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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000152009 SCV000053215 benign not specified 2021-07-27 criteria provided, single submitter clinical testing Variant summary: TGFBR2 c.1159G>T (p.Val387Leu) results in a conservative amino acid change located in the Serine-threonine/tyrosine-protein kinase, catalytic domain (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 250480 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is approximately 112-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. p.Val387Leu has been reported in the literature in individuals affected with Marfan Syndrome (MFS), Loeys-Dietz Syndrome (LDS) or Thoracic Aortic Aneurysms and Dissections (TAAD) (Matyas_2006, Stheneur_2008, Lerner-Ellis_2014), while it was also reported in a case of Brain arteriovenous malformation (Scimone_2020). Two of these studies reported the variant as likely benign or polymorphism. These reports 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 ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign and two ClinVar submitters (evaluation after 2014) cite it as uncertain significance. Based on the evidence outlined above, the variant was classified as 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 RCV001703428 SCV000250936 likely benign not provided 2020-09-09 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 18781618, 16791849, 17061023, 24793577)
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,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 In silico models in agreement (benign);Subpopulation frequency in support of benign classification
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000414949 SCV000492956 uncertain significance Dilatation of ascending aorta; Aneurysm 2014-05-27 criteria provided, single submitter clinical testing
Invitae RCV000249454 SCV000548116 benign Familial thoracic aortic aneurysm and aortic dissection 2020-11-11 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 Health, Inc RCV000249454 SCV000903193 likely benign Familial thoracic aortic aneurysm and aortic dissection 2018-05-07 criteria provided, single submitter clinical testing

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