Submissions for variant NM_000138.5(FBN1):c.4081T>C (p.Cys1361Arg)

dbSNP: rs1566906506

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen FBN1 Variant Curation Expert Panel, ClinGen	RCV002246009	SCV004218516	likely pathogenic	Marfan syndrome	2023-12-29	reviewed by expert panel	curation	NM_000138.5 c.4081T>C is a missense variant in FBN1 predicted to cause a substitution of a cysteine by arginine at amino acid 1361 (p.Cys1361Arg). This variant has been identified in at least two individuals with clinical diagnoses of Marfan syndrome and in an individual with a clinical suspicion of Marfan syndrome (PP4, PS4_supporting; PMID: 35058154; CHEO internal data). It is absent from gnomAD (PM2_supporting; https://gnomad.broadinstitute.org/). This variant affects a cysteine residue in a calcium-binding EGF-like domain; cysteine residues are involved in the formation of disulfide bridges which are essential for the protein structure (PM1_strong). Computational prediction tools and conservation analysis support that this variant is likely to impact the protein (PP3; REVEL = 0.920). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as likely pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PM1_strong, PS4_supporting, PP2, PP3, PP4, PM2_supporting.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770672	SCV000902131	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2023-02-08	criteria provided, single submitter	clinical testing
Centre of Medical Genetics, University of Antwerp	RCV002246009	SCV002025296	pathogenic	Marfan syndrome	2021-03-01	criteria provided, single submitter	research	PM2, PVS2, PP4
Invitae	RCV003768317	SCV004593579	likely pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-02-13	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 1361 of the FBN1 protein (p.Cys1361Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Marfan syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 626882). 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.Cys1361 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (PMID: 10486319; Invitae), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.