Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000497407 | SCV000590201 | uncertain significance | not provided | 2017-06-15 | criteria provided, single submitter | clinical testing | The M2269V variant in the FBN2 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The M2269V variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The M2269V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Methionine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret M2269V as a variant of uncertain significance. |
| Ambry Genetics | RCV002314856 | SCV000739032 | uncertain significance | Familial thoracic aortic aneurysm and aortic dissection | 2017-05-25 | criteria provided, single submitter | clinical testing | The p.M2269V variant (also known as c.6805A>G), located in coding exon 54 of the FBN2 gene, results from an A to G substitution at nucleotide position 6805. The methionine at codon 2269 is replaced by valine, an amino acid with highly similar properties, and is located in a cbEGF-like domain. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Invitae | RCV003640903 | SCV004537202 | uncertain significance | Congenital contractural arachnodactyly | 2022-12-01 | criteria provided, single submitter | clinical testing | 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. ClinVar contains an entry for this variant (Variation ID: 432473). This variant has not been reported in the literature in individuals affected with FBN2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2269 of the FBN2 protein (p.Met2269Val). |