Total submissions: 13
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000760481 | SCV000890370 | pathogenic | not provided | 2022-03-03 | 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; This variant is associated with the following publications: (PMID: 30006736, 29489754, 25335493, 30859559, 29469822) |
Ce |
RCV000760481 | SCV001249400 | pathogenic | not provided | 2024-02-01 | criteria provided, single submitter | clinical testing | LZTR1: PVS1, PM2:Supporting, PS4:Supporting |
Baylor Genetics | RCV001330297 | SCV001521938 | pathogenic | Noonan syndrome 10 | 2019-07-12 | criteria provided, single submitter | clinical testing | This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. |
Revvity Omics, |
RCV000760481 | SCV002017209 | pathogenic | not provided | 2021-03-29 | criteria provided, single submitter | clinical testing | |
Labcorp Genetics |
RCV000760481 | SCV002187412 | pathogenic | not provided | 2024-01-19 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Arg210*) 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 (rs150419186, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with autosomal dominant schwannomatosis or autosomal recessive Noonan syndrome (PMID: 25335493, 29469822, 30859559). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 599030). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. |
MGZ Medical Genetics Center | RCV002290002 | SCV002581852 | pathogenic | LZTR1-related schwannomatosis | 2022-08-29 | criteria provided, single submitter | clinical testing | |
Ambry Genetics | RCV002360863 | SCV002656646 | pathogenic | Hereditary cancer-predisposing syndrome; Cardiovascular phenotype | 2023-03-22 | criteria provided, single submitter | clinical testing | The p.R210* pathogenic mutation (also known as c.628C>T), located in coding exon 7 of the LZTR1 gene, results from a C to T substitution at nucleotide position 628. This changes the amino acid from an arginine to a stop codon within coding exon 7. This alteration has been reported in several individuals with schwannomatosis as well as in patients with features of autosomal recessive Noonan syndrome (Paganini I et al. Eur. J. Hum. Genet. 2015 Jul;23:963-8; Gröbner SN et al. Nature 2018 03;555:321-327; Johnston JJ et al. Genet. Med. 2018 10;20:1175-1185; Kehrer-Sawatzki H et al. Hum. Genet. 2018 Jul;137:543-552; Pagnamenta AT et al. Clin. Genet. 2019 Jun;95:693-703). In addition to the clinical data 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. |
Genetics and Molecular Pathology, |
RCV002290002 | SCV004175296 | pathogenic | LZTR1-related schwannomatosis | 2020-03-20 | criteria provided, single submitter | clinical testing | |
Baylor Genetics | RCV002290002 | SCV004191278 | pathogenic | LZTR1-related schwannomatosis | 2024-03-24 | criteria provided, single submitter | clinical testing | |
Center for Genomic Medicine, |
RCV002290002 | SCV004807048 | pathogenic | LZTR1-related schwannomatosis | 2024-03-26 | criteria provided, single submitter | clinical testing | |
Juno Genomics, |
RCV002290002 | SCV005416908 | pathogenic | LZTR1-related schwannomatosis | criteria provided, single submitter | clinical testing | PM2_Supporting+PVS1+PM6_Supporting+PM3 | |
OMIM | RCV000735431 | SCV000863566 | pathogenic | Noonan syndrome 2 | 2018-12-17 | no assertion criteria provided | literature only | |
Prevention |
RCV004535887 | SCV004120641 | pathogenic | LZTR1-related disorder | 2023-12-19 | no assertion criteria provided | clinical testing | The LZTR1 c.628C>T variant is predicted to result in premature protein termination (p.Arg210*). This variant has been reported in a patient with schwannomatosis and was listed as de novo (Paganini et al. 2015. PubMed ID: 25335493). It has also been reported in trans with another LZTR1 variant in unrelated patients with Noonan syndrome (Johnston et al. 2018. PubMed ID: 29469822; Pagnamenta et al. 2019. PubMed ID: 30859559). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/22-21343948-C-T) and has been interpreted as pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/599030/). Nonsense variants in LZTR1 are expected to be pathogenic for autosomal recessive Noonan syndrome and autosomal dominant susceptibility to schwannomatosis. This variant is interpreted as pathogenic for autosomal recessive Noonan syndrome and autosomal dominant susceptibility to schwannomatosis. However, in the context of autosomal dominant Noonan syndrome it is of uncertain clinical significance. |