ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.139G>A (p.Gly47Ser) (rs762400500)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000414982 SCV000492707 uncertain significance Dental crowding; Arachnodactyly; Dolichocephaly; Joint hypermobility; Aortic regurgitation; High, narrow palate 2015-10-20 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000726149 SCV000342417 uncertain significance not provided 2016-07-07 criteria provided, single submitter clinical testing
GeneDx RCV000726149 SCV000233804 uncertain significance not provided 2017-07-21 criteria provided, single submitter clinical testing p.Gly47Ser (G47S) GGT>AGT: c.139 G>A in exon 2 of the FBN1 gene (NM_000138.4) The G47S variant in the FBN1 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. G47S 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 G47S is probably damaging to the protein structure/function. The G47S 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. Mutations in nearby residues (G55E, N57D) have been reported in association with Marfan syndrome, supporting the functional importance of this region of the protein. However, Cysteine substitutions in FBN1 represent the vast majority of pathogenic missense changes associated with Marfan syndrome.With the clinical and molecular information available at this time, we cannot definitively determine if G47S is a disease-causing mutation or a rare benign variant. The variant is found in TAAD panel(s).
Invitae RCV000533830 SCV000627835 uncertain significance Marfan syndrome; Thoracic aortic aneurysm and aortic dissection 2017-05-04 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 47 of the FBN1 protein (p.Gly47Ser). The glycine residue is moderately conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs762400500, ExAC 0.001%) but has not been reported in the literature in individuals with a FBN1-related disease. ClinVar contains an entry for this variant (Variation ID: 200029). 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: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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