Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| MGZ Medical Genetics Center | RCV002288407 | SCV002580730 | likely pathogenic | LZTR1-related schwannomatosis | 2022-01-21 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV003097766 | SCV002947959 | pathogenic | not provided | 2022-09-17 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Ser327Glnfs*7) 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 not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with LZTR1-related conditions. For these reasons, this variant has been classified as Pathogenic. |
| Ambry Genetics | RCV003164433 | SCV003911680 | pathogenic | Hereditary cancer-predisposing syndrome; Cardiovascular phenotype | 2022-11-15 | criteria provided, single submitter | clinical testing | The c.978_985delCAGCTCCG variant, located in coding exon 9 of the LZTR1 gene, results from a deletion of 8 nucleotides at nucleotide positions 978 to 985, causing a translational frameshift with a predicted alternate stop codon (p.S327Qfs*7). Cohort studies of patients with schwannomatosis have identified this variant in affected individuals (Farschtschi SC et al. Int J Mol Sci, 2020 May;21; Godel T et al. Diagnostics (Basel), 2022 Mar;12:). This mutation was also identified in one individual from a cohort of healthy volunteers; this individual lacked LZTR1-associated disease on deep phenotype analysis (Hou YC et al. Proc Natl Acad Sci U S A, 2020 02;117:3053-3062). 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. |
| Institute of Immunology and Genetics Kaiserslautern | RCV002288407 | SCV004803200 | pathogenic | LZTR1-related schwannomatosis | 2024-03-09 | criteria provided, single submitter | clinical testing | ACMG Criteria: PVS1, PM2, PP5; Variant was found in heterozygous state |