ClinVar Miner

Submissions for variant NM_003242.6(TGFBR2):c.412T>G (p.Cys138Gly) (rs863223838)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000195915 SCV000250924 uncertain significance not provided 2017-03-01 criteria provided, single submitter clinical testing The C138G has not been published as a pathogenic or benign variant to our knowledge. However, a different disease-causing variant at the same residue (C138R) has been reported as apparently de novo in an individual with spontaneous carotid artery dissection (Pezzini et al., 2011). In this study, C138R was not observed in 500 control chromosomes. Similarly, C138G has not been 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. C138G is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Furthermore, the C138 residue is likely important to TGFBR2 protein stability as this residue participates in disulfide bond formation (Pezzini et al., 2011). The C138 residue is completely conserved across species. Nevertheless, no missense variants in nearby residues have been reported in the Human Gene Mutation Database in association with TGFBR2-related disorder (Stenson et al., 2014).
Invitae RCV000471319 SCV000548112 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2017-07-27 criteria provided, single submitter clinical testing This sequence change replaces cysteine with glycine at codon 138 of the TGFBR2 protein (p.Cys138Gly). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and glycine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a TGFBR2-related disease. ClinVar contains an entry for this variant (Variation ID: 213915). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.
GenomeConnect, ClinGen RCV000509415 SCV000607137 not provided Loeys-Dietz syndrome; Familial thoracic aortic aneurysm no assertion provided phenotyping only GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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