ClinVar Miner

Submissions for variant NM_001999.4(FBN2):c.4418G>A (p.Arg1473His) (rs140812463)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000196344 SCV000250210 uncertain significance not provided 2017-02-14 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the FBN2 gene. The R1473H variant has not been publishedas pathogenic or been reported as benign to our knowledge. This variant is not observed at a significant frequency inlarge population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Thissubstitution occurs at a position that is conserved across species, and in silico analysis predicts this variant isprobably damaging to the protein structure/function. However, the R1473H variant is a conservative amino acidsubstitution, which is not likely to impact secondary protein structure as these residues share similar properties.Furthermore, although this variant occurs within a calcium-binding EGF-like domain of the FBN2 gene, it does notaffect a Cysteine residue. Cysteine substitutions in the calcium-binding EGF-like domains represent the majority ofpathogenic missense changes associated with congenital arachnodactyly (Collod-Beroud et al., 2003; Frédéric et al.,2009).
Invitae RCV000466570 SCV000553203 uncertain significance Congenital contractural arachnodactyly 2019-03-19 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 1473 of the FBN2 protein (p.Arg1473His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs140812463, ExAC 0.002%). This variant has been observed in an individual affected with aortic dilation (PMID: 29907982). ClinVar contains an entry for this variant (Variation ID: 213327). 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: Benign; 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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001002171 SCV001160031 uncertain significance not specified 2018-11-07 criteria provided, single submitter clinical testing The FBN2 c.4418G>A; p.Arg1473His variant (rs140812463) to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 213327). This variant is found on five chromosomes in the Genome Aggregation Database, indicating it is not a common polymorphism. The arginine at codon 1473 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. However, due to limited information, the clinical significance of the p.Arg1473His variant is uncertain at this time.

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