ClinVar Miner

Submissions for variant NM_003239.5(TGFB3):c.965T>C (p.Ile322Thr)

gnomAD frequency: 0.00001  dbSNP: rs762643638
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV002526428 SCV000550897 likely pathogenic Rienhoff syndrome 2024-12-05 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 322 of the TGFB3 protein (p.Ile322Thr). This variant is present in population databases (rs762643638, gnomAD 0.007%). This missense change has been observed in individuals with syndromic aortic aneurysms and dissections and/or TGFB3-related conditions (PMID: 25835445; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 410276). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt TGFB3 protein function with a positive predictive value of 80%. 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.
Fulgent Genetics, Fulgent Genetics RCV000763946 SCV000894892 uncertain significance Arrhythmogenic right ventricular dysplasia 1; Rienhoff syndrome 2018-10-31 criteria provided, single submitter clinical testing
Ambry Genetics RCV002374793 SCV002690715 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2020-06-16 criteria provided, single submitter clinical testing The p.I322T variant (also known as c.965T>C), located in coding exon 6 of the TGFB3 gene, results from a T to C substitution at nucleotide position 965. The isoleucine at codon 322 is replaced by threonine, an amino acid with similar properties. This variant was reported in an individual from a thoracic aortic aneurysm and dissection (TAAD) cohort, and showed co-segregation with disease in his two children; however, clinical details were limited (Bertoli-Avella AM et al. J. Am. Coll. Cardiol., 2015 Apr;65:1324-1336). 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.
GeneDx RCV003227758 SCV003924965 uncertain significance not provided 2022-11-15 criteria provided, single submitter clinical testing 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; This variant is associated with the following publications: (PMID: 29392890, 25835445)

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