ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.2147G>A (p.Gly716Glu) (rs794728185)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181453 SCV000233755 likely pathogenic not provided 2013-08-05 criteria provided, single submitter clinical testing p.Gly716Glu (GGA>GAA): c.2147 G>A in exon 18 of the FBN1 gene (NM_000138.4) The Gly716Glu variant in the FBN1 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Gly716Glu results in a non-conservative amino acid substitution of non-polar Glycine with a negatively charged Glutamic acid at a position that is conserved across species. In silico analysis predicts Gly716Glu is damaging to the protein structure/function. Mutations in nearby residues (Cys711Tyr, Gly721Cys, Asp723Val, Asp723Ala, Ile724Val, Ile724Arg) have been reported in association with Marfan syndrome, further supporting the functional importance of this region of the protein. Furthermore, the Gly716Glu 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.In summary, while Gly716Glu 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 RCV000536158 SCV000627850 uncertain significance Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2017-04-26 criteria provided, single submitter clinical testing This sequence change replaces glycine with glutamic acid at codon 716 of the FBN1 protein (p.Gly716Glu). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has been observed in one individual with aortic dilation and in one individual with aortic dilation and ectopia lentis (Invitae). ClinVar contains an entry for this variant (Variation ID: 199989). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. While it is absent from the population and reported in affected individuals, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000622454 SCV000740515 likely pathogenic Marfan syndrome 2017-06-28 criteria provided, single submitter clinical testing

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