Submissions for variant NM_006767.4(LZTR1):c.1397G>A (p.Arg466Gln)

gnomAD frequency: 0.00006  dbSNP: rs587777180

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001260384	SCV001437345	likely pathogenic	Schwannomatosis	2020-09-16	criteria provided, single submitter	clinical testing	Variant summary: LZTR1 c.1397G>A (p.Arg466Gln) results in a conservative amino acid change located in the BTB/POZ domain (IPR000210) of 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 3.2e-05 in 247306 control chromosomes (gnomAD). c.1397G>A has been reported in the literature in at least three individuals affected with Schwannomatosis (Piotrowski_2014, Steklov_2018). These data indicate that the variant may be associated with disease. The variant has also been reported in compound heterozygosity with another missense variant in LZTR1 (c.2455G>C (p.Asp819His)) in a patient affected with Noonan Syndrome, where the patient's mother also carried the variant of interest, but was unaffected (Li_2019). This report does not provide unequivocal conclusions about association of the variant with Noonan Syndrome and Related Conditions (NSRD). Publications also reported experimental evidence, and demonstrated that the variant increased Ras signaling, and resulted in impaired subcellular location (Steklov_2018, Bigenzahn_2018). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic for the risk of multiple schwannomas, and as a variant of uncertain clinical significance for the NSRD phenotype.
Invitae	RCV001312780	SCV001503248	likely pathogenic	not provided	2024-01-21	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 466 of the LZTR1 protein (p.Arg466Gln). This variant is present in population databases (rs587777180, gnomAD 0.01%). This missense change has been observed in individuals with clinical features of schwannomatosis and Noonan syndrome (PMID: 24362817, 30442762, 31130284, 31219622; Invitae). ClinVar contains an entry for this variant (Variation ID: 101038). 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: 30442762). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813376	SCV002060484	likely pathogenic	Noonan syndrome and Noonan-related syndrome	2021-03-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002390252	SCV002701699	likely pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2023-03-08	criteria provided, single submitter	clinical testing	The p.R466Q variant (also known as c.1397G>A), located in coding exon 13 of the LZTR1 gene, results from a G to A substitution at nucleotide position 1397. The arginine at codon 466 is replaced by glutamine, an amino acid with highly similar properties. This variant 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). The alteration was also 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). One functional study suggested that this alteration may impair complex formation with CUL3 and cellular localization (Steklov M et al. Science, 2018 12;362:1177-1182). 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 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 variant on the other allele.
Revvity Omics, Revvity	RCV001312780	SCV003832301	likely pathogenic	not provided	2023-02-12	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000087296	SCV004193635	likely pathogenic	Schwannomatosis 2	2023-06-23	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001312780	SCV004564302	likely pathogenic	not provided	2022-12-29	criteria provided, single submitter	clinical testing	The LZTR1 c.1397G>A; p.Arg466Gln variant (rs587777180) is reported in the literature in multiple heterozygous individuals affected with schwannomatosis (Piotrowski 2014, Steklov 2018), as well as an individual with Noonan syndrome that carried a second missense variant in trans (Li 2019). The p.Arg466Gln variant is found in the general population with an overall allele frequency of 0.003% (8/247,306 alleles) in the Genome Aggregation Database. The arginine at codon 466 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.918). Consistent with predictions, functional studies suggest the variant protein has altered cellular localization, reduced interaction with the binding partner protein CUL3, and is associated with elevated levels of Ras signaling (Bigenzahn 2018, Steklov 2018). Based on available information, this variant is considered to be likely pathogenic in association with schwannoma susceptibility and autosomal recessive Noonan syndrome. References: Bigenzahn JW et al. LZTR1 is a regulator of RAS ubiquitination and signaling. Science. 2018 Dec 7;362(6419):1171-1177. PMID: 30442766. Li X et al. Molecular and phenotypic spectrum of Noonan syndrome in Chinese patients. Clin Genet. 2019 Oct;96(4):290-299. PMID: 31219622. Piotrowski A et al. Germline loss-of-function mutations in LZTR1 predispose to an inherited disorder of multiple schwannomas. Nat Genet. 2014 Feb;46(2):182-7. PMID: 24362817. Steklov M et al. Mutations in LZTR1 drive human disease by dysregulating RAS ubiquitination. Science. 2018 Dec 7;362(6419):1177-1182. PMID: 30442762.
OMIM	RCV000087296	SCV000120174	pathogenic	Schwannomatosis 2	2014-02-01	no assertion criteria provided	literature only