Submissions for variant NM_006767.4(LZTR1):c.1084C>T (p.Arg362Ter)

gnomAD frequency: 0.00007  dbSNP: rs189150283

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000329167	SCV000344439	pathogenic	not provided	2016-08-03	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763074	SCV000893584	pathogenic	Schwannomatosis 2; Noonan syndrome 10	2018-10-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193024	SCV001361558	likely pathogenic	Schwannomatosis	2019-11-25	criteria provided, single submitter	clinical testing	Variant summary: LZTR1 c.1084C>T (p.Arg362X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Germline loss of function mutations in LZTR1 have been reported to predispose to an inherited disorder of multiple schwannomas (Piotrowski_2014). The variant allele was found at a frequency of 6e-05 in 251042 control chromosomes (gnomAD). As a gene with a pLI score of 0 (gnomAD) this gene is expected to be tolerant to loss of function variants. Therefore, this frequency does not allow any conclusions about variant significance in relation to Schwannomatosis. The variant, c.1084C>T, has been reported in the literature in individuals affected with Schwannomatosis (Jordan_2018, Louvrier_2018) as well as one individual in the 1000 Genome cohort without phenotypic information (Piotrowski_2014) and in a sequencing study of healthy participants (Hou_2018). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae	RCV000329167	SCV001406539	pathogenic	not provided	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg362*) in the LZTR1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LZTR1 are known to be pathogenic (PMID: 24362817, 25335493, 25480913, 25795793, 29469822, 30368668, 30442762, 30442766, 30481304, 30859559). This variant is present in population databases (rs189150283, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with schwannomatosis and autosomal recessive Noonan syndrome (PMID: 29384852, 31182298). 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: 289969). For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001706423	SCV001934511	pathogenic	Noonan syndrome 2	2020-09-08	criteria provided, single submitter	clinical testing	This variant was identified as compound heterozygous with NM_006767.3:c.347C>G.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001799649	SCV002044431	likely pathogenic	Schwannomatosis 2	2021-11-23	criteria provided, single submitter	clinical testing	_x000D_ Criteria applied: PVS1, PS4_SUP
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813447	SCV002060661	likely pathogenic	Noonan syndrome and Noonan-related syndrome	2020-04-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000329167	SCV002102605	likely pathogenic	not provided	2023-07-07	criteria provided, single submitter	clinical testing	Occurred with another LZTR1 variant on the opposite allele (in trans) in a patient with features consistent with a RASopathy in published literature (Perin F et al., 2019); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31980526, 35840934, Santoro2021[abstract], 35251316, 29384852, 29409008, 31182298, 34308104)
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002252087	SCV002522823	pathogenic	See cases	2021-09-15	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1, PS4, PM2, PM3
Ambry Genetics	RCV002429235	SCV002727316	pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2023-01-31	criteria provided, single submitter	clinical testing	The p.R362* pathogenic mutation (also known as c.1084C>T), located in coding exon 10 of the LZTR1 gene, results from a C to T substitution at nucleotide position 1084. This changes the amino acid from an arginine to a stop codon within coding exon 10. This alteration has been reported in an individual with clinically diagnosed schwannomatosis as well as in a patient with autosomal recessive Noonan syndrome (Jordan JT et al. Medicine (Baltimore), 2018 Feb;97:e9717; Perin F et al. Rev Esp Cardiol (Engl Ed), 2019 Nov;72:978-980). 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 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.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV003387519	SCV004099262	pathogenic	Noonan syndrome 10	2023-07-05	criteria provided, single submitter	clinical testing	PVS1, PM2, PM3
Baylor Genetics	RCV001799649	SCV004193671	pathogenic	Schwannomatosis 2	2023-05-04	criteria provided, single submitter	clinical testing
Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg	RCV000736158	SCV000864455	pathogenic	Short stature	2001-11-18	no assertion criteria provided	case-control
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV001799649	SCV004099432	pathogenic	Schwannomatosis 2	2023-10-30	no assertion criteria provided	clinical testing