Submissions for variant NM_006767.4(LZTR1):c.2428C>T (p.Arg810Trp)

gnomAD frequency: 0.00009  dbSNP: rs776893978

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001320703	SCV001511499	uncertain significance	not provided	2024-01-18	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 810 of the LZTR1 protein (p.Arg810Trp). This variant is present in population databases (rs776893978, gnomAD 0.01%). 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: 1021020). 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%. Experimental studies have shown that this missense change affects LZTR1 function (PMID: 23917401, 30442766). 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	RCV001320703	SCV001811419	likely pathogenic	not provided	2023-09-05	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: increased glioma sphere formation, increased MEK/ERK phosphorylation indicating MAPK pathway activation (Frattini et al., 2013; Bigenzahn et al., 2018); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 23917401, 30368668, 28191889, 36445254, 30442766)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002271641	SCV002556022	uncertain significance	not specified	2022-06-20	criteria provided, single submitter	clinical testing	Variant summary: LZTR1 c.2428C>T (p.Arg810Trp) 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 allele was found at a frequency of 4.4e-05 in 250298 control chromosomes. The observed variant frequency is approximately 9 fold of the estimated maximal expected allele frequency for a pathogenic variant in LZTR1 causing Noonan Syndrome phenotype (5e-06), strongly suggesting that the variant is benign. c.2428C>T has been reported in the literature in one individual affected with neurodevelopmental disorder (Stessman_2017). This report does not provide unequivocal conclusions about association of the variant with Noonan Syndrome. Experimental evidence showed that the steady state and half-life of the LZTR-1 R810W mutant protein were markedly increased and R810W abolished LZTR1 ability to impair glioma sphere formation (Frattini_2013). However, LZTR1-R810W still could restore sensitivity to imatinib treatment in knockout cells (Bigenzahn_2018). 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 conflicting evidence outlined above, the variant was classified as VUS.
Ambry Genetics	RCV002447356	SCV002732905	uncertain significance	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2023-01-26	criteria provided, single submitter	clinical testing	The p.R810W variant (also known as c.2428C>T), located in coding exon 21 of the LZTR1 gene, results from a C to T substitution at nucleotide position 2428. The arginine at codon 810 is replaced by tryptophan, an amino acid with dissimilar properties. In one functional assay, R810W failed to reduce MAPK pathway activation, despite being expressed at higher amount (Bigenzahn JW et al. Science, 2018 Dec;362:1171-1177). 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.
Genetics and Molecular Pathology, SA Pathology	RCV003447589	SCV004175348	uncertain significance	Schwannomatosis 2	2023-02-15	criteria provided, single submitter	clinical testing	The LZTR1 c.2428C>T variant is classified as a Variant of Uncertain Significance (PM1) The LZTR1 c.2428C>T variant is a single nucleotide change in exon 21/21 of the LZTR1 gene, which is predicted to change the amino acid arginine at position 810 in the protein to tryptophan. This variant is located in the second BTB-BACK domain (PMID:33792302, PMID:34113392) (PM1). The variant has been reported in dbSNP (rs776893978) and as of unknown significance in neurodevelopment disorder in the HGMD database (CM1726700). It has been reported as Conflicting interpretations of pathogenicity by other diagnostic laboratories (ClinVar Variation ID: 1021020). The variant has been reported as a somatic variant in glioblastoma (PMID:23917401) and is present in population databases (gnomAD 13/152202, 0 hom, 0.0085%).
Baylor Genetics	RCV003447589	SCV004191218	uncertain significance	Schwannomatosis 2	2024-03-24	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004545200	SCV004760357	uncertain significance	LZTR1-related disorder	2024-02-01	criteria provided, single submitter	clinical testing	The LZTR1 c.2428C>T variant is predicted to result in the amino acid substitution p.Arg810Trp. This variant has been reported in an individual with a neurodevelopmental disorder (Table S11, Stessman et al. 2017. PubMed ID: 28191889). This variant has also been reported as a somatic variant in glioblastoma and although functional studies suggest it may be impair LZTR1 function the significance in regard to Noonan syndrome is uncertain (Frattini et al. 2013. PubMed ID: 23917401; Ko et al. 2023. PubMed ID: 36445254). This variant is reported in 0.010% of alleles in individuals of East Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.