Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000472675 | SCV000548118 | uncertain significance | Familial thoracic aortic aneurysm and aortic dissection | 2023-11-21 | criteria provided, single submitter | clinical testing | This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 72 of the TGFBR2 protein (p.Ser72Asn). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TGFBR2-related conditions. ClinVar contains an entry for this variant (Variation ID: 408442). 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 with a negative predictive value of 95%. 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. |
| Ambry Genetics | RCV000472675 | SCV002728469 | uncertain significance | Familial thoracic aortic aneurysm and aortic dissection | 2016-08-15 | criteria provided, single submitter | clinical testing | The p.S72N variant (also known as c.215G>A), located in coding exon 2 of the TGFBR2 gene, results from a G to A substitution at nucleotide position 215. The serine at codon 72 is replaced by asparagine, an amino acid with highly similar properties, and is located in the cysteine-rich EC domain . This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. This amino acid position is well conserved in available vertebrate species; however, asparagine is the reference amino acid in other 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. |
| Fulgent Genetics, |
RCV002489048 | SCV002778904 | uncertain significance | Loeys-Dietz syndrome 2; Malignant tumor of esophagus; Colorectal cancer, hereditary nonpolyposis, type 6 | 2021-12-06 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003488611 | SCV004241336 | likely benign | not specified | 2023-12-19 | criteria provided, single submitter | clinical testing | Variant summary: TGFBR2 c.215G>A (p.Ser72Asn) results in a conservative amino acid change located in the ectodomain (IPR015013) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.1e-05 in 1456070 control chromosomes (gnomAD database, v4.0 dataset). The observed variant frequency is approximately 8-fold of the estimated maximal expected allele frequency for a pathogenic variant in TGFBR2 causing Aortopathy phenotype (1.3e-06), suggesting that the variant is benign. To our knowledge, no occurrence of c.215G>A in individuals affected with Aortopathy and no experimental evidence demonstrating its impact on protein function have been reported. Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. |