Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000253481 | SCV000320065 | pathogenic | Familial thoracic aortic aneurysm and aortic dissection | 2017-07-06 | criteria provided, single submitter | clinical testing | The p.C393Y pathogenic mutation (also known as c.1178G>A), located in coding exon 4 of the TGFBR2 gene, results from a G to A substitution at nucleotide position 1178. The cysteine at codon 393 is replaced by tyrosine, an amino acid with highly dissimilar properties, and is located in a protein kinase domain. This alteration was confirmed as de novo in a proband whose clinical presentation is consistent with Loeys-Dietz syndrome (LDS). Another alteration at the same codon, p.C393G (c.1177T>G), has been observed in an individual with LDS (Frischmeyer-Guerrerio PA et al. Sci Transl Med 2013; 5(195):195ra94) and in a thoracic aortic disease cohort (Jondeau G et al. Circ Cardiovasc Genet, 2016 Dec;9:548-558); however, clinical details were limited. Based on the supporting evidence, p.C393Y is interpreted as a disease-causing mutation. |
| Invitae | RCV000253481 | SCV002991592 | pathogenic | Familial thoracic aortic aneurysm and aortic dissection | 2022-03-22 | criteria provided, single submitter | clinical testing | This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. 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 TGFBR2 protein function. ClinVar contains an entry for this variant (Variation ID: 264260). This missense change has been observed in individual(s) with TGFBR2-related conditions (Invitae). In at least one individual the variant was observed to be de novo. This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 393 of the TGFBR2 protein (p.Cys393Tyr). |