Submissions for variant NM_003242.6(TGFBR2):c.1168G>A (p.Asp390Asn)

dbSNP: rs2125436704

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Department of Vascular Biology, Beijing Anzhen Hospital	RCV001374780	SCV001439497	uncertain significance	Isolated thoracic aortic aneurysm	2018-09-01	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV003528283	SCV004286256	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2024-12-02	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 390 of the TGFBR2 protein (p.Asp390Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with TGFBR2-related conditions (PMID: 29543232, 33824467). ClinVar contains an entry for this variant (Variation ID: 982333). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TGFBR2 protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV003528283	SCV004359817	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-05-08	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with asparagine at codon 390 of the TGFBR2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with thoracic aortic aneurysm and dissection (PMID: 29543232). This variant has not been identified 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.
All of Us Research Program, National Institutes of Health	RCV004004931	SCV004838463	uncertain significance	Loeys-Dietz syndrome 2	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with asparagine at codon 390 of the TGFBR2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with thoracic aortic aneurysm and dissection (PMID: 29543232). This variant has not been identified 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.
Ambry Genetics	RCV003528283	SCV005954489	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2025-01-03	criteria provided, single submitter	clinical testing	The p.D390N variant (also known as c.1168G>A), located in coding exon 4 of the TGFBR2 gene, results from a G to A substitution at nucleotide position 1168. The aspartic acid at codon 390 is replaced by asparagine, an amino acid with highly similar properties. This variant was reported in individual(s) with features consistent with thoracic aortic aneurysm or dissection (Weerakkody R et al. Genet Med, 2018 Nov;20:1414-1422; Li Y et al. Eur J Hum Genet, 2021 Jul;29:1129-1138). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.