Submissions for variant NM_006767.4(LZTR1):c.344C>T (p.Pro115Leu)

gnomAD frequency: 0.00002  dbSNP: rs756852884

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000414293	SCV000491539	uncertain significance	not provided	2023-12-20	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; Observed in a cohort of patients with schwannomatosis (PMID: 30442762); This variant is associated with the following publications: (PMID: 33792302, 34113392, 30442762)
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813469	SCV002060777	uncertain significance	Noonan syndrome and Noonan-related syndrome	2020-12-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001824756	SCV002074320	uncertain significance	not specified	2022-01-17	criteria provided, single submitter	clinical testing	Variant summary: LZTR1 c.344C>T (p.Pro115Leu) results in a non-conservative amino acid change located in the Kelch domains (Zhang_2021) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 250854 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.344C>T has been reported in the literature in at-least one individual affected with Schwannomatosis (example, Steklov_2018). These data do not allow any conclusion about variant significance. To our knowledge, no variant specific experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000414293	SCV002199663	uncertain significance	not provided	2023-08-23	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 372993). This missense change has been observed in individual(s) with schwannomatosis (PMID: 30442762). This variant is present in population databases (rs756852884, gnomAD 0.007%). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 115 of the LZTR1 protein (p.Pro115Leu).
Ambry Genetics	RCV002450954	SCV002616194	uncertain significance	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2023-07-07	criteria provided, single submitter	clinical testing	The p.P115L variant (also known as c.344C>T), located in coding exon 4 of the LZTR1 gene, results from a C to T substitution at nucleotide position 344. The proline at codon 115 is replaced by leucine, an amino acid with similar properties. This alteration was identified in one cohort of individuals with schwannomatosis (Steklov M et al. Science 2018 12;362(6419):1177-1182). 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.
Baylor Genetics	RCV003463820	SCV004191220	uncertain significance	Schwannomatosis 2	2024-02-02	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000414293	SCV005410196	uncertain significance	not provided	2024-09-04	criteria provided, single submitter	clinical testing