Submissions for variant NM_000138.5(FBN1):c.6772T>G (p.Cys2258Gly)

gnomAD frequency: 0.00001  dbSNP: rs1057520617

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	RCV002236396	SCV002507311	likely pathogenic	Marfan syndrome	2021-12-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002363726	SCV002661703	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2021-06-28	criteria provided, single submitter	clinical testing	The p.C2258G variant (also known as c.6772T>G), located in coding exon 55 of the FBN1 gene, results from a T to G substitution at nucleotide position 6772. The cysteine at codon 2258 is replaced by glycine, an amino acid with highly dissimilar properties, and is located in the cb EGF-like domain #35. The majority of FBN1 mutations identified to date have involved the substitution or generation of cysteine residues within cbEGF domains (Vollbrandt T et al. J Biol Chem. 2004;279(31):32924-32931). Based on internal structural assessment, this alteration eliminates a structurally critical disulfide bond in the structurally sensitive cb EGF-like domain #35. Two other alterations at the same codon, p.C2258R (c.6772T>C) and p.C2258Y (c.6773G>A), have been described in individuals with Marfan syndrome (Hayward C et al. Hum Mutat, 1997;10:280-9; Halliday D et al. Hum Genet, 1999 Dec;105:587-97). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003774684	SCV004570898	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-07-14	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys2258 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (PMID: 9338581, 10647894, 27906200, 31211624), 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: 1679954). This missense change has been observed in individual(s) with clinical features of Marfan syndrome (Invitae). 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 2258 of the FBN1 protein (p.Cys2258Gly).
GeneDx	RCV004719242	SCV005326140	likely pathogenic	not provided	2024-03-08	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign in association with an FBN1-related disorder to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); 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 (PMID: 12938084); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12938084, 10486319, 27906200)
Mayo Clinic Laboratories, Mayo Clinic	RCV004719242	SCV005414266	likely pathogenic	not provided	2023-07-17	criteria provided, single submitter	clinical testing	PP2, PP3, PM1_strong, PM2