Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000483417 | SCV000574276 | uncertain significance | not provided | 2017-03-20 | criteria provided, single submitter | clinical testing | A variant of uncertain significance has been identified in the FBN2 gene. The Y841C variant has not been published as pathogenic or been reported as benign to our knowledge. Additionally, this variant 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 Y841C 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. Furthermore, this substitution occurs at a position that is conserved in mammals and in silico analysis predicts this variant is probably damaging to the protein structure/function. Moreover, the Y841C variant introduces a Cysteine residue within a calcium-binding EGF-like domain of the FBN2 gene, which may affect disulfide bonding and is predicted to alter the structure and function of the protein. Cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with FBN2-related disorders (Frederic et al., 2009). Nevertheless, this variant has not been observed in a significant number of affected individuals and it lacks both segregation and functional studies which would further clarify its pathogenicity. |
| Invitae | RCV000539467 | SCV000630202 | uncertain significance | Congenital contractural arachnodactyly | 2022-10-02 | criteria provided, single submitter | clinical testing | ClinVar contains an entry for this variant (Variation ID: 424465). This missense change has been observed in individual(s) with clinical features of FBN2-related conditions (Invitae). This variant is present in population databases (rs762606715, gnomAD 0.002%). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 841 of the FBN2 protein (p.Tyr841Cys). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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. |