ClinVar Miner

Submissions for variant NM_001999.4(FBN2):c.2651G>C (p.Ser884Thr) (rs139035999)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000198286 SCV000250171 uncertain significance not provided 2020-03-26 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 213288; Landrum et al., 2016); 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 (Collod-Beroud et al., 2003; Frederic et al. 2009)
Ambry Genetics RCV000252144 SCV000318739 uncertain significance Cardiovascular phenotype 2013-06-13 criteria provided, single submitter clinical testing There is insufficient or conflicting evidence for classification of this alteration.
Invitae RCV001316692 SCV001507323 uncertain significance Congenital contractural arachnodactyly 2020-07-20 criteria provided, single submitter clinical testing This sequence change replaces serine with threonine at codon 884 of the FBN2 protein (p.Ser884Thr). The serine residue is moderately conserved and there is a small physicochemical difference between serine and threonine. This variant is present in population databases (rs139035999, ExAC 0.06%). This variant has not been reported in the literature in individuals with FBN2-related disease. ClinVar contains an entry for this variant (Variation ID: 213288). 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.

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