ClinVar Miner

Submissions for variant NM_003242.6(TGFBR2):c.1580C>T (p.Ala527Val) (rs727503476)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000152012 SCV000200580 uncertain significance not specified 2011-08-15 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The Ala527Val v ariant has been previously reported in 1 individual with clinical features of Lo eys-Dietz syndrome and was absent from 200 control chromosomes (Loeys 2006). Ala nine (Ala) at position 527 is highly conserved across evolutionarily distant spe cies, increasing the likelihood that the change is pathogenic. However, computer predictions are mixed (AlignGVGD = benign, Polyphen2 & SIFT = pathogenic), thou gh these tools have not been validated sufficiently to assume pathogenicity. Alt hough these data suggests that the Ala527Val variant may be disease causing, add itional information is required to fully assess this variant. Therefore, the cli nical significance of this variant cannot be determined at this time.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000588481 SCV000698195 likely pathogenic Loeys-Dietz syndrome 2016-09-07 criteria provided, single submitter clinical testing Variant summary: The TGFBR2 c.1580C>T (p.Ala527Val) variant involves the alteration of a highly conserved nucleotide and is located in the protein kinase domain of the protein (InterPro, UniProt). The alanine residue at this codon is highly conserved across species, and 4/4 in silico tools predict a damaging outcome for this variant. This variant was absent in 121254 control chromosomes from the broad and large populations of ExAC. In the literature, this variant was reported as a pathogenic variant found in three patients with Loeys-Dietz syndrome (Loeys_2006, Frischmeyer-Guerrerio_2013). Another missense change at the same residue, p.Ala527Thr, has also been reported in patients with Loeys-Dietz syndrome (Frischmeyer-Guerrerio_2013, Poninska_ J Transl Med_2016). In addition, several other potentially/likely pathogenic variants, such as p.Asp524Asn, p.Glu526Gln, p.Arg528Cys, p.Arg528His, and p.Ala531Thr have also been reported in this region, suggesting the region is mutational hot-spot. Furthermore, one reputable database has classified it as disease-causing. Taken together, this variant is currently classified as Likely Pathogenic.
Invitae RCV001066818 SCV001231838 likely pathogenic Familial thoracic aortic aneurysm and aortic dissection 2019-12-29 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 527 of the TGFBR2 protein (p.Ala527Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with TGFBR2-related disease (PMID: 16928994, 18852674, Invitae). ClinVar contains an entry for this variant (Variation ID: 165398). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant disrupts the p.Ala527 amino acid residue in TGFBR2. Other variant(s) that disrupt this residue have been observed in individuals with TGFBR2-related conditions (PMID: 27508510, 27146836), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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