Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV002442561 | SCV002737921 | uncertain significance | Hereditary cancer-predisposing syndrome; Cardiovascular phenotype | 2023-05-18 | criteria provided, single submitter | clinical testing | The p.R755Q variant (also known as c.2264G>A), located in coding exon 19 of the LZTR1 gene, results from a G to A substitution at nucleotide position 2264. The arginine at codon 755 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in an individual with concerns for Noonan syndrome, which was found in trans with an additional alteration in LZTR1 (Johnston JJ et al. Genet Med, 2018 10;20:1175-1185). 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 |
RCV002535430 | SCV003462418 | uncertain significance | not provided | 2025-01-23 | 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 755 of the LZTR1 protein (p.Arg755Gln). This variant is present in population databases (rs762834512, gnomAD 0.0009%). This missense change has been observed in individual(s) with autosomal recessive Noonan syndrome (PMID: 29469822). ClinVar contains an entry for this variant (Variation ID: 599032). 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. |
| Gene |
RCV002535430 | SCV005080467 | uncertain significance | not provided | 2023-09-25 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 29469822) |
| OMIM | RCV000735433 | SCV000863568 | pathogenic | Noonan syndrome 2 | 2018-12-17 | no assertion criteria provided | literature only |