2258R variant was not observed inapproximately 6500 individuals of European and African American ancestry in the NHLBI Exome SequencingProject, indicating it is not a common benign variant in these populations. The C2258R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residuesdiffer in polarity, charge, size and/or other properties. This substitution occurs at a position that is conservedacross species. In silico analysis predicts this variant is probably damaging to the protein structure/function.C2258R affects a Cysteine residue within a calcium-binding EGF-like domain of the FBN1, which may affectdisulfide bonding and is predicted to alter the structure and function of the protein. Cysteine substitutions inthe calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated withMarfan syndrome (Collod-Beroud et al., 2003). Additionally a missense variant in the same residue(C2258Y) and in nearby residues (C2265F, C2265Y) have been reported in HGMD in association with Marfansyndrome (Stenson P et al., 2014), further supporting the functional importance of this residue and region ofthe protein. In summary, C2258R in the FBN1 gene is interpreted as a pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003766212	SCV004570899	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-06-27	criteria provided, single submitter	clinical testing	This missense change has been observed in individuals with clinical features of Marfan syndrome and thoracic aortic aneurysm and dissection (PMID: 9338581, 31211624). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 2258 of the FBN1 protein (p.Cys2258Arg). ClinVar contains an entry for this variant (Variation ID: 379489). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys2258 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (PMID: 10647894), 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000663899	SCV004847723	likely pathogenic	Marfan syndrome	2019-04-17	criteria provided, single submitter	clinical testing	The p.Cys2258Arg variant in FBN1 has been identified in at least 2 individuals with Marfan syndrome (Hayward 1997, Stheneur 2009) and was absent from large population studies. In addition, 2 other variants at the same position (p.Cys2258Gly and p.Cys2258Tyr) have also been identified in individuals with Marfan syndrome, suggesting that changes at this position are not tolerated. 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; PM2; PP3; PS4_Supporting.
Center for Medical Genetics Ghent, University of Ghent	RCV000663899	SCV000787265	likely pathogenic	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing