Submissions for variant NM_000138.5(FBN1):c.3290G>A (p.Cys1097Tyr)

dbSNP: rs1555398627

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen FBN1 Variant Curation Expert Panel, ClinGen	RCV000663622	SCV004218528	pathogenic	Marfan syndrome	2023-12-29	reviewed by expert panel	curation	The NM_00138 c.3290G>A, is a missense variant in FBN1 predicted to cause a substitution of a cysteine by tyrosine at amino acid 1097 (p.Cys1097Tyr). This variant was found in a proband with a neonatal onset of Marfan syndrome (internal data, PP4). This variant has been reported four times in ClinVar: once as pathogenic, twice as likely pathogenic, and once as uncertain significance (Variation ID: 549150). This variant has been reported in the literature in individuals with clinical diagnosis of Marfan syndrome and/or features of Marfan syndrome (PMID 37684520, 29357934, Invitae ClinVar entry, internal data; PS4_Mod), and was observed de novo without parental confirmation in one individual with a highly specific phenotype (PMID 37684520; PM6). This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/ v2.1.1). 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: PM1_Strong, PS4_moderate, PM6, PM2_Sup, PP2, PP3, PP4.
Invitae	RCV002530611	SCV003461890	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2022-12-06	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 549150). This missense change has been observed in individuals with clinical features of Marfan syndrome (PMID: 29357934; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 1097 of the FBN1 protein (p.Cys1097Tyr).
Revvity Omics, Revvity	RCV003144465	SCV003834002	uncertain significance	not provided	2019-12-24	criteria provided, single submitter	clinical testing
Center for Medical Genetics Ghent, University of Ghent	RCV000663622	SCV000786944	likely pathogenic	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing
deCODE genetics, Amgen	RCV000663622	SCV003915957	likely pathogenic	Marfan syndrome	2023-04-10	no assertion criteria provided	case-control	The p.(Cys1097Tyr) variant was identified in an individual diagnosed with Marfan syndrome. The variant occurred de novo in the individual, maternity and paternity confirmed. Applied ACMG criteria: PS2, PM1, PM2, PP2, PP4