ClinVar Miner

Submissions for variant NM_003242.6(TGFBR2):c.367A>T (p.Met123Leu) (rs768385200)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766907 SCV000250960 uncertain significance not provided 2018-11-01 criteria provided, single submitter clinical testing The M123L variant of uncertain significance in the TGFBR2 gene has not been published as a pathogenic or benign variant to our knowledge. This variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project or with any significant frequency in the Exome Aggregation Consortium, indicating it is not a common benign variant in these populations. The M123L variant has been identified in several other individuals referred for Marfan/TAAD genetic testing at GeneDx; however, the majority of individuals harbored a second cardiogenetic variant. This substitution occurs at a position that is conserved across species, and the majority of in silico tools predict this variant is probably damaging to the protein structure/function. Nevertheless, the M123L variant is a conservative amino acid substitution, which may not impact secondary protein structure as these residues share similar properties. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Ambry Genetics RCV000253449 SCV000320500 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2017-12-27 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Illumina Clinical Services Laboratory,Illumina RCV000323333 SCV000442835 likely benign Loeys-Dietz syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000380176 SCV000442836 likely benign Marfan syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000253449 SCV000442837 likely benign Familial thoracic aortic aneurysm and aortic dissection 2016-06-14 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000198358 SCV000605376 uncertain significance not specified 2017-01-06 criteria provided, single submitter clinical testing
Invitae RCV000253449 SCV000658829 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2019-12-08 criteria provided, single submitter clinical testing This sequence change replaces methionine with leucine at codon 123 of the TGFBR2 protein (p.Met123Leu). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and leucine. This variant is present in population databases (rs768385200, ExAC 0.05%). This variant has not been reported in the literature in individuals with TGFBR2-related disease. ClinVar contains an entry for this variant (Variation ID: 213939). 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: "Deleterious"; 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.
Color RCV000253449 SCV001358499 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2019-06-17 criteria provided, single submitter clinical testing

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