Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ce |
RCV000762050 | SCV000892297 | uncertain significance | not provided | 2018-04-01 | criteria provided, single submitter | clinical testing | |
| Gene |
RCV000762050 | SCV001765862 | uncertain significance | not provided | 2023-08-14 | criteria provided, single submitter | clinical testing | Observed with another LZTR1 variant on the opposite allele (in trans) in individuals with Noonan syndrome features referred for genetic testing at GeneDx and in published literature (Jenkins et al., 2020; Gabriel et al., 2022); 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: 32575496, 32004086, 34958143, 29409008) |
| Labcorp Genetics |
RCV000762050 | SCV002204278 | pathogenic | not provided | 2024-01-15 | criteria provided, single submitter | clinical testing | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 465 of the LZTR1 protein (p.Ala465Val). This variant is present in population databases (rs753757778, gnomAD 0.004%). This missense change has been observed in individuals with autosomal dominant and autosomal recessive LZTR1-related conditions (PMID: 32004086, 32575496, 34958143; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 623976). 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%. This variant disrupts the p.Ala465 amino acid residue in LZTR1. Other variant(s) that disrupt this residue have been observed in individuals with LZTR1-related conditions (PMID: 25335493, 28365909), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. |
| Ambry Genetics | RCV002388385 | SCV002697112 | uncertain significance | Hereditary cancer-predisposing syndrome; Cardiovascular phenotype | 2023-06-07 | criteria provided, single submitter | clinical testing | The p.A465V variant (also known as c.1394C>T), located in coding exon 13 of the LZTR1 gene, results from a C to T substitution at nucleotide position 1394. The alanine at codon 465 is replaced by valine, an amino acid with similar properties. This variant has been reported in a patient with schwannomatosis (Louvrier C et al. Neuro Oncol, 2018 06;20:917-929) and in a patient with pediatric hypertrophic cardiomyopathy (Ware SM et al. Am J Hum Genet, 2022 Feb;109:282-298). This alteration has been reported in trans with another LZTR1 variant, p.D441N, in two siblings, who had phenotypes consistent with Noonan syndrome (Jenkins J et al. Circ Genom Precis Med, 2020 04;13:e002690). In a study of 250 patients referred for suspected Neurofibromatosis, this variant was observed with a PTPN11 pathogenic mutation, p.T468M , in a six year old male with diffuse freckling, pectum excavatum, scleral nevi (Bianchessi D et al. Genes (Basel), 2020 06;11:). 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. |
| Mayo Clinic Laboratories, |
RCV000762050 | SCV005410198 | uncertain significance | not provided | 2024-04-09 | criteria provided, single submitter | clinical testing | BP5 |