Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV002447879 | SCV002679875 | uncertain significance | Hereditary cancer-predisposing syndrome; Cardiovascular phenotype | 2023-05-03 | criteria provided, single submitter | clinical testing | The p.G286R variant (also known as c.856G>A), located in coding exon 9 of the LZTR1 gene, results from a G to A substitution at nucleotide position 856. The glycine at codon 286 is replaced by arginine, an amino acid with dissimilar properties. This variant has been reported in a patient with schwannomatosis (Smith MJ et al. Neurology, 2015 Jan;84:141-7). Limited functional studies using cDNA constructs showed no significant difference in protein stability from wild type protein; however, studies examining the impact of this variant on subcellular localization, binding to cullin 3 (CUL3), and mitogen-associated protein kinase (MAPK) signaling were not conducted (Motta M et al. Hum Mol Genet, 2019 03;28:1007-1022). 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. |
| Labcorp Genetics |
RCV003099974 | SCV003510743 | uncertain significance | not provided | 2023-10-08 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 286 of the LZTR1 protein (p.Gly286Arg). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with schwannomatosis (PMID: 25480913). ClinVar contains an entry for this variant (Variation ID: 1763885). 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 not expected to disrupt LZTR1 protein function. 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. |
| Baylor Genetics | RCV003471364 | SCV004193660 | uncertain significance | Schwannomatosis 2 | 2024-03-28 | criteria provided, single submitter | clinical testing |