Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000226439 | SCV000288619 | uncertain significance | Familial thoracic aortic aneurysm and aortic dissection | 2023-05-22 | 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 123 of the TGFBR1 protein (p.Pro123Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TGFBR1-related conditions. ClinVar contains an entry for this variant (Variation ID: 239961). 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 TGFBR1 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. |
| Gene |
RCV000493898 | SCV000582315 | uncertain significance | not provided | 2017-12-11 | criteria provided, single submitter | clinical testing | The P123L variant has not beenpublished as pathogenic or been reported as benign to our knowledge. However, it has been reported as a variant ofuncertain significance in ClinVar by one other clinical laboratory (SCV000288619.2; Landrum et al., 2016). Thisvariant has not been observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015;Exome Variant Server). The P123L variant is a semi-conservative amino acid substitution, which may impactsecondary protein structure as these residues differ in some properties. Moreover, this substitution occurs at a positionthat is conserved across species, and in silico analysis predicts this variant is probably damaging to the proteinstructure/function. Nonetheless, this variant lacks observation in a significant number of affected individuals,segregation data, and functional evidence, which would further clarify its pathogenicity. |