ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.3650G>A (p.Gly1217Asp) (rs1555398397)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000706570 SCV000835629 uncertain significance Marfan syndrome; Thoracic aortic aneurysm and aortic dissection 2018-02-27 criteria provided, single submitter clinical testing This sequence change replaces glycine with aspartic acid at codon 1217 of the FBN1 protein (p.Gly1217Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with Marfan syndrome (PMID: 27112580). 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 disruptive, 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.
Petrovsky Russian Research Center of Surgery, The Federal Agency for Scientific Organizations RCV000663659 SCV000965674 likely pathogenic Marfan syndrome 2019-08-02 criteria provided, single submitter clinical testing The p.Gly1217Asp variant was found in one individual with MFS (PMID: 27112580) and is absent in large population studies (ExAC no frequency). The substitution of 1217 codon occurs in cbEGF-like domain and it participates in domain-domain packing (UMD-FBN1 Record ID: 2293). FBN1 gene is known to be less tolerant to missense variants (ExAC Z score = 5.33). ClinVar has an entry for this variant (Variation ID: 549180). Computational tools like Provean, PolyPhen2, MutationTaster show a deleterious result. Classification was based on ACMG criteria, concluding p.Gly1217Asp variant as Likely Pathogenic (PM1, PM2, PP2, PP3, PP4), although without function study we can't exclude the possibility of benign.
Center for Medical Genetics Ghent,University of Ghent RCV000663659 SCV000786987 uncertain significance Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing

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