Submissions for variant NM_006767.4(LZTR1):c.1396C>T (p.Arg466Trp)

gnomAD frequency: 0.00006  dbSNP: rs550922200

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000355063	SCV000330246	uncertain significance	not provided	2022-07-01	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with schwannomatosis referred for genetic testing at GeneDx and in published literature (Jordan 2018, Steklov 2018); This variant is associated with the following publications: (PMID: 29384852, 30442762, 31475041, 28191889)
Invitae	RCV000355063	SCV001567380	pathogenic	not provided	2024-01-31	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 466 of the LZTR1 protein (p.Arg466Trp). This variant is present in population databases (rs550922200, gnomAD 0.01%). This missense change has been observed in individuals with clinical features of schwannomatosis (PMID: 29384852, 29409008, 30442762; Invitae). ClinVar contains an entry for this variant (Variation ID: 280342). 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.Arg466 amino acid residue in LZTR1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24362817, 30442762, 31130284, 31219622; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001797700	SCV002041711	uncertain significance	not specified	2024-02-19	criteria provided, single submitter	clinical testing	Variant summary: LZTR1 c.1396C>T (p.Arg466Trp) results in a non-conservative amino acid change located in the BTB/POZ domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.5e-05 in 247444 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in LZTR1 causing Noonan Syndrome 2 (6.5e-05 vs 0.0032), allowing no conclusion about variant significance. c.1396C>T has been reported in the literature in individuals affected with autism (Stessman_2017), schwannomatosis (Jordan_2018, Louvrier_2018, Steklov_2018), increased nuchal translucency (Choy_2019) and autosomal recessive Noonan Syndrome (in trans with a VUS change, Li_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Noonan Syndrome 2. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. In addition, p.Arg466Gln has been classified as likely pathogenic for Schwannomatosis by our laboratory. The following publications have been ascertained in the context of this evaluation (PMID: 31475041, 29384852, 29409008, 30442762, 28191889, 31219622).ClinVar contains an entry for this variant (Variation ID: 280342). Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV002392792	SCV002697673	pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2023-12-28	criteria provided, single submitter	clinical testing	The p.R466W variant (also known as c.1396C>T), located in coding exon 13 of the LZTR1 gene, results from a C to T substitution at nucleotide position 1396. The arginine at codon 466 is replaced by tryptophan, an amino acid with dissimilar properties. This variant has been reported in multiple individuals with schwannomatosis (Jordan JT et al. Medicine (Baltimore), 2018 Feb;97:e9717; Louvrier C et al. Neuro Oncol, 2018 06;20:917-929; Steklov M et al. Science, 2018 12;362:1177-1182; Ambry internal data). Another alteration at the same codon, p.R466Q (c.1397G>A), has been detected in multiple individuals with schwannomatosis (Piotrowski A et al. Nat Genet, 2014 Feb;46:182-7; Steklov M et al. Science, 2018 12;362:1177-1182; Ambry internal data) and identified in an individual with Noonan syndrome who had another LZTR1 alteration in trans (Li X et al. Clin Genet, 2019 10;96:290-299). Based on internal structural analysis, R466W is moderately destabilizing to the local structure (van Geersdaele LK et al. Acta Crystallogr D Biol Crystallogr, 2013 Sep;69:1677-84). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is 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 variant on the other allele.
Eurofins-Biomnis	RCV003236580	SCV003935035	likely pathogenic	Schwannomatosis 2	2022-12-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004535249	SCV004117999	likely pathogenic	LZTR1-related disorder	2023-08-02	criteria provided, single submitter	clinical testing	The LZTR1 c.1396C>T variant is predicted to result in the amino acid substitution p.Arg466Trp. This variant has been reported in patients with schwannomatosis (Jordan et al. 2018. PubMed ID: 29384852; Figure 3A, Steklov et al. 2018. PubMed ID: 30442762; Tabele S8, Louvrier et al. 2018. PubMed ID: 29409008). This variant has also been reported in the compound heterozygous state in an individual with Noonan syndrome (Li et al. 2019. PubMed ID: PMID: 31219622), in a fetus with increased nuchal translucency (Supplementary Table S3, Case 18C0096, Choy et al. 2019. PubMed ID: 31475041) and in an individual with autism (Table S11, Stessman et al. 2017. PubMed ID: 28191889). This variant is reported in 0.011% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/22-21348255-C-T) and is interpreted as likely pathogenic and uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/280342/). An alternate variant at this codon (p.Arg466Gln) has been reported in association with schwannomatosis (Steklov et al. 2018. PubMed ID: 30442762; Piotrowski et al. 2014. PubMed ID: 24362817). This variant is interpreted as likely pathogenic for schwannomatosis and autosomal recessive Noonan syndrome.
Baylor Genetics	RCV003236580	SCV004191214	uncertain significance	Schwannomatosis 2	2024-01-17	criteria provided, single submitter	clinical testing