Submissions for variant NM_003242.6(TGFBR2):c.412T>G (p.Cys138Gly)

gnomAD frequency: 0.00001  dbSNP: rs863223838

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000195915	SCV000250924	uncertain significance	not provided	2024-06-10	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function
Labcorp Genetics (formerly Invitae), Labcorp	RCV000471319	SCV000548112	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2024-01-04	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 138 of the TGFBR2 protein (p.Cys138Gly). This variant is present in population databases (no rsID available, gnomAD 0.002%). This missense change has been observed in individuals with clinical features of TGFBR2-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 213915). 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 95%. This variant disrupts the p.Cys138 amino acid residue in TGFBR2. Other variant(s) that disrupt this residue have been observed in individuals with TGFBR2-related conditions (PMID: 21270064), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
AiLife Diagnostics, AiLife Diagnostics	RCV000195915	SCV002502443	uncertain significance	not provided	2022-01-28	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002478686	SCV002786091	uncertain significance	Loeys-Dietz syndrome 2; Malignant tumor of esophagus; Colorectal cancer, hereditary nonpolyposis, type 6	2021-09-08	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003996927	SCV004833944	uncertain significance	Loeys-Dietz syndrome 2	2023-09-17	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with glycine at codon 138 of the TGFBR2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with thoracic aortic aneurysm and dissection, one individual affected with hypermobile Ehlers-Danlos syndrome, and a few with other features related to connective tissue disorders (ClinVar SCV000548112.3, SCV000250924.14, SCV000607137.1). This variant has been identified in 2/250894 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion for a pathogenic role, 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	RCV004020380	SCV005016369	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 rs863223838 with diabetic retinopathy.
GenomeConnect, ClinGen	RCV000509415	SCV000607137	not provided	Congenital aneurysm of ascending aorta; Loeys-Dietz syndrome		no assertion provided	phenotyping only	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.