Total submissions: 7
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| 3billion | RCV004728717 | SCV005328917 | likely benign | Noonan syndrome 2 | 2024-09-20 | criteria provided, single submitter | clinical testing | The homozygous variant was found in patients diagnosed with another variant in a different gene, with no symptoms related to the gene containing the homozygous variant. |
| Baylor Genetics | RCV003470846 | SCV004191223 | uncertain significance | LZTR1-related schwannomatosis | 2023-10-16 | criteria provided, single submitter | clinical testing | |
| St. |
RCV003154035 | SCV003843042 | uncertain significance | Noonan syndrome 10 | 2022-01-06 | criteria provided, single submitter | clinical testing | The LZTR1 c.946G>A (p.Val316Met) missense change has a maximum frequency of 0.015% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. To our knowledge, this variant has not been reported in individuals with Noonan syndrome or Schwannomatosis. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. |
| Labcorp Genetics |
RCV001806178 | SCV003028451 | uncertain significance | not provided | 2026-01-04 | criteria provided, single submitter | clinical testing | This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 316 of the LZTR1 protein (p.Val316Met). This variant is present in population databases (rs370315661, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of autosomal dominant Noonan syndrome (PMID: 39140257). ClinVar contains an entry for this variant (Variation ID: 1098836). 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 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 | RCV002449141 | SCV002683226 | uncertain significance | Hereditary cancer-predisposing syndrome; Cardiovascular phenotype | 2025-04-28 | criteria provided, single submitter | clinical testing | The p.V316M variant (also known as c.946G>A), located in coding exon 9 of the LZTR1 gene, results from a G to A substitution at nucleotide position 946. The valine at codon 316 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. |
| Gene |
RCV001806178 | SCV002050355 | uncertain significance | not provided | 2025-11-13 | criteria provided, single submitter | clinical testing | Reported in a patient in published literature from a cohort of individuals with multiple cafe-au-lait macules; however, detailed clinical information was not provided on the patient (PMID: 39140257); In silico analysis suggests that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 39140257) |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001420965 | SCV001623444 | uncertain significance | not specified | 2021-05-17 | criteria provided, single submitter | clinical testing | Variant summary: LZTR1 c.946G>A (p.Val316Met) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5e-05 in 158726 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.946G>A in individuals affected with Noonan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. |