ClinVar Miner

Submissions for variant NM_003242.6(TGFBR2):c.1159G>T (p.Val387Leu) (rs35766612)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000152009 SCV000053215 likely benign not specified 2018-02-26 criteria provided, single submitter clinical testing Variant summary: TGFBR2 c.1159G>T (p.Val387Leu) results in a conservative amino acid change located in the catalytic domain of the Serine-threonine/tyrosine-protein kinase (IPR001245) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00035 in 276080 control chromosomes in the gnomAD database, including 1 homozygotes. The observed variant frequency is approximately 112.43 fold of the estimated maximal expected allele frequency for a pathogenic variant in TGFBR2 causing Loeys-Dietz Syndrome phenotype (3.1e-06), strongly suggesting that the variant is benign. c.1159G>T has been reported in the literature in individuals affected with Loeys-Dietz Syndrome or Marfan Syndrome, with 2/3 studies classifying it as likely benign or polymorphism (Stheneur_2008, Lerner-Ellis_2014, Matyas_2006). These report(s) do not provide unequivocal conclusions about association of the variant with Loeys-Dietz Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000152009 SCV000200575 likely benign not specified 2010-08-20 criteria provided, single submitter clinical testing
GeneDx RCV000152009 SCV000250936 likely benign not specified 2017-12-04 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000030544 SCV000296973 uncertain significance Loeys-Dietz syndrome 2015-09-28 criteria provided, single submitter clinical testing
Ambry Genetics RCV000617160 SCV000319271 likely benign Cardiovascular phenotype 2019-09-19 criteria provided, single submitter clinical testing Subpopulation frequency in support of benign classification;In silico models in agreement (benign)
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000414949 SCV000492956 uncertain significance Dilatation of ascending aorta; Dilatation 2014-05-27 criteria provided, single submitter clinical testing
Invitae RCV000249454 SCV000548116 benign Familial thoracic aortic aneurysm and aortic dissection 2019-12-31 criteria provided, single submitter clinical testing
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000249454 SCV000782369 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2016-11-01 criteria provided, single submitter clinical testing
Color RCV000249454 SCV000903193 likely benign Familial thoracic aortic aneurysm and aortic dissection 2018-05-07 criteria provided, single submitter clinical testing

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