Submissions for variant NM_004612.4(TGFBR1):c.1425G>T (p.Trp475Cys)

gnomAD frequency: 0.00001  dbSNP: rs767589799

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000490239	SCV000577693	likely pathogenic	not provided	2015-07-10	criteria provided, single submitter	clinical testing	The W475C variant has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. However, it has been observed in one other individual who had DNA-based testing at GeneDx due to a possible connective tissue disorder. The W475C variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Additionally, the W475C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties, and this substitution occurs at a position that is conserved across species. Furthermore, a missense variants in a nearby residue (N478S) has been reported in the Human Gene Mutation Database in association with Loeys-Dietz syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. Finally, in silico analysis predicts this variant is probably damaging to the protein structure/function.Therefore, this variant is a strong candidate for a pathogenic variant, however the possibility that it is a benign variant cannot be excluded
Color Diagnostics, LLC DBA Color Health	RCV001188451	SCV001355510	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-04-03	criteria provided, single submitter	clinical testing	This missense variant replaces tryptophan with cysteine at codon 475 of the TGFBR1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with TGFBR1-related disorders in the literature. This variant has been identified in 19/250078 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.
Invitae	RCV001188451	SCV001539705	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-08-07	criteria provided, single submitter	clinical testing	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. 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 TGFBR1 protein function. ClinVar contains an entry for this variant (Variation ID: 427067). This variant has not been reported in the literature in individuals affected with TGFBR1-related conditions. This variant is present in population databases (rs767589799, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 475 of the TGFBR1 protein (p.Trp475Cys).