Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000197266 | SCV000250939 | uncertain significance | not provided | 2013-11-27 | criteria provided, single submitter | clinical testing | The Pro406Leu variant in the TGFBR2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. The Pro406Leu variant is a semi-conservative amino acid substitution as these residues share similar properties, but differ in size, charge, or other properties which may impact secondary structure. The Pro406 residue is conserved in mammals and birds. In addition, In silico analysis was inconsistent with regard to the effect this variant may have on the protein structure/function. Mutations in nearby residues Cys396Trp, Ala414Pro) have been reported in association with Marfan syndrome and Loeys-Dietz syndrome, respectively, supporting the functional importance of this region of the protein. The Pro406Leu variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. With the clinical and molecular information available at this time, we cannot definitively determine if Pro406Leu is a disease-causing mutation or a rare benign variant. This variant was found in TAAD |
| Blueprint Genetics | RCV000208444 | SCV000264248 | uncertain significance | Familial thoracic aortic aneurysm and aortic dissection | 2015-10-23 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV000208444 | SCV003005061 | uncertain significance | Familial thoracic aortic aneurysm and aortic dissection | 2022-10-19 | criteria provided, single submitter | clinical testing | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 406 of the TGFBR2 protein (p.Pro406Leu). This variant is present in population databases (rs748480163, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with TGFBR2-related conditions. ClinVar contains an entry for this variant (Variation ID: 213926). 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 TGFBR2 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. |