ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.7051G>A (p.Gly2351Ser) (rs746127796)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Human Genetics, Inc RCV000659575 SCV000781411 uncertain significance Marfan syndrome 2016-11-01 criteria provided, single submitter clinical testing
GeneDx RCV000766957 SCV000233891 uncertain significance not provided 2017-01-25 criteria provided, single submitter clinical testing p.Gly2351Ser (GGC>AGC): c.7051 G>A in exon 58 of the FBN1 gene (NM_000138.4)The G2351S variant in the FBN1 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. The G2351S variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. G2351S 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. However, mutations in nearby residues have not been reported in association with Marfan syndrome indicating this region of the protein may tolerate change. Additionally, the G2351 residue is only well conserved in mammals, and in silico algorithms yielded conflicting results regarding the effect of G2351S on protein structure/function. With the clinical and molecular information available at this time, we cannot definitively determine if G2351S is a disease-causing mutation or a rare benign variant. The variant is found in TAAD panel(s).
Invitae RCV000631985 SCV000753088 uncertain significance Marfan syndrome; Thoracic aortic aneurysm and aortic dissection 2018-02-18 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 2351 of the FBN1 protein (p.Gly2351Ser). The glycine residue is moderately conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs746127796, ExAC 0.01%). This variant has not been reported in the literature in individuals with FBN1-related disease. ClinVar contains an entry for this variant (Variation ID: 200102). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
PreventionGenetics RCV000181588 SCV000302587 likely benign not specified criteria provided, single submitter clinical testing

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