Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000154616 | SCV000204289 | uncertain significance | not specified | 2011-09-20 | criteria provided, single submitter | clinical testing | Variant classified as Uncertain Significance - Favor Pathogenic. The 1570G>T (As p524Tyr) variant in TGFBR2 has not been reported in the literature. This varian t has been identified in one individual with clinical features of Loeys-Dietz sy ndrome (this individual's mother) out of 269 probands screened by our laboratory . A different variant at the same position, Asp524Asn, has been reported in the literature in one proband with manifestations of Loeys-Dietz syndrome type II (L oeys 2006). The aspartic acid (Asp) residue at position 524 is highly conserved across evolutionarily distant species. Computational analyses (amino acid bioche mical properties, homology, PolyPhen2, SIFT) predict that the Asp524Tyr variant may impact the protein. However, this information is not sufficient to establish pathogenicity. In summary, the clinical significance of this variant cannot be determined with certainty at this time. |
| Invitae | RCV001051221 | SCV001215365 | uncertain significance | Familial thoracic aortic aneurysm and aortic dissection | 2019-04-18 | criteria provided, single submitter | clinical testing | This variant has been observed in an individual with clinical features of TGFBR2-related disease (PMID: 23884466, Invitae). ClinVar contains an entry for this variant (Variation ID: 177953). 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. This variant disrupts the p.Asp524 amino acid residue in TGFBR2. Other variant(s) that disrupt this residue have been observed in individuals with TGFBR2-related conditions (PMID: 16928994), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). This variant is not present in population databases (ExAC no frequency). This sequence change replaces aspartic acid with tyrosine at codon 524 of the TGFBR2 protein (p.Asp524Tyr). The aspartic acid residue is highly conserved and there is a large physicochemical difference between aspartic acid and tyrosine. |