Submissions for variant NM_006767.4(LZTR1):c.1889G>A (p.Arg630Gln)

gnomAD frequency: 0.00001  dbSNP: rs781776791

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000681423	SCV000808886	uncertain significance	not provided	2018-07-26	criteria provided, single submitter	clinical testing	The R630Q variant in the LZTR1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The R630Q variant is observed in 1/18846 (0.0053%) alleles from individuals of East Asian background, and in 3/276560 total alleles, in large population cohorts (Lek et al., 2016). The R630Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret R630Q as a variant of uncertain significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001797782	SCV002041709	uncertain significance	not specified	2021-11-01	criteria provided, single submitter	clinical testing	Variant summary: LZTR1 c.1889G>A (p.Arg630Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250692 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1889G>A has been reported in the literature in one individual affected with metastatic glioblastoma (Franceschi_2016). This report does 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. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV002406526	SCV002723850	uncertain significance	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2021-04-13	criteria provided, single submitter	clinical testing	The p.R630Q variant (also known as c.1889G>A), located in coding exon 16 of the LZTR1 gene, results from a G to A substitution at nucleotide position 1889. The arginine at codon 630 is replaced by glutamine, an amino acid with highly similar properties. This variant was reported in a seventy year-old male patient with glioblastoma, who had whole-exome sequencing (Franceschi S et al. Neuro Oncol, 2016 Feb;18:298-300). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000681423	SCV003251832	uncertain significance	not provided	2023-12-30	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 630 of the LZTR1 protein (p.Arg630Gln). This variant is present in population databases (rs781776791, gnomAD 0.005%). This variant has not been reported in the literature in individuals affected with LZTR1-related conditions. ClinVar contains an entry for this variant (Variation ID: 561963). 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.
Revvity Omics, Revvity	RCV000681423	SCV003815339	uncertain significance	not provided	2023-07-28	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003420202	SCV004115216	uncertain significance	LZTR1-related condition	2022-09-28	criteria provided, single submitter	clinical testing	The LZTR1 c.1889G>A variant is predicted to result in the amino acid substitution p.Arg630Gln. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0050% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/22-21349262-G-A). In ClinVar, this variant has conflicting interpretations of pathogenicity, ranging from uncertain to likely pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/561963). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
CeGaT Center for Human Genetics Tuebingen	RCV000681423	SCV004152224	uncertain significance	not provided	2023-05-01	criteria provided, single submitter	clinical testing	LZTR1: PS2:Supporting
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001196404	SCV001367011	likely pathogenic	Schwannomatosis 2	2020-03-31	flagged submission	clinical testing	This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PM2,PM3,PP1,PP3.