Submissions for variant NM_000138.5(FBN1):c.7531T>C (p.Cys2511Arg)

dbSNP: rs794728272

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181605	SCV000233908	pathogenic	not provided	2020-12-15	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); 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; Reported in ClinVar as pathogenic or likely pathogenic (ClinVar Variant ID# 200115; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 11826022, 9338581, 21542060, 24941995, 8136837, 32154576)
Invitae	RCV000470534	SCV000544960	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: 200115). This missense change has been observed in individuals with Marfan syndrome (PMID: 9401003, 10756346, 21542060). 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 2511 of the FBN1 protein (p.Cys2511Arg).
Centre of Medical Genetics, University of Antwerp	RCV000663960	SCV002025451	pathogenic	Marfan syndrome	2021-03-01	criteria provided, single submitter	research	PM2, PVS2, PP4
PreventionGenetics, part of Exact Sciences	RCV004539702	SCV004796784	pathogenic	FBN1-related disorder	2024-01-30	criteria provided, single submitter	clinical testing	The FBN1 c.7531T>C variant is predicted to result in the amino acid substitution p.Cys2511Arg. This variant was reported in multiple individuals with Marfan syndrome or nonsyndromic aortic dissection (described as C1613R in Table 1, Kainulainen et al. 1994. PubMed ID: 8136837; Table S1A, Meester et al. 2022. PubMed ID: 35058154; Pan et al. 2022. PubMed ID: 35154271). This variant substitutes a cysteine residue that is located within the epidermal growth factor-like domain of the FBN1 protein. Missense variants in FBN1 that substitute or create a cysteine residue are well-documented to cause Marfan syndrome (Dietz and Dietz. 1993. PubMed ID: 20301510; Comeglio et al. 2007. PubMed ID: 17657824; Stheneur et al. 2009. PubMed ID: 19293843). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic.
Center for Medical Genetics Ghent, University of Ghent	RCV000663960	SCV000787337	likely pathogenic	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing