ClinVar Miner

Submissions for variant NM_004612.4(TGFBR1):c.889G>A (p.Val297Ile)

gnomAD frequency: 0.00001  dbSNP: rs757284158
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000555698 SCV000658862 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2023-10-23 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 297 of the TGFBR1 protein (p.Val297Ile). This variant is present in population databases (rs757284158, gnomAD 0.0009%). 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: 477564). 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 not expected to disrupt TGFBR1 protein function with a negative 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.
Color Diagnostics, LLC DBA Color Health RCV000555698 SCV001358910 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2021-04-14 criteria provided, single submitter clinical testing This missense variant replaces valine with isoleucine at codon 297 of the TGFBR1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. 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 1/251036 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.
Ambry Genetics RCV000555698 SCV002685360 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2022-03-17 criteria provided, single submitter clinical testing The p.V297I variant (also known as c.889G>A), located in coding exon 5 of the TGFBR1 gene, results from a G to A substitution at nucleotide position 889. The valine at codon 297 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics RCV002483508 SCV002787982 uncertain significance Loeys-Dietz syndrome 1; Multiple self-healing squamous epithelioma 2021-08-31 criteria provided, single submitter clinical testing

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