Submissions for variant NM_000138.5(FBN1):c.4414T>C (p.Cys1472Arg)

dbSNP: rs1555397403

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen FBN1 Variant Curation Expert Panel, ClinGen	RCV000663725	SCV004037319	pathogenic	Marfan syndrome	2023-09-28	reviewed by expert panel	curation	The NM_00138 c.4414T>C is a missense variant in FBN1 predicted to cause a substitution of a cysteine by arginine at amino acid 1472 (p.Cys1472Arg). This variant was found in a proband with thoracic aortic aneurysm and/or dissection, ectopia lentis, and a systemic score of 7, which is a highly specific phenotype for Marfan syndrome (internal data-Ghent University Hospital) (PP4). This variant has been reported 3 times in ClinVar, once as pathogenic and twice as likely pathogenic (Variation ID: 549229). 6 other probands with a clinical diagnosis of Marfan syndrome or clinical features of Marfan syndrome carry the same variant (PMID 33087052, InvitaeClinVarentry, University of Antwerp ClinVar entry, internal data, PS4). This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/ version 2.1.1). This variant affects a cysteine residue in a calcium binding EGF domain. Cysteine residues are believed to be involved in the formation of disulfide bridges which are essential for the protein structure (PM1_strong). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (REVEL: 0.979) (PP3). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PS4, PM1_Strong, PP2, PP3, PP4
Invitae	RCV001379825	SCV001577697	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-12-07	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 1472 of the FBN1 protein (p.Cys1472Arg). 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: 35058154; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 549229). 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.Cys1472 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (PMID: 26787436), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Centre of Medical Genetics, University of Antwerp	RCV000663725	SCV002025316	pathogenic	Marfan syndrome	2021-03-01	criteria provided, single submitter	research	PM2, PVS2, PP4
Center for Medical Genetics Ghent, University of Ghent	RCV000663725	SCV000787061	likely pathogenic	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing