Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV002526427 | SCV000550895 | uncertain significance | Rienhoff syndrome | 2022-07-05 | criteria provided, single submitter | clinical testing | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 291 of the TGFB3 protein (p.Pro291Leu). This variant is present in population databases (rs145121701, gnomAD 0.01%). 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: 410274). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest 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. |
| Gene |
RCV000482159 | SCV000573474 | uncertain significance | not provided | 2019-12-24 | criteria provided, single submitter | clinical testing | Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar as a variant of uncertain significance, but additional evidence is not available (ClinVar Variant ID# 410274; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function |
| Ambry Genetics | RCV002374792 | SCV002685283 | uncertain significance | Familial thoracic aortic aneurysm and aortic dissection | 2023-10-18 | criteria provided, single submitter | clinical testing | The p.P291L variant (also known as c.872C>T), located in coding exon 5 of the TGFB3 gene, results from a C to T substitution at nucleotide position 872. The proline at codon 291 is replaced by leucine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Fulgent Genetics, |
RCV002496780 | SCV002813279 | uncertain significance | Arrhythmogenic right ventricular dysplasia 1; Rienhoff syndrome | 2021-10-01 | criteria provided, single submitter | clinical testing | |
| Clinical Genomics Laboratory, |
RCV003985017 | SCV004801296 | uncertain significance | Arrhythmogenic right ventricular dysplasia 1 | 2021-04-29 | criteria provided, single submitter | clinical testing | The p.Pro291Leu variant in the TGFB3 gene has not been previously reported in association with disease. This variant has been identified in 2/16,254 African/African American chromosomes (8/251,428 chromosomes overall) by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Although this variant has been seen in the general population, it has not been seen at a high enough frequency to rule out pathogenicity. The proline at position 291 is highly evolutionarily conserved in mammals; however, leucine is observed in one lower species (zebrafish). Computational tools do not predict that the p.Pro291Leu variant is deleterious; however, the accuracy of in silico algorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, the significance of the p.Pro291Leu variant is uncertain. Additional information is needed to resolve the significance of this variant. [ACMG evidence codes used: None] |