Submissions for variant NM_004612.4(TGFBR1):c.965G>A (p.Gly322Asp)

dbSNP: rs863223833

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000197792	SCV000250908	uncertain significance	not provided	2015-06-22	criteria provided, single submitter	clinical testing	p.Gly322Asp (G322D) (GGT>GAT): c.965 G>A in exon 5 of the TGFBR1 gene (NM_004612.2) The G322D variant of unknown significance in the TGFBR1 gene has not been published as a mutation or reported as a benign polymorphism to our knowledge. The G322D variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G322D 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 occurs at a position that is conserved across species. Consequently, in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense mutations in nearby residues (G312S, H315R, M318R) have been reported in association with TGFBR1-related disorders, supporting the functional importance of this region of the protein. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. This variant was found in TAADV2-PANCARD
Invitae	RCV001373794	SCV001570526	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-11-22	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 322 of the TGFBR1 protein (p.Gly322Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of thoracic aortic aneurysm and dissection (Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 213901). 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 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.
PreventionGenetics, part of Exact Sciences	RCV003982941	SCV004800432	uncertain significance	TGFBR1-related condition	2024-02-01	criteria provided, single submitter	clinical testing	The TGFBR1 c.965G>A variant is predicted to result in the amino acid substitution p.Gly322Asp. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.