Submissions for variant NM_006767.4(LZTR1):c.2062C>T (p.Arg688Cys)

gnomAD frequency: 0.00006  dbSNP: rs587777178

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001055087	SCV001219453	uncertain significance	not provided	2022-10-09	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 688 of the LZTR1 protein (p.Arg688Cys). This variant is present in population databases (rs587777178, gnomAD 0.01%). This missense change has been observed in individual(s) with autosomal dominant schwannomatosis and/or autosomal recessive Noonan syndrome (PMID: 24362817, 25480913, 30859559). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 101036). 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. Experimental studies have shown that this missense change affects LZTR1 function (PMID: 30442762). This variant disrupts the p.Arg688 amino acid residue in LZTR1. Other variant(s) that disrupt this residue have been observed in individuals with LZTR1-related conditions (PMID: 29469822, 30859559), which suggests that this may be a clinically significant amino acid residue. 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.
Department of Molecular Diagnostics, Institute of Oncology Ljubljana	RCV000087294	SCV001499793	likely pathogenic	Schwannomatosis 2	2020-04-02	criteria provided, single submitter	clinical testing
GeneDx	RCV001055087	SCV001823060	uncertain significance	not provided	2023-10-11	criteria provided, single submitter	clinical testing	Reported as de novo in a patient with unexplained developmental delay (DD) or intellectual disability (ID), but this patient also harbored a de novo pathogenic variant in the TCF4 gene which could explain the phenotype (Hiraide et al., 2021); Published functional studies suggests this variant may have an affect on cellular localization of the LZTR1 protein (Steklov et al., 2018); 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: 35840934, 29469822, 33792302, 34913528, 25480913, 33407364, 30442762, 24362817, 33644862, 30859559)
Ambry Genetics	RCV002415585	SCV002724842	likely pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2022-03-24	criteria provided, single submitter	clinical testing	The p.R688C variant (also known as c.2062C>T), located in coding exon 17 of the LZTR1 gene, results from a C to T substitution at nucleotide position 2062. The arginine at codon 688 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been detected in conjunction with LZTR1 c.1149-1G>T (phase unknown) in a patient with a presumed Noonan syndrome diagnosis (Pagnamenta AT et al. Clin. Genet., 2019 Jun;95:693-703). This variant has also been reported in multiple individuals with schwannomatosis (Piotrowski A et al. Nat. Genet., 2014 Feb;46:182-7; Smith MJ et al. Neurology, 2015 Jan;84:141-7; Steklov M et al. Science, 2018 12;362:1177-1182). A functional study suggests that this alteration may impair complex formation with CUL3 and affect subcellular localization (Steklov M et al. Science, 2018 12;362:1177-1182). Based on data from gnomAD, the T allele has an overall frequency of 0.005% (14/279562) total alleles studied. The highest observed frequency was 0.01% (3/24262) of African/African American alleles. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the supporting evidence, this variant is likely pathogenic for an increased risk of schwannomas and would be expected to cause autosomal recessive Noonan syndrome when present along with a second pathogenic variant on the other allele.
PreventionGenetics, part of Exact Sciences	RCV003415871	SCV004115199	likely pathogenic	LZTR1-related condition	2023-02-03	criteria provided, single submitter	clinical testing	The LZTR1 c.2062C>T variant is predicted to result in the amino acid substitution p.Arg688Cys. This variant was reported individuals with autosomal dominant schwannomatosis (Piotrowski et al. 2014. PubMed ID: 24362817; Smith et al. 2015. PubMed ID: 25480913, Steklov et al. 2018. PubMed ID: 30442762) and in a patient with autosomal recessive Noonan syndrome (Patient 279914 in Pagnamenta et al. 2019. PubMed ID: 30859559). It was also reported to be de novo in a patient from a cohort of individuals with developmental delay/intellectual disability; however, this patient also had a de novo pathogenic variant in TCF4 (Hiraide et al. 2021. PubMed ID: 33644862). However, one of the cases reported in Piotrowski et al. found that the variant was inherited from an asymptomatic father (Piotrowski et al. 2014. PubMed ID: 24362817). Functional analysis showed that the variant lead to reduced CUL3 binding (Steklov et al. 2018. PubMed ID: 30442762). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/22-21350154-C-T). This variant has conflicting interpretations of pathogenicity in ClinVar ranging from likely pathogenic to uncertain (https://ncbi.nlm.nih.gov/clinvar/variation/). Of note, different variants at the same amino acid (p.Arg688Gly and p.Arg688His) have also been reported in a patient with autosomal recessive Noonan syndrome (Johnston et al. 2018. PubMed ID: 29469822) and in patients with schwannomatosis (Steklov et al. 2018. PubMed ID: 30442762). Based on this evidence, we interpret the c.2062C>T (p.Arg688Cys) variant as likely pathogenic.
Baylor Genetics	RCV000087294	SCV004193645	likely pathogenic	Schwannomatosis 2	2023-06-07	criteria provided, single submitter	clinical testing
OMIM	RCV000087294	SCV000120172	pathogenic	Schwannomatosis 2	2014-02-01	no assertion criteria provided	literature only