Submissions for variant NM_006767.4(LZTR1):c.1175C>T (p.Ala392Val)

gnomAD frequency: 0.00002  dbSNP: rs767354230

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001235475	SCV001408162	uncertain significance	not provided	2023-12-07	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 392 of the LZTR1 protein (p.Ala392Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of schwannomatosis (PMID: 25480913, 35638454). ClinVar contains an entry for this variant (Variation ID: 961729). 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.
GeneDx	RCV001235475	SCV001988708	uncertain significance	not provided	2023-11-29	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; No data available from control populations to assess the frequency of this variant; This variant is associated with the following publications: (PMID: 25480913, 35638454)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001779139	SCV002015161	uncertain significance	not specified	2021-10-03	criteria provided, single submitter	clinical testing	Variant summary: LZTR1 c.1175C>T (p.Ala392Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 234192 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1175C>T has been reported in the literature in at-least one individual affected with Schwannomatosis (example, Smith_2015) and has been subsequently cited by others (example, Umeki_2019, Motta_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Noonan Syndrome. To our knowledge, no 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 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV002327567	SCV002629221	uncertain significance	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2023-09-08	criteria provided, single submitter	clinical testing	The p.A392V variant (also known as c.1175C>T), located in coding exon 11 of the LZTR1 gene, results from a C to T substitution at nucleotide position 1175. The alanine at codon 392 is replaced by valine, an amino acid with similar properties. This alteration has been reported in an individual with a personal history of 5 peripheral nerve schwannomas at age 20 (Smith MJ et al. Neurology, 2015 Jan;84:141-7). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Baylor Genetics	RCV003469431	SCV004193657	uncertain significance	Schwannomatosis 2	2024-03-11	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV001235475	SCV005198698	uncertain significance	not provided	2023-07-11	criteria provided, single submitter	clinical testing