Submissions for variant NM_006767.4(LZTR1):c.2306C>T (p.Thr769Met)

gnomAD frequency: 0.00004  dbSNP: rs531211534

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001913154	SCV002169314	uncertain significance	not provided	2025-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 769 of the LZTR1 protein (p.Thr769Met). This variant is present in population databases (rs531211534, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of intellectual disability (PMID: 30564305). ClinVar contains an entry for this variant (Variation ID: 1401826). 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	RCV002449559	SCV002734887	uncertain significance	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2024-09-18	criteria provided, single submitter	clinical testing	The p.T769M variant (also known as c.2306C>T), located in coding exon 19 of the LZTR1 gene, results from a C to T substitution at nucleotide position 2306. The threonine at codon 769 is replaced by methionine, an amino acid with 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.
Revvity Omics, Revvity	RCV001913154	SCV003815324	uncertain significance	not provided	2021-04-22	criteria provided, single submitter	clinical testing
GeneDx	RCV001913154	SCV003919341	uncertain significance	not provided	2022-10-21	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been observed in individuals with LZTR1-related tumors to our knowledge, but has been reported in an individual with intellectual disability (Guo et al., 2018); This variant is associated with the following publications: (PMID: 30564305)
Baylor Genetics	RCV004571577	SCV005060619	uncertain significance	LZTR1-related schwannomatosis	2024-03-04	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV001913154	SCV005195313	uncertain significance	not provided		criteria provided, single submitter	not provided
Fulgent Genetics, Fulgent Genetics	RCV005038473	SCV005656773	uncertain significance	Noonan syndrome 2; LZTR1-related schwannomatosis; Noonan syndrome 10	2024-01-06	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV005055179	SCV005689112	uncertain significance	Noonan syndrome 10	2024-11-14	criteria provided, single submitter	clinical testing	The LZTR1 c.2306C>T (p.Thr769Met) missense change has a maximum subpopulation frequency of 0.02% 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.