ClinVar Miner

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

gnomAD frequency: 0.00002  dbSNP: rs200018073
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000199482 SCV000250906 uncertain significance not provided 2024-02-06 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
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
Labcorp Genetics (formerly Invitae), Labcorp 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
All of Us Research Program, National Institutes of Health RCV003996923 SCV004840393 uncertain significance Loeys-Dietz syndrome 2023-10-27 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.

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