Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000481440 | SCV000573694 | likely pathogenic | not provided | 2023-03-23 | criteria provided, single submitter | clinical testing | Reported in supplemental data with limited evidence regarding pathogenicity (Piotrowski et al., 2014; de Voer et al., 2016); 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: 26901136, 24362817, 31883238, Hakim2022[article]) |
| Department of Pediatrics, |
RCV001507320 | SCV001712281 | likely pathogenic | Noonan syndrome 2 | 2021-05-27 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV000481440 | SCV002139637 | uncertain significance | not provided | 2024-01-29 | 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 796 of the LZTR1 protein (p.Ile796Thr). This variant is present in population databases (rs141672122, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with LZTR1-related conditions. ClinVar contains an entry for this variant (Variation ID: 423930). 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 with a negative 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. |
| Ambry Genetics | RCV002455940 | SCV002737303 | likely pathogenic | Hereditary cancer-predisposing syndrome; Cardiovascular phenotype | 2023-05-09 | criteria provided, single submitter | clinical testing | The p.I796T variant (also known as c.2387T>C), located in coding exon 20 of the LZTR1 gene, results from a T to C substitution at nucleotide position 2387. The isoleucine at codon 796 is replaced by threonine, an amino acid with similar properties. This variant has been identified with another LZTR1 pathogenic mutation in siblings with cardiac features of Noonan syndrome (Nakagama Y et al. Mol Genet Genomic Med, 2020 03;8:e1107), as well as additional individuals with a phenotype consistent with Noonan syndrome who were tested at another laboratory (personal communication). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is likely pathogenic for autosomal recessive Noonan syndrome when present along with a second pathogenic variant on the other allele. This variant is also likely to cause an increased risk of LZTR1-related schwannomatosis (SWN); however, direct evidence is unavailable. The association of this alteration with autosomal dominant Noonan syndrome is unlikely. |
| Baylor Genetics | RCV003470588 | SCV004191253 | uncertain significance | Schwannomatosis 2 | 2024-03-17 | criteria provided, single submitter | clinical testing |