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

gnomAD frequency: 0.00009  dbSNP: rs776893978

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001320703	SCV001511499	uncertain significance	not provided	2025-02-02	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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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	2024-07-02	criteria provided, single submitter	clinical testing	Identified in individuals with clinical features consistent with LZTR1-related disorder referred for genetic testing at GeneDx and in published literature (PMID: 28191889); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23917401, 30368668, 36445254, 30442766, 28191889, 33057194, 35982159)
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	likely pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2024-11-01	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. This variant has been observed in multiple individuals with features consistent with LZTR1-related schwannomatosis (external communication, Ambry internal data). This variant has also been identified in conjunction with other LZTR1 variant(s) in individuals with features consistent with Noonan syndrome; in at least one instance, the variants were identified in trans (external communication). 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. Loss-of-function variants in LZTR1 are related to an increased risk for schwannomas and autosomal recessive Noonan syndrome; however, such associations with autosomal dominant Noonan syndrome have not been observed (Piotrowski A et al. Nat Genet. 2014 Feb;46:182-7; Yamamoto GL et al. J Med Genet. 2015 Jun;52:413-21; Johnston JJ et al. Genet Med. 2018 10;20:1175-1185). Based on the supporting evidence, this variant is likely pathogenic for an increased risk of LZTR1-related schwannomatosis (SWN) and would be expected to cause autosomal recessive Noonan syndrome when present along with a second pathogenic or likely pathogenic variant on the other allele; however, the association of this alteration with autosomal dominant Noonan syndrome is unlikely.
Genetics and Molecular Pathology, SA Pathology	RCV003447589	SCV004175348	uncertain significance	LZTR1-related schwannomatosis	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	LZTR1-related schwannomatosis	2024-03-24	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV004815363	SCV005438802	likely pathogenic	Noonan syndrome 2		criteria provided, single submitter	clinical testing	The observed missense c.2428C>Tp.Arg810Trp variant in LZTR1 gene has been reported previously in homozygous or compound heterozygous state in individuals affected with Noonan syndrome Bigenzahn et al., 2018. This variant is reported with the allele frequency of 0.004% in the gnomAD Exomes. This variant has been reported to the ClinVar database as Uncertain Significance / Likely Pathogenic. The amino acid Arg at position 810 is changed to a Trp changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Arg810Trp in LZTR1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Multiple lines of computational evidence Polyphen - Possibly Damaging, SIFT - Damaging, and MutationTaster - Disease causing predict a damaging effect on protein structure and function for this variant. For these reasons, this variant has been classified as Likely Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV005023035	SCV005656776	uncertain significance	Noonan syndrome 2; LZTR1-related schwannomatosis; Noonan syndrome 10	2024-06-13	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004545200	SCV004760357	uncertain significance	LZTR1-related disorder	2024-02-01	no assertion criteria provided	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.