ClinVar Miner

Submissions for variant NM_003242.6(TGFBR2):c.1483C>T (p.Arg495Ter) (rs104893819)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000253575 SCV000319544 pathogenic Thoracic aortic aneurysm and aortic dissection 2015-04-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Blueprint Genetics RCV000157519 SCV000207264 likely pathogenic Loeys-Dietz syndrome 2014-07-21 no assertion criteria provided clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763512 SCV000894313 pathogenic Loeys-Dietz syndrome 2; Malignant tumor of esophagus; Hereditary nonpolyposis colorectal cancer type 6 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000195964 SCV000250967 pathogenic not provided 2018-05-18 criteria provided, single submitter clinical testing The R495X variant in the TGFBR2 gene has been previously reported in several individuals with LDS (Loeys et al., 2006; Togashi et al., 2007; Akutsu et al., 2007; Yang et al., 2012). Loeys et al. (2006) initially identified the R495X variant in an individual with LDS and immunostaining of this patient's aortic tissue indicated increased TGF-beta signaling compared to controls. Moreover, this variant was reported to segregate with disease in at least 2 unrelated families (Togashi et al., 2007; Yang et al., 2012). The R495X variant has been identified in multiple individuals referred for genetic testing at GeneDx, though no segregation data are available. In addition, this variant is not observed in large population cohorts (Lek et al., 2016).The R495X variant is located in the penultimate exon of the TGFBR2 gene and is expected to result in an abnormal, truncated protein product. If the protein produced is stable, the expected result is loss of the last 73 amino acid residues. Barnett et al. (2011) demonstrated that R495X results in intracellular accumulation of collagen type 1 in patient-derived cultured fibroblasts. Moreover, other downstream nonsense and frameshift variants in the TGFBR2 gene have been reported in Human Gene Mutation Database in association with Loeys-Dietz syndrome or TAAD (Stenson et al., 2014).In summary, R495X in the TGFBR2 gene is interpreted as a pathogenic variant.
Integrated Genetics/Laboratory Corporation of America RCV000157519 SCV000918308 pathogenic Loeys-Dietz syndrome 2018-01-30 criteria provided, single submitter clinical testing Variant summary: TGFBR2 c.1483C>T (p.Arg495X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 245910 control chromosomes. The c.1483C>T variant has been reported in the literature in multiple individuals affected with Loeys-Dietz Syndrome, including segregation with disease in a family (Togashi_2007). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, where an increase in intracellular collagen was observed in patient fibroblasts (Barnett_2011). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, each of which classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000253575 SCV000658821 pathogenic Thoracic aortic aneurysm and aortic dissection 2018-10-08 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal at codon 495 (p.Arg495*) of the TGFBR2 gene. It is expected to result in a disrupted protein product. While this is not anticipated to result in nonsense mediated decay, it is expected to result in a shortened TGFBR2 protein. This variant is not present in population databases (rs104893819, ExAC no frequency). This variant has been reported in several unrelated individuals affected with Loeys-Dietz syndrome (PMID: 16928994, 17652900, 18084123, 22113417). ClinVar contains an entry for this variant (Variation ID: 12519). A splicing variant located at the donor splice site of exon 6 that generates a similar truncated protein in the last exon of TGFBR2 was shown to segregate with Marfan syndrome in a large multigenerational family (PMID: 15235604), suggesting that this truncation disrupts residues that are necessary for normal protein function. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000013344 SCV000033591 pathogenic Loeys-Dietz syndrome 2 2006-08-24 no assertion criteria provided literature only

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