Submissions for variant NM_000138.5(FBN1):c.6490T>G (p.Cys2164Gly)

dbSNP: rs2141240296

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001986903	SCV002277688	likely pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2021-02-15	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine with glycine at codon 2164 of the FBN1 protein (p.Cys2164Gly). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and glycine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of 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). 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.
PreventionGenetics, part of Exact Sciences	RCV004538721	SCV004110544	likely pathogenic	FBN1-related disorder	2023-01-06	criteria provided, single submitter	clinical testing	The FBN1 c.6490T>G variant is predicted to result in the amino acid substitution p.Cys2164Gly. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. 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). Additionally, different nucleotide substitutions affecting the same amino acid (p.Cys2164Ser, p.Cys2164Arg, p.Cys2164Tyr) have been reported in individuals with Marfan syndrome (Takeda et al. 2018. PubMed ID: 29848614; Stark et al. 2020. PubMed ID: 32679894; Mannucci et al. 2019. PubMed ID: 31730815). Taken together, the c.6490T>G (p.Cys2164Gly) variant is interpreted as likely pathogenic.