Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV001758460 | SCV001995382 | uncertain significance | not provided | 2019-12-23 | criteria provided, single submitter | clinical testing | Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge |
Ambry Genetics | RCV002405302 | SCV002711008 | uncertain significance | Familial thoracic aortic aneurysm and aortic dissection | 2021-09-07 | criteria provided, single submitter | clinical testing | The p.G561S variant (also known as c.1681G>A), located in coding exon 7 of the TGFBR2 gene, results from a G to A substitution at nucleotide position 1681. The glycine at codon 561 is replaced by serine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
Victorian Clinical Genetics Services, |
RCV002471149 | SCV002769443 | uncertain significance | Loeys-Dietz syndrome 2 | 2020-05-25 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as VUS – 3C. Following criteria are met: 0103 - Both loss- and gain-of-function are known mechanisms of disease for this gene. Loss of function has been demonstrated by missense and NMD-predicted variants (PMID: 28679693, PMID: 22772368). A single 5- UTR variant was shown to have gain of function ability (PMID: 16799921). (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from glycine to serine (exon 7). (N) 0251 - Variant is heterozygous. (N) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (3 heterozygotes, 0 homozygotes). (P) 0504 - Same amino acid change has been observed in mammals. (B) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0807 - Variant has not previously been reported in a clinical context. (N) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1206 - Variant is paternally inherited. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign |
Labcorp Genetics |
RCV002405302 | SCV003444022 | uncertain significance | Familial thoracic aortic aneurysm and aortic dissection | 2023-03-11 | criteria provided, single submitter | clinical testing | 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. 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 TGFBR2 protein function. ClinVar contains an entry for this variant (Variation ID: 1310951). This variant has not been reported in the literature in individuals affected with TGFBR2-related conditions. This variant is present in population databases (rs768103695, gnomAD 0.003%). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 561 of the TGFBR2 protein (p.Gly561Ser). |