Submissions for variant NM_000138.5(FBN1):c.5014T>G (p.Cys1672Gly)

dbSNP: rs112930491

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588782	SCV000695553	likely pathogenic	Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections	2016-02-11	criteria provided, single submitter	clinical testing	Variant summary: The c.5014T>G (p.Cys1672Gly) in FBN1 gene is a missense variant that alters a conserved nucleotide and 5/5 in silico tools predict deleterious outcome. This variant lies within highly conserved EGF-like motif #24; the alteration at cysteine residue within any EGF-like domains in FBN1 would disrupt disulfide bonds and will impair protein structure and function. The variant is absent from the broad control population dataset of ExAC. The variant has been identified and proven to segregate with the disease phenotype in 1 family referred for genetic testing (internal LCA data). Lastly, codon Cys1672 appears to be a mutational hot-spot; variants leading to the alteration of the same codon, such as p.Cys1672Arg, p.Cys1672Tyr, p.Cys1672Ser, p.Cys1672Phe have been reported in multiple affected individuals presented with a Classical MFS. However, the variant of interest has not, to our knowledge, been reported in the literature or reputable databases/diagnostic centers. Taking together, the variant was classified as Likely Pathogenic.
Invitae	RCV000813638	SCV000954005	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2022-08-02	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys1672 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (PMID: 10486319, 18435798), 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: 495617). This variant has not been reported in the literature in individuals affected with FBN1-related conditions. This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 1672 of the FBN1 protein (p.Cys1672Gly).
GeneDx	RCV003318603	SCV004022838	pathogenic	not provided	2023-07-28	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed in large population cohorts (gnomAD); At the protein level, in silico analysis supports that this missense variant has a deleterious effect on protein structure/function; 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); This variant is associated with the following publications: (PMID: 12938084)