Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000424321 | SCV000532536 | uncertain significance | not provided | 2017-01-17 | criteria provided, single submitter | clinical testing | The E1898K variant of uncertain significance in the FBN2 gene has not been published as pathogenic or been reported as benign to our knowledge. E1898K is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The E1898K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Moreover, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Nevertheless, although the E1898K variant is located within a calcium-binding EGF-like domain of the FBN2 gene, it does not affect a Cysteine residue. Cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with congenital arachnodactyly (Collod-Beroud et al., 2003; Frédéric et al., 2009). |
| Invitae | RCV001063160 | SCV001227995 | uncertain significance | Congenital contractural arachnodactyly | 2023-07-12 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1898 of the FBN2 protein (p.Glu1898Lys). This variant is present in population databases (rs767932789, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with FBN2-related conditions. ClinVar contains an entry for this variant (Variation ID: 389867). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt FBN2 protein function. 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. |
| Ambry Genetics | RCV002348228 | SCV002647859 | uncertain significance | Familial thoracic aortic aneurysm and aortic dissection | 2022-06-16 | criteria provided, single submitter | clinical testing | The p.E1898K variant (also known as c.5692G>A), located in coding exon 45 of the FBN2 gene, results from a G to A substitution at nucleotide position 5692. The glutamic acid at codon 1898 is replaced by lysine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |