Submissions for variant NM_003242.6(TGFBR2):c.340G>C (p.Glu114Gln)

gnomAD frequency: 0.00005  dbSNP: rs771551560

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001190092	SCV001357507	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-11-01	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with glutamine at codon 114 of the TGFBR2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with TGFBR2-related disorders in the literature. This variant has been identified in 1/250966 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics	RCV002491568	SCV002778437	uncertain significance	Loeys-Dietz syndrome 2; Malignant tumor of esophagus; Colorectal cancer, hereditary nonpolyposis, type 6	2021-08-17	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001190092	SCV003998020	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-12-18	criteria provided, single submitter	clinical testing	The c.340G>C (p.E114Q) alteration is located in exon 3 (coding exon 3) of the TGFBR2 gene. This alteration results from a G to C substitution at nucleotide position 340, causing the glutamic acid (E) at amino acid position 114 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001190092	SCV004279061	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-12-23	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 114 of the TGFBR2 protein (p.Glu114Gln). This variant is present in population databases (rs771551560, gnomAD 0.003%). 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: 927079). 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 not expected to disrupt TGFBR2 protein function with a negative 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.
All of Us Research Program, National Institutes of Health	RCV004010407	SCV004839159	uncertain significance	Loeys-Dietz syndrome 2	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with glutamine at codon 114 of the TGFBR2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 1/250966 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV004033399	SCV005016457	uncertain risk allele	Diabetic retinopathy		criteria provided, single submitter	research	Potent mutations in TGFBR2 gene encodes the transforming growth factor that have been associated with angiogenesis and diabetic retinopathy. More clinical studies are needed for stronger association. However, more evidence is required to confer the association of this particular variant rs771551560 with diabetic retinopathy.