Submissions for variant NM_003242.6(TGFBR2):c.76C>T (p.Pro26Ser)

gnomAD frequency: 0.00001  dbSNP: rs764160271

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001064639	SCV001229550	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2021-12-22	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 26 of the TGFBR2 protein (p.Pro26Ser). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 858705). 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. 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.
Color Diagnostics, LLC DBA Color Health	RCV001064639	SCV001358262	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-04-27	criteria provided, single submitter	clinical testing	This missense variant replaces proline with serine at codon 26 of the TGFBR2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with TGFBR2-related disorders in the literature. This variant has been identified in 4/252882 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics	RCV002505641	SCV002814475	uncertain significance	Loeys-Dietz syndrome 2; Malignant tumor of esophagus; Colorectal cancer, hereditary nonpolyposis, type 6	2021-08-05	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001064639	SCV003912862	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2022-11-30	criteria provided, single submitter	clinical testing	The p.P26S variant (also known as c.76C>T), located in coding exon 1 of the TGFBR2 gene, results from a C to T substitution at nucleotide position 76. The proline at codon 26 is replaced by serine, an amino acid with similar properties. This amino acid position is 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.
GeneDx	RCV003325539	SCV004031927	uncertain significance	not provided	2023-03-02	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function