Submissions for variant NM_000138.5(FBN1):c.7775G>T (p.Cys2592Phe)

dbSNP: rs112118237

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000484944	SCV000573203	likely pathogenic	not provided	2017-02-28	criteria provided, single submitter	clinical testing	The C2592F likely pathogenic variant in the FBN1 gene has not been published as pathogenic or been reported as benign to our knowledge. C2592F is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The C2592F variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Additionally, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, the C2592F variant 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 Marfan syndrome (Collod-Beroud et al., 2003). Finally, a missense variant at the same residue (C2592S), and multiple missense variants in nearby residues (R2589G, C2590Y, G2595A, G2595S, Y2596C) have been reported in the Human Gene Mutation Database in association with Marfan syndrome/TAAD (Stenson et al., 2014), supporting the functional importance of this residue and region of the protein.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780264	SCV000917374	uncertain significance	not specified	2017-12-22	criteria provided, single submitter	clinical testing	Variant summary: The FBN1 c.7775G>T (p.Cys2592Phe) variant located in the EGF-like domain #41 involves the alteration of a conserved nucleotide affecting a Cysteine residue. The sulfhydryl group of cysteine is unique in its ability to participate in disulfide covalent cross-linkage. In fact, two thirds of fibrillin cysteine residues exist in the half-cystinyl form, suggesting their participation in intramolecular disulfide linkage. The cysteine residues in the EGF-like motif may also be necessary for intermolecular interactions with other fibrillin molecules or with other proteins (Dietz_1992). Therefore, alteration of cysteine in this domain could disrupt disulfide binding, effecting secondary or tertiary structure or possibly impairing fibrillin interactions. In further support, 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). However, these predictions have yet to be functionally assessed. This variant is absent in 245656 control chromosomes (gnomAD). In addition, a clinical diagnostic laboratory classified this variant as likely pathogenic. Furthermore, a missense variant at this residue, Cys2592Ser, along with missense variants nearby, Arg2589Gly, Cys2590Tyr, Gly2595Ala, Gly2595Ser, and Tyr2596Cys, have been reported in affected individuals, therefore, suggesting the area is important for protein function. Taken together, this variant is classified as a "Variant of Uncertain Significance - Possibly Pathogenic."
Invitae	RCV001378272	SCV001575809	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-04-18	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: 423498). This missense change has been observed in individuals with clinical features of FBN1-related conditions (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 2592 of the FBN1 protein (p.Cys2592Phe).