ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.3886T>C (p.Cys1296Arg) (rs397515797)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 2
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare 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).

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.