Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000198137 | SCV000250940 | likely pathogenic | not provided | 2019-01-17 | criteria provided, single submitter | clinical testing | The V419L likely pathogenic variant in the TGFBR2 gene has been published in individual with features suggestive of a heritable connective tissue disorder, including thoracic aortic aneurysm, iliac artery aneurysms, and cervical artery tortuosity (Cousin et al., 2017). Functional analysis demonstrated the V419L variant led to a perturbation in the TFG-beta canonical signaling pathway (Cousin et al., 2017). Though the V419L variant is a conservative amino acid substitution, it occurs at a position within the protein kinase domain that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, missense variants in nearby residues (A414P, A414T, M425V, A426T, P427S, P427L) have been reported in the Human Gene Mutation Database in association TAAD and related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Finally, the V419L variant was not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server), indicating it is not a common benign variant. In summary, V419L in the TGFBR2 gene is interpreted as a likely pathogenic variant. |
| Ambry Genetics | RCV002408874 | SCV002675659 | likely pathogenic | Familial thoracic aortic aneurysm and aortic dissection | 2022-01-05 | criteria provided, single submitter | clinical testing | The p.V419L variant (also known as c.1255G>T) is located in coding exon 5 of the TGFBR2 gene. The valine at codon 419 is replaced by leucine, an amino acid with highly similar properties. This change occurs in the first base pair of coding exon 5. This variant has been previously reported in an individual with Loeys-Dietz syndrome (LDS) who inherited this allele from his unaffected mother (Cousin MA et al. Cold Spring Harb Mol Case Stud. 2017;3:a001727). In the same study, in vitro assays indicated p.V419L causes deficient TGFBR2 protein function. A different variant causing the same amino acid substitution (c.1255G>C, p.V419L) cosegregates with disease in one family tested in our laboratory (Ambry internal data). A third variant in the same codon, p.V419E, has been reported in a LDS cohort, though clinical details were limited (Jani P et al. J Med Genet, 2020 Oct;57:699-707). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |