Submissions for variant NM_003242.6(TGFBR2):c.1153A>G (p.Ile385Val)

gnomAD frequency: 0.00001  dbSNP: rs137908708

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000250474	SCV000319357	uncertain significance	Cardiovascular phenotype	2014-11-21	criteria provided, single submitter	clinical testing	There is insufficient or conflicting evidence for classification of this alteration.
Invitae	RCV000822694	SCV000963506	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2022-07-11	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 263878). This variant has not been reported in the literature in individuals affected with TGFBR2-related conditions. This variant is present in population databases (rs137908708, gnomAD 0.01%). This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 385 of the TGFBR2 protein (p.Ile385Val). 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.
GeneDx	RCV002466481	SCV002762496	uncertain significance	not provided	2022-06-08	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function
Fulgent Genetics, Fulgent Genetics	RCV002503959	SCV002816600	uncertain significance	Loeys-Dietz syndrome 2; Malignant tumor of esophagus; Colorectal cancer, hereditary nonpolyposis, type 6	2021-11-09	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000822694	SCV004359816	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-03-20	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 385 of the TGFBR2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 5/250320 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.