ClinVar Miner

Submissions for variant NM_006767.4(LZTR1):c.1385T>C (p.Ile462Thr)

gnomAD frequency: 0.00003  dbSNP: rs147684991
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Clinical and Biomedical Sciences, University of Exeter RCV000754925 SCV000787760 uncertain significance Noonan syndrome 2 2018-07-02 criteria provided, single submitter research
Labcorp Genetics (formerly Invitae), Labcorp RCV001237988 SCV001410782 uncertain significance not provided 2025-02-02 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 462 of the LZTR1 protein (p.Ile462Thr). This variant is present in population databases (rs147684991, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of autosomal recessive Noonan syndrome (PMID: 30859559). ClinVar contains an entry for this variant (Variation ID: 549756). 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.
GeneDx RCV001237988 SCV002762206 uncertain significance not provided 2022-12-06 criteria provided, single submitter clinical testing Variant observed in a compound heterozygous state in an individual with suspected Noonan syndrome in the published literature (Pagnamenta 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30859559)
Ambry Genetics RCV003163053 SCV003869189 uncertain significance Hereditary cancer-predisposing syndrome; Cardiovascular phenotype 2023-01-12 criteria provided, single submitter clinical testing The p.I462T variant (also known as c.1385T>C), located in coding exon 13 of the LZTR1 gene, results from a T to C substitution at nucleotide position 1385. The isoleucine at codon 462 is replaced by threonine, an amino acid with similar properties. This alteration was detected in a 28-year-old patient with features of Noonan syndrome who was also found to carry another LZTR1 variant in trans (Pagnamenta AT et al. Clin Genet, 2019 Jun;95:693-703). 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.

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