ClinVar Miner

Submissions for variant NM_003242.6(TGFBR2):c.671G>A (p.Arg224His)

gnomAD frequency: 0.00003  dbSNP: rs112465572
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Diagnostics, LLC DBA Color Health RCV000773801 SCV000907501 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2023-03-21 criteria provided, single submitter clinical testing This missense variant replaces arginine with histidine at codon 224 in the TGFBR2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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 12/282242 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 RCV000773801 SCV001225779 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2022-07-29 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 224 of the TGFBR2 protein (p.Arg224His). This variant is present in population databases (rs112465572, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with TGFBR2-related conditions. ClinVar contains an entry for this variant (Variation ID: 629112). 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 TGFBR2 protein function. 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.
Ambry Genetics RCV000773801 SCV002665042 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2016-06-21 criteria provided, single submitter clinical testing The p.R224H variant (also known as c.671G>A), located in coding exon 4 of the TGFBR2 gene, results from a G to A substitution at nucleotide position 671. The arginine at codon 224 is replaced by histidine, an amino acid with highly similar properties. This variant was previously reported in the SNPDatabase as rs112465572. Based on data from ExAC, the A allele has an overall frequency less than 0.01% (6/106094). Based on data from the NHLBI Exome Sequencing Project (ESP), the A allele has an overall frequency of approximately 0.02% (2/13006) total alleles studied and 0.02% (2/8600) European American alleles. Allele frequency data for this nucleotide position is not currently available from the 1000 Genomes Project. This amino acid position is not well conserved in available vertebrate species, and histidine is the reference amino acid in other vertebrate species. 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV000773801 SCV003838803 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2021-11-23 criteria provided, single submitter clinical testing
GeneDx RCV003226974 SCV003924004 uncertain significance not provided 2023-05-03 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
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden RCV003226974 SCV004026263 uncertain significance not provided 2023-04-19 criteria provided, single submitter clinical testing PM2_SUP

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