Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV001046474 | SCV000319595 | uncertain significance | Familial thoracic aortic aneurysm and aortic dissection | 2023-04-05 | criteria provided, single submitter | clinical testing | The p.M379T variant (also known as c.1136T>C), located in coding exon 7 of the TGFBR1 gene, results from a T to C substitution at nucleotide position 1136. The methionine at codon 379 is replaced by threonine, an amino acid with similar properties. This alteration has also been detected in multiple individuals in a thoracic aortic disease cohort (Jondeau G et al. Circ Cardiovasc Genet, 2016 Dec;9:548-558). 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. |
| Invitae | RCV001046474 | SCV001210379 | uncertain significance | Familial thoracic aortic aneurysm and aortic dissection | 2023-11-08 | criteria provided, single submitter | clinical testing | This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 379 of the TGFBR1 protein (p.Met379Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Loeys Dietz syndrome and/or clinical features of Loeys-Dietz syndrome (PMID: 27879313; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 263993). 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 TGFBR1 protein function with a positive predictive value of 80%. 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 |
RCV001764237 | SCV001989937 | uncertain significance | not provided | 2019-05-20 | criteria provided, single submitter | clinical testing | Previously reported in individuals with thoracic aortic disease and a three generation family with Loeys-Dietz syndrome (Jondeau et al., 2016; Biggin et al., 2018); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported in ClinVar but additional evidence is not available (ClinVar Variant ID# 263993; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 29524015, 27879313) |