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

dbSNP: rs35766612

Total submissions: 12

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, Mass General Brigham 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	RCV000249454	SCV000319271	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2019-09-19	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000414949	SCV000492956	uncertain significance	Ascending tubular aorta aneurysm; Vascular dilatation	2014-05-27	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000249454	SCV000548116	benign	Familial thoracic aortic aneurysm and aortic dissection	2024-01-26	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 Diagnostics, LLC DBA Color Health	RCV000249454	SCV000903193	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2018-05-07	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002277109	SCV002566151	uncertain significance	Ehlers-Danlos syndrome	2020-02-01	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000249454	SCV003838805	benign	Familial thoracic aortic aneurysm and aortic dissection	2021-08-20	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004754278	SCV005362568	likely benign	TGFBR2-related disorder	2024-04-18	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).