Submissions for variant NM_000138.5(FBN1):c.6793T>G (p.Cys2265Gly)

dbSNP: rs1057522272

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000425848	SCV000526929	likely pathogenic	not provided	2017-01-16	criteria provided, single submitter	clinical testing	The C2265G likely pathogenic variant in the FBN1 gene has been reported previously in association with Marfansyndrome (Sakai et al., 2012; Franken et al., 2016). Sakai et al. (2012) identified C2265G in a Japanese patient witha personal and family history of Marfan syndrome; however, familial segregation data was not provided. Subsequently,the C2265G variant was reported in one individual from a cohort of 357 Dutch patients with a clinical diagnosis ofMarfan syndrome who harbored pathogenic" FBN1 variants (Franken et al., 2016). The authors proposed thatC2265G causes a dominant-negative effect on FBN1 gene function, and asserted that patients with dominant-negativeFBN1 variants had a lower risk of aortic complications/dissections and cardiovascular death when compared topatients with haploinsufficient variants (Franken et al., 2016). C2265G was not observed in approximately 6,500individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is nota common benign variant in these populations. The C2265G 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 otherproperties. Moreover, this substitution occurs at a position that is conserved across species. Consequently, in silicoanalysis predicts this variant is probably damaging to the protein structure/function. In addition, the C2265G variantaffects a Cysteine residue within a calcium-binding EGF-like domain of the FBN1 gene, which may affect disulfidebonding and is predicted to alter the structure and function of the protein. Cysteine substitutions in the calciumbindingEGF-like domains represent the majority of pathogenic missense changes associated with Marfan syndrome(Collod-Beroud et al., 2003). Finally, one missense variant in the same residue (C2265Y) has been reported in theHuman Gene Mutation Database in association with Marfan syndrome (Stenson et al., 2014), supporting thefunctional importance of this residue.Therefore, this variant is likely pathogenic. In order to definitively determine its clinical significance, additional datais required."
Labcorp Genetics (formerly Invitae), Labcorp	RCV003766302	SCV004570958	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-08-17	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys2265 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (PMID: 19293843, 26787436), which suggests that this may be a clinically significant amino acid residue. 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: 385605). This missense change has been observed in individuals with Marfan syndrome (PMID: 26787436, 32431097). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 2265 of the FBN1 protein (p.Cys2265Gly).