Submissions for variant NM_000138.5(FBN1):c.1884C>G (p.Cys628Trp)

dbSNP: rs150421653

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Centre of Medical Genetics, University of Antwerp	RCV002246089	SCV002025519	pathogenic	Marfan syndrome	2021-03-01	criteria provided, single submitter	research	PM2, PVS2, PP4
Labcorp Genetics (formerly Invitae), Labcorp	RCV002541220	SCV003022561	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2022-05-16	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 628 of the FBN1 protein (p.Cys628Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with 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). This variant disrupts the p.Cys628 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (PMID: 12402346; Invitae), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV003325581	SCV004032038	likely pathogenic	not provided	2023-08-29	criteria provided, single submitter	clinical testing	Identified in a patient with ectopia lentis in published literature (Chen et al., 2021); the variant was also present in this individual's father who also had a history of ectopia lentis; 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); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12938084, 34281902, 35612688, 35058154, CaseReport-Gusina2020)