ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.5443G>A (p.Gly1815Ser) (rs745680336)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181544 SCV000233847 likely pathogenic not provided 2013-02-06 criteria provided, single submitter clinical testing p.Gly1815Ser (GGC>AGC): c.5443 G>A in exon 45 of the FBN1 gene (NM_000138.4)The Gly1815Ser variant in the FBN1 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Gly1815Ser results in a non-conservative amino acid substitution of a non-polar Glycine with a polar Serine at a position that is conserved across species. In silico analysis predicts Gly1815Ser is damaging to the protein structure/function. Mutations in nearby residues (Glu1811Lys, Cys1812Arg, Cys1812Tyr, Cys1818Gly, Cys1818Tyr) have been reported in association with Marfan syndrome, further supporting the functional importance of this region of the protein. Furthermore, the Gly1815Ser 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 Gly1815Ser 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 RCV000702613 SCV000831473 uncertain significance Marfan syndrome; Thoracic aortic aneurysm and aortic dissection 2018-04-17 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 1815 of the FBN1 protein (p.Gly1815Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs745680336, ExAC 0.003%). This variant has not been reported in the literature in individuals with FBN1-related disease. ClinVar contains an entry for this variant (Variation ID: 200064). 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, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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