ClinVar Miner

Submissions for variant NM_000138.5(FBN1):c.6454G>A (p.Glu2152Lys)

gnomAD frequency: 0.00001  dbSNP: rs777877864
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000631917 SCV000753020 uncertain significance Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2021-08-31 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 2152 of the FBN1 protein (p.Glu2152Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs777877864, ExAC 0.002%). This missense change has been observed in individuals with ectopia lentis (PMID: 19293843). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly 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.
GeneDx RCV003126876 SCV003803262 uncertain significance not provided 2022-08-12 criteria provided, single submitter clinical testing Identified in patient with ectopia lentis in published literature (Stheneur et al., 2009); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Although located in a calcium-binding EGF-like domain of the FBN1 gene, it does not affect a cysteine residue within this domain; cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with FBN1-related disorders (Collod-Beroud et al., 2003); This variant is associated with the following publications: (PMID: 19293843, 12938084)
All of Us Research Program, National Institutes of Health RCV004003814 SCV004834401 uncertain significance Marfan syndrome 2024-01-11 criteria provided, single submitter clinical testing

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