Submissions for variant NM_003239.5(TGFB3):c.397C>T (p.Arg133Cys)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002375535	SCV002625176	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2019-11-21	criteria provided, single submitter	clinical testing	The p.R133C variant (also known as c.397C>T), located in coding exon 2 of the TGFB3 gene, results from a C to T substitution at nucleotide position 397. The arginine at codon 133 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003102494	SCV003462019	likely pathogenic	Rienhoff syndrome	2024-05-16	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 133 of the TGFB3 protein (p.Arg133Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Loeys Dietz syndrome (Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 1736684). 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 TGFB3 protein function with a negative predictive value of 80%. This variant disrupts the p.Arg133 amino acid residue in TGFB3. Other variant(s) that disrupt this residue have been observed in individuals with TGFB3-related conditions (Invitae), 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.