Submissions for variant NM_003239.5(TGFB3):c.865G>A (p.Asp289Asn)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002449654	SCV002682539	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-06-22	criteria provided, single submitter	clinical testing	The p.D289N variant (also known as c.865G>A), located in coding exon 5 of the TGFB3 gene, results from a G to A substitution at nucleotide position 865. The aspartic acid at codon 289 is replaced by asparagine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated 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	RCV003099997	SCV003274661	uncertain significance	Rienhoff syndrome	2024-11-19	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 289 of the TGFB3 protein (p.Asp289Asn). This variant is present in population databases (rs777949995, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with TGFB3-related conditions. ClinVar contains an entry for this variant (Variation ID: 1764216). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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.
GeneDx	RCV003151894	SCV003840497	uncertain significance	not provided	2022-09-09	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
PreventionGenetics, part of Exact Sciences	RCV003418485	SCV004116961	uncertain significance	TGFB3-related disorder	2023-09-25	criteria provided, single submitter	clinical testing	The TGFB3 c.865G>A variant is predicted to result in the amino acid substitution p.Asp289Asn. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0079% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/14-76429720-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.