ClinVar Miner

Submissions for variant NM_004612.4(TGFBR1):c.613A>G (p.Ile205Val) (rs200018073)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000619245 SCV000739753 uncertain significance Cardiovascular phenotype 2017-02-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000696683 SCV000904905 uncertain significance Thoracic aortic aneurysm and aortic dissection 2018-10-05 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the cytoplasmic domain of the TGFBR1 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 7/277040 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
Fulgent Genetics,Fulgent Genetics RCV000766034 SCV000897473 uncertain significance Loeys-Dietz syndrome 1; Multiple self healing squamous epithelioma 2018-10-31 criteria provided, single submitter clinical testing
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
Invitae RCV000696683 SCV000825256 uncertain significance Thoracic aortic aneurysm and aortic dissection 2018-03-27 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 205 of the TGFBR1 protein (p.Ile205Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with TGFBR1-related disease. ClinVar contains an entry for this variant (Variation ID: 213899). Algorithms developed to predict the effect of missense changes on protein structure and function 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.
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

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