Submissions for variant NM_004612.4(TGFBR1):c.1216T>A (p.Leu406Ile)

dbSNP: rs200062984

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000660316	SCV000739758	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2017-07-12	criteria provided, single submitter	clinical testing	The p.L406I variant (also known as c.1216T>A), located in coding exon 7 of the TGFBR1 gene, results from a T to A substitution at nucleotide position 1216. The leucine at codon 406 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000660316	SCV000782359	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2016-11-01	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000660316	SCV001333562	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-03-15	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000660316	SCV001352017	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-05-12	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with isoleucine at codon 406 of the TGFBR1 protein. Computational prediction tool 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 performed for this variant. This variant has been reported in an individual affected with thoracic aortic aneurysm, which was inherited from the affected father (PMID: 35830949). This variant has also been reported in an individual suspected of having genetic vascular disease, mainly due to a personal or family history of aortic or arterial aneurysms and dissections (PMID: 29510914). This variant has been identified in 2/251216 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.
Invitae	RCV000660316	SCV002204684	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-12-05	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 406 of the TGFBR1 protein (p.Leu406Ile). This variant is present in population databases (rs200062984, gnomAD 0.003%). This missense change has been observed in individual(s) with vascular disease (PMID: 29510914). ClinVar contains an entry for this variant (Variation ID: 520226). 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 expected to disrupt TGFBR1 protein function with a positive predictive value of 80%. 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.