Submissions for variant NM_003242.6(TGFBR2):c.1126G>A (p.Val376Met)

dbSNP: rs755967723

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000457732	SCV000548110	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2024-01-01	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 376 of the TGFBR2 protein (p.Val376Met). This variant is present in population databases (rs755967723, gnomAD 0.005%). This missense change has been observed in individual(s) with clinical features of TGFBR2-related conditions (PMID: 24199744; Invitae). ClinVar contains an entry for this variant (Variation ID: 408436). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TGFBR2 protein function with a positive predictive value of 80%. 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.
Fulgent Genetics, Fulgent Genetics	RCV000765724	SCV000897091	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
GeneDx	RCV001591087	SCV001826929	uncertain significance	not provided	2020-09-14	criteria provided, single submitter	clinical testing	Has been reported previously in a teenage female with pes planus, pectus excavatum, and a family history of fatal aortic dissection (Pees et al., 2014); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 408436; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 24199744)
Ambry Genetics	RCV000457732	SCV002753983	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2018-11-20	criteria provided, single submitter	clinical testing	The p.V376M variant (also known as c.1126G>A), located in coding exon 4 of the TGFBR2 gene, results from a G to A substitution at nucleotide position 1126. The valine at codon 376 is replaced by methionine, an amino acid with highly similar properties, and is located in the protein kinase domain. This variant was reported in a 15 year old female with pes planus and pectus excavatum who was reported to have a family history of aortic dissection or Loeys-Dietz syndrome (Pees C et al. Clin Genet. 2014;86(6):552-7). This amino acid position is 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 variant remains unclear.
Mayo Clinic Laboratories, Mayo Clinic	RCV001591087	SCV004226055	uncertain significance	not provided	2023-05-25	criteria provided, single submitter	clinical testing	PP3