Submissions for variant NM_006767.4(LZTR1):c.1018C>T (p.Arg340Ter)

gnomAD frequency: 0.00005  dbSNP: rs149850248

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000578630	SCV000680819	pathogenic	not provided	2024-10-21	criteria provided, single submitter	clinical testing	Observed in patients with schwannomatosis at GeneDx and in published literature, including at least once as an apparently de novo variant (PMID: 25335493, 30006736); 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: 25335493, 30006736, 38983105, 33413596, 35150601, 39258154)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000578630	SCV001390708	pathogenic	not provided	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg340*) 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 (rs149850248, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with schwannomatosis (PMID: 25335493). ClinVar contains an entry for this variant (Variation ID: 488877). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV001293930	SCV001482630	pathogenic	Noonan syndrome 10	2020-12-22	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported in a patient affected by schwannomatosis [PMID 25335493]
Department of Molecular Diagnostics, Institute of Oncology Ljubljana	RCV001310194	SCV001499794	pathogenic	Schwannomatosis 2	2020-04-02	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV001310194	SCV001934240	pathogenic	Schwannomatosis 2	2023-04-20	criteria provided, single submitter	clinical testing	_x000D_ Criteria applied: PVS1, PS4, PM2_SUP
Revvity Omics, Revvity	RCV000578630	SCV002022744	likely pathogenic	not provided	2021-08-20	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004767415	SCV002051209	pathogenic	Schwannomatosis	2024-08-26	criteria provided, single submitter	clinical testing	Variant summary: LZTR1 c.1018C>T (p.Arg340X) 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. The variant allele was found at a frequency of 6.8e-05 in 250398 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in LZTR1 causing Schwannomatosis, allowing no conclusion about variant significance. c.1018C>T has been reported in the literature in individuals affected with Schwannomatosis (e.g. Paganini_2015, Kehrer-Sawatzki_2017). 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. The following publications have been ascertained in the context of this evaluation (PMID: 24362817, 25795793, 27921248, 25335493, 30368668, 33413596, 30665374). ClinVar contains an entry for this variant (Variation ID: 488877). Germline loss of function mutations in LZTR1 have been reported to predispose to an inherited disorder of multiple schwannomas (Piotrowski_2014) and recessive Noonan syndrome (Johnston_2018). Based on the evidence outlined above, the variant was classified as pathogenic for the risk of multiple schwannomas and recessive Noonan syndrome.
MGZ Medical Genetics Center	RCV001310194	SCV002579979	pathogenic	Schwannomatosis 2	2022-05-10	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002358639	SCV002647703	pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2023-03-27	criteria provided, single submitter	clinical testing	The p.R340* pathogenic mutation (also known as c.1018C>T), located in coding exon 10 of the LZTR1 gene, results from a C to T substitution at nucleotide position 1018. This changes the amino acid from an arginine to a stop codon within coding exon 10. This alteration has been reported in more than one individual with a clinical dx of schwannomatosis (Paganini I et al. Eur J Hum Genet, 2015 Jul;23:963-8; Kehrer-Sawatzki H et al. Hum Genet, 2018 Jul;137:543-552). In addition to the information presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. 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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001310194	SCV002767215	pathogenic	Schwannomatosis 2	2020-10-19	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain-of-function is a known mechanism of disease for this gene (PMID 30481304). (N) 0108 - This gene is known to be associated with both recessive and dominant disease (OMIM). (N) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (exon 10 of 21). (P) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (18 heterozygotes, 0 homozygotes). (P) 0701 - Comparable variants have very strong previous evidence for pathogenicity. Multiple NMD-predicted variants have previously been reported pathogenic in clinical cases (ClinVar). (P) 0802 - Moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported in individuals with Schwannomatosis (ClinVar; PMID: 30368668, 25335493, 30006736). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
Illumina Laboratory Services, Illumina	RCV001310194	SCV004014741	pathogenic	Schwannomatosis 2	2023-03-21	criteria provided, single submitter	clinical testing	The LZTR1 c.1018C>T (p.Arg340Ter) nonsense variant results in a premature termination of the protein at amino acid position 340. Loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay is expected. This variant has been reported in a heterozygous state in a female with schwannomatosis, in whom the variant was assumed to have occurred de novo (PMID: 25335493). This variant is reported in the Genome Aggregation Database in six alleles at a frequency of 0.000209 in the East Asian population (version 3.1.2). This frequency is high but may be consistent with reduced penetrance. Based on the available evidence, the c.1018C>T (p.Arg340Ter) variant is classified as pathogenic with reduced penetrance for schwannomatosis.
CeGaT Center for Human Genetics Tuebingen	RCV000578630	SCV004033925	pathogenic	not provided	2024-01-01	criteria provided, single submitter	clinical testing	LZTR1: PVS1, PM6, PS4:Moderate, PM2:Supporting
Baylor Genetics	RCV001310194	SCV004191196	pathogenic	Schwannomatosis 2	2023-10-26	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000578630	SCV004562406	pathogenic	not provided	2023-08-10	criteria provided, single submitter	clinical testing	The LZTR1 c.1018C>T; p.Arg340Ter variant (rs149850248) is reported de novo in the literature in an individual affected with schwannomatosis (Paganini 2015). This variant is also reported in ClinVar (Variation ID: 488877). This variant is found in the general population with an allele frequency of 0.006% (18/281,776 alleles) in the Genome Aggregation Database. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Paganini I et al. Expanding the mutational spectrum of LZTR1 in schwannomatosis. Eur J Hum Genet. 2015 Jul;23(7):963-8. PMID: 25335493.
Mayo Clinic Laboratories, Mayo Clinic	RCV000578630	SCV005413397	pathogenic	not provided	2023-11-17	criteria provided, single submitter	clinical testing	PM6_supporting, PS4_moderate, PVS1