Submissions for variant NM_006767.4(LZTR1):c.2089C>T (p.Arg697Trp)

gnomAD frequency: 0.00006  dbSNP: rs751516987

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001360462	SCV001556379	uncertain significance	not provided	2024-01-08	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 697 of the LZTR1 protein (p.Arg697Trp). This variant is present in population databases (rs751516987, gnomAD 0.02%). This missense change has been observed in individual(s) with schwannomatosis (PMID: 25335493). ClinVar contains an entry for this variant (Variation ID: 1052307). 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%. This variant disrupts the p.Arg697 amino acid residue in LZTR1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28191889, 29469822; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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	RCV001360462	SCV002013508	uncertain significance	not provided	2024-08-16	criteria provided, single submitter	clinical testing	Observed in a patient with multiple schwannomas (PMID: 25335493); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 25335493, 39062695, 29469822)
Ambry Genetics	RCV002420785	SCV002726575	uncertain significance	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2023-07-05	criteria provided, single submitter	clinical testing	The p.R697W variant (also known as c.2089C>T), located in coding exon 18 of the LZTR1 gene, results from a C to T substitution at nucleotide position 2089. The arginine at codon 697 is replaced by tryptophan, an amino acid with dissimilar properties. This variant has been reported in a 39 year old female diagnosed with with multiple vertebral schwannomas (Paganini I et al. Eur J Hum Genet. 2015 Jul;23:963-8). 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.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV003230282	SCV003928058	uncertain significance	Noonan syndrome 10	2023-03-15	criteria provided, single submitter	clinical testing	The LZTR1 c.2089C>T (p.Arg697Trp) missense change has a maximum frequency of 0.016% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a deleterious effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported as de novo in an individual with schwannomatosis (PMID: 25335493). 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.??
Baylor Genetics	RCV003469594	SCV004191224	uncertain significance	Schwannomatosis 2	2023-11-10	criteria provided, single submitter	clinical testing