ClinVar Miner

Submissions for variant NM_004612.4(TGFBR1):c.977A>G (p.Lys326Arg) (rs863223834)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000200025 SCV000250909 uncertain significance not provided 2015-01-29 criteria provided, single submitter clinical testing p.Lys326Arg (AAG>AGG): c.977 A>G in exon 6 of the TGFBR1 gene (NM_004612.2) The K326R variant of unknown significance in the TGFBR1 gene has not been published as a mutation or as a benign polymorphism to our knowledge. The K326R 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. In addition, this substitution occurs at a position that is conserved in mammals. Moreover, in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, missense mutations in nearby residues (M318R, K335Q) have been reported in association with TAAD-related disorders, supporting the functional importance of this region of the protein. Nevertheless, the K326R variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. 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 TAADV2-1
Invitae RCV000459749 SCV000548345 uncertain significance Thoracic aortic aneurysm and aortic dissection 2016-11-28 criteria provided, single submitter clinical testing This sequence change replaces lysine with arginine at codon 326 of the TGFBR1 protein (p.Lys326Arg). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and arginine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a TGFBR1-related disease. ClinVar contains an entry for this variant (Variation ID: 213902). 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 rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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