Submissions for variant NM_000138.5(FBN1):c.3886T>C (p.Cys1296Arg)

dbSNP: rs397515797

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035182	SCV000058824	likely pathogenic	Marfan syndrome	2013-01-30	criteria provided, single submitter	clinical testing	The Cys1296Arg variant in FBN1 has not previously been identified by our laborat ory or in the literature. This variant affects a cysteine residue and cysteine s ubstitutions are a common finding in patients with Marfan syndrome (Schrijver 19 99). This variant has not been identified in large and broad African American an d European American populations by the NHLBI Exome Sequencing Project (http://ev s.gs.washington.edu/EVS/). Computational analyses (biochemical amino acid proper ties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that the Cys1296Arg variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, this variant is likely pathogenic, thou gh additional studies are required to fully establish its clinical significance.
GeneDx	RCV000181498	SCV000233801	likely pathogenic	not provided	2014-01-18	criteria provided, single submitter	clinical testing	The C1296R variant in the FBN1 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. The C1296R variant is a non-conservative amino acid substitution as these residues differ in polarity, charge, size and/or other properties and is more likely to impact secondary structure. The C1296 residue is conserved across species. In silico analysis predicts C1296R is damaging to the protein structure/function. Mutations in nearby residues (C1284G, C1284R, C1284Y, K1300E, C1307Y) have been reported in association with Marfan syndrome, further supporting the functional importance of this region of the protein. Furthermore, the C1296R variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Lastly, Cysteine substitutions in FBN1 represent the vast majority of pathogenic missense changes associated with Marfan syndrome.In summary, while C1296R is a good candidate for a disease-causing mutation, with the clinical and molecular information available at this time we cannot unequivocally determine the clinical significance of this variant. The variant is found in TAAD panel(s).
Invitae	RCV001852709	SCV002315593	likely pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2020-11-21	criteria provided, single submitter	clinical testing	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. 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. 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). This variant has been observed in individual(s) with clinical features of Marfan syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 42344). This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with arginine at codon 1296 of the FBN1 protein (p.Cys1296Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine.