Submissions for variant NM_003242.6(TGFBR2):c.1015C>T (p.Arg339Trp)

gnomAD frequency: 0.00004  dbSNP: rs761991787

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Fulgent Genetics, Fulgent Genetics	RCV000765723	SCV000897090	uncertain significance	Loeys-Dietz syndrome 2; Malignant tumor of esophagus; Colorectal cancer, hereditary nonpolyposis, type 6	2018-10-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781901	SCV000920292	likely benign	not specified	2018-07-30	criteria provided, single submitter	clinical testing	Variant summary: TGFBR2 c.1015C>T (p.Arg339Trp) results in a non-conservative amino acid change located in the catalytic domain of the Serine-threonine/tyrosine-protein kinase (IPR001245) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.4e-05 in 245908 control chromosomes (gnomAD and publications). The observed variant frequency is approximately 75-fold of the estimated maximal expected allele frequency for a pathogenic variant in TGFBR2 causing Aortopathy phenotype (1.3e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.1015C>T in individuals affected with Aortopathy and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely benign.
Invitae	RCV000809777	SCV000949952	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 339 of the TGFBR2 protein (p.Arg339Trp). This variant is present in population databases (rs761991787, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with TGFBR2-related conditions. ClinVar contains an entry for this variant (Variation ID: 374980). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt TGFBR2 function with a positive predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000809777	SCV001333523	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2018-09-18	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000809777	SCV001735604	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2020-01-23	criteria provided, single submitter	clinical testing
GeneDx	RCV001310482	SCV001785603	uncertain significance	not provided	2023-03-06	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function
Ambry Genetics	RCV000809777	SCV002639889	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2020-01-16	criteria provided, single submitter	clinical testing	The p.R339W variant (also known as c.1015C>T), located in coding exon 4 of the TGFBR2 gene, results from a C to T substitution at nucleotide position 1015. The arginine at codon 339 is replaced by tryptophan, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV001310482	SCV003819483	uncertain significance	not provided	2021-03-21	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003902462	SCV004720814	likely benign	TGFBR2-related disorder	2023-01-23	criteria provided, single submitter	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).
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000415648	SCV000493809	uncertain significance	Lynch syndrome	2016-01-27	no assertion criteria provided	clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000415679	SCV000493810	uncertain significance	Loeys-Dietz syndrome	2016-01-27	no assertion criteria provided	clinical testing