Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV002310878 | SCV000319344 | uncertain significance | Familial thoracic aortic aneurysm and aortic dissection | 2017-06-05 | criteria provided, single submitter | clinical testing | The p.E1366Q variant (also known as c.4096G>C), located in coding exon 33 of the FBN1 gene, results from a G to C substitution at nucleotide position 4096. The glutamic acid at codon 1366 is replaced by glutamine, an amino acid with some highly similar properties, and is located in the cb EGF-like #19 domain. An alteration affecting the same amino acid (p.E1366K, c.4096G>A) has been previously reported in association with Marfan syndrome related features (Biggin A et al. Hum Mut 2004;23:99-106). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Labcorp Genetics |
RCV002518700 | SCV003280891 | likely pathogenic | Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection | 2022-05-31 | criteria provided, single submitter | clinical testing | This variant is present in population databases (rs763449629, gnomAD 0.0009%). This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 1366 of the FBN1 protein (p.Glu1366Gln). This variant has not been reported in the literature in individuals affected with FBN1-related conditions. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Glu1366 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14695540, 16342915, 17657824, 24199744, 27611364, 27724990, 31098894). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 expected to disrupt FBN1 protein function. ClinVar contains an entry for this variant (Variation ID: 263872). |