Submissions for variant NM_004612.4(TGFBR1):c.613A>G (p.Ile205Val)

gnomAD frequency: 0.00002  dbSNP: rs200018073

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000199482	SCV000250906	uncertain significance	not provided	2018-12-06	criteria provided, single submitter	clinical testing	p.Ile205Val (ATT>GTT): c.613 A>G in exon 4 of the TGFBR1 gene (NM_004612.2) The I205V variant of unknown significance in the TGFBR1 gene has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The I205V variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Although the I205V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties, this substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense mutations in nearby residues (T200P, T200I) have been reported in association with Loeys-Dietz syndrome, supporting the functional importance of this region of the protein. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. This variant was found in TAAD
Ambry Genetics	RCV000696683	SCV000739753	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2018-11-29	criteria provided, single submitter	clinical testing	The p.I205V variant (also known as c.613A>G), located in coding exon 4 of the TGFBR1 gene, results from an A to G substitution at nucleotide position 613. The isoleucine at codon 205 is replaced by valine, an amino acid with highly similar properties, and is in the protein kinase domain. Another alteration affecting this amino acid, p.I205M (c.615T>G), was reported in a study of clinical genetic testing; however, clinical details were limited (Pepin MG et al. Genet. Med., 2016 Jan;18:20-4). 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.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000623797	SCV000740522	uncertain significance	Loeys-Dietz syndrome 1	2016-05-11	criteria provided, single submitter	clinical testing
Invitae	RCV000696683	SCV000825256	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2022-07-23	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 205 of the TGFBR1 protein (p.Ile205Val). This variant is present in population databases (rs200018073, gnomAD 0.005%). This variant has not been reported in the literature in individuals affected with TGFBR1-related conditions. ClinVar contains an entry for this variant (Variation ID: 213899). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Fulgent Genetics, Fulgent Genetics	RCV000766034	SCV000897473	uncertain significance	Loeys-Dietz syndrome 1; Multiple self-healing squamous epithelioma	2021-10-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000696683	SCV000904905	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-07-24	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 205 of the TGFBR1 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 not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 7/282706 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000696683	SCV003838878	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2021-09-29	criteria provided, single submitter	clinical testing