Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001056588 | SCV001221038 | uncertain significance | not provided | 2024-01-22 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 237 of the LZTR1 protein (p.Arg237Gln). This variant is present in population databases (rs773696598, gnomAD 0.02%). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 25049390). ClinVar contains an entry for this variant (Variation ID: 852048). 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. |
| St. |
RCV002291714 | SCV002584780 | uncertain significance | Noonan syndrome 10 | 2022-08-02 | criteria provided, single submitter | clinical testing | The LZTR1 c.710G>A (p.Arg237Gln) missense change has a maximum subpopulation frequency of 0.017% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in an individual with Noonan syndrome (PMID: 25049390). 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. |
| Ambry Genetics | RCV002365716 | SCV002662641 | uncertain significance | Hereditary cancer-predisposing syndrome; Cardiovascular phenotype | 2022-10-28 | criteria provided, single submitter | clinical testing | The p.R237Q variant (also known as c.710G>A), located in coding exon 8 of the LZTR1 gene, results from a G to A substitution at nucleotide position 710. The arginine at codon 237 is replaced by glutamine, an amino acid with highly similar properties. This alteration was identified in a cohort of 27 individuals with a clinical diagnosis of Noonan syndrome (Chen PC et al. Proc. Natl. Acad. Sci. U.S.A., 2014 Aug;111:11473-8). This alteration was also detected in a cohort of 73 Polish limb-girdle muscular dystrophy patients (Fichna JP et al. Hum Genomics, 2018 07;12:34). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Gene |
RCV001056588 | SCV003936526 | uncertain significance | not provided | 2024-05-24 | criteria provided, single submitter | clinical testing | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with features of Noonan syndrome (PMID: 25049390); This variant is associated with the following publications: (PMID: 29970176, 25049390) |
| Baylor Genetics | RCV004570218 | SCV005060608 | uncertain significance | Schwannomatosis 2 | 2024-03-13 | criteria provided, single submitter | clinical testing |