ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.2547C>G (p.Ile849Met) (rs778258207)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769647 SCV000901048 uncertain significance Thoracic aortic aneurysm and aortic dissection 2017-08-23 criteria provided, single submitter clinical testing
Center for Medical Genetics Ghent,University of Ghent RCV000663552 SCV000786863 likely benign Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780241 SCV000917349 uncertain significance not specified 2018-04-02 criteria provided, single submitter clinical testing Variant summary: FBN1 c.2547C>G (p.Ile849Met) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. This frequency of this variant in Latino cohort is similar to expected for a pathogenic variant in FBN1 causing Marfan Syndrome (0.00012 vs 0.00011), allowing no conclusion about variant significance. In the literature, c.2547C>G was identified in one individual affected with Marfan Syndrome who also carried a co-occurring pathogenic FBN1 mutation (Proost_2015), suggesting the variant is in the benign spectrum. To our knowledge, no experimental evidence demonstrating its impact on protein function have been reported. Co-occurrence with another pathogenic variant has been reported (FBN1 c.6871+1G>T), providing further support for a benign role. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly normal.
Invitae RCV000474691 SCV000544889 uncertain significance Marfan syndrome; Thoracic aortic aneurysm and aortic dissection 2016-09-26 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with methionine at codon 849 of the FBN1 protein (p.Ile849Met). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and methionine. This variant is present in population databases (rs778258207, ExAC 0.003%) but has not been reported in the literature in individuals with a FBN1-related disease. 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. In summary, this variant is a rare missense change that is not predicted to affect 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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