ClinVar Miner

Submissions for variant NM_001999.4(FBN2):c.2557A>G (p.Ile853Val) (rs148598779)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000633583 SCV000754829 uncertain significance Congenital contractural arachnodactyly 2017-10-24 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 853 of the FBN2 protein (p.Ile853Val). The isoleucine residue is weakly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs148598779, ExAC 0.002%). This variant has not been reported in the literature in individuals with FBN2-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000659606 SCV000781445 likely benign Connective tissue disease 2016-11-01 criteria provided, single submitter clinical testing
GeneDx RCV001554961 SCV001776302 uncertain significance not provided 2021-05-24 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Although located in a calcium-binding EGF-like domain of the FBN2 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 FBN2-related disorders (Frederic et al., 2009).; Reported in ClinVar (ClinVar Variant ID# 528399; Landrum et al., 2016)

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