Submissions for variant NM_006767.4(LZTR1):c.465C>G (p.Tyr155Ter)

gnomAD frequency: 0.00001  dbSNP: rs753295968

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV002037971	SCV002231331	pathogenic	not provided	2023-08-20	criteria provided, single submitter	clinical testing	This premature translational stop signal has been observed in individual(s) with developmental disorders (PMID: 28135719). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 1453718). This variant is present in population databases (no rsID available, gnomAD 0.006%). This sequence change creates a premature translational stop signal (p.Tyr155*) 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).
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002243491	SCV002512499	likely pathogenic	Noonan syndrome 2; Noonan syndrome 10	2021-04-07	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1, PM2
GeneDx	RCV002037971	SCV002576869	pathogenic	not provided	2022-09-26	criteria provided, single submitter	clinical testing	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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 33128510, 28135719, 31785789)
Ambry Genetics	RCV002331528	SCV002633772	pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2020-07-09	criteria provided, single submitter	clinical testing	The p.Y155* pathogenic mutation (also known as c.465C>G), located in coding exon 5 of the LZTR1 gene, results from a C to G substitution at nucleotide position 465. This changes the amino acid from a tyrosine to a stop codon within coding exon 5. This variant has been reported as de novo in a cohort of individuals with developmental disorders, however clinical details were not provided (McRae J et al. Nature, 2017 02;542:433-438). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Illumina Laboratory Services, Illumina	RCV003389264	SCV004101299	likely pathogenic	Schwannomatosis 2	2023-09-07	criteria provided, single submitter	clinical testing	The LZTR1 c.465C>G (p.Tyr155Ter) nonsense variant results in the loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. The p.Tyr155Ter variant was identified in one case from a cohort of individuals with non-small cell lung cancer and was shown to be absent from controls (PMID: 36113475). In addition, this variant was reported in an individual with Noonan syndrome; however, no additional details are provided on zygosity or presence of a second variant in this individual (PMID: 33128510). This variant is reported in the Genome Aggregation Database in three alleles at a frequency of 0.000012 in the total population (version 2.1.1). Based on the available evidence, the c.465C>G (p.Tyr155Ter) variant is classified as likely pathogenic with reduced penetrance for schwannomatosis.
Baylor Genetics	RCV003389264	SCV004193661	likely pathogenic	Schwannomatosis 2	2023-05-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003994364	SCV004812984	pathogenic	Noonan syndrome 2	2024-02-14	criteria provided, single submitter	clinical testing	Variant summary: LZTR1 c.465C>G (p.Tyr155X) 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, however the molecular mechanism of disease attributed to LZTR1 is gain-of-function. The variant allele was found at a frequency of 1.2e-05 in 251352 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.465C>G has been reported in the literature in at-least one individual affected with Noonan Syndrome (example, Bertola_2020) and as a de novo change in unspecified patient(s) with developmental delay (example, Kaplanis_2020, Zhou_2022). It has also been reported in unspecified individual with Non-small cell lung cancer (Wang_2022). These data do not allow any conclusion about variant significance. 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: 33128510, 33057194, 35982159, 36113475). ClinVar contains an entry for this variant (Variation ID: 1453718). Based on the evidence outlined above, the variant was classified as pathogenic for recessive Noonan syndrome (NS2).
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004017884	SCV004847494	likely pathogenic	Noonan syndrome	2024-04-18	criteria provided, single submitter	clinical testing	The p.Tyr155X variant in LZTR1 has been reported in at least 1 individual with a neurodevelopmental disorder, where is was reported as a de novo occurrence, and in 1 individual with Noonan syndrome, however no information about zygosity or presence of a second variant was provided (McRae 2017 PMID: 28135719, Bertola 2020 PMID: 33128510, Kaplanis 2020 PMID: 33057194, Zhou 2022 PMID: 35982159). It was also found in an individual with non-small cell lung cancer (Wang 2022 PMID: 36113475). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 1453718) and has been identified in 0.01% (5/44894) of East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org, v4.0.0). This nonsense variant leads to a premature termination codon at position 155, which is predicted to lead to a truncated or absent protein. Loss of function of variants in LZTR1 gene has been associated with autosomal dominant schwannomatosis in the heterozygous state and with autosomal recessive Noonan syndrome in the compound heterozygous or homozygous state. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Noonan syndrome (ACMG/AMP Criteria applied: PVS1, PM2_Supporting). Due to the frequency of this variant in gnomAD, the significance of this variant for autosomal dominant schwannomatosis is unclear (Deng 2022 PMID: 35391499; ACMG/AMP Criteria applied: PVS1).