ClinVar Miner

Submissions for variant NM_001999.4(FBN2):c.3883G>A (p.Asp1295Asn) (rs759131544)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000199913 SCV000250289 uncertain significance not provided 2020-09-22 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 has a deleterious effect on 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 (Collod-Beroud et al., 2003; Frederic et al., 2009) Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 213405; Landrum et al., 2016)
Invitae RCV000465682 SCV000553177 uncertain significance Congenital contractural arachnodactyly 2020-08-03 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 1295 of the FBN2 protein (p.Asp1295Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs759131544, ExAC 0.004%) but has not been reported in the literature in individuals with a FBN2-related disease. ClinVar contains an entry for this variant (Variation ID: 213405). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Possibly Damaging; Align-GVGD: Class C1). In summary, this variant is a rare missense change with uncertain impact on 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.
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000680528 SCV000807931 uncertain significance Connective tissue disease 2018-06-01 criteria provided, single submitter clinical testing

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