Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Labcorp Genetics |
RCV002785496 | SCV003028196 | likely pathogenic | not provided | 2022-07-17 | criteria provided, single submitter | clinical testing | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant has not been reported in the literature in individuals affected with LZTR1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 1 of the LZTR1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in LZTR1 are known to be pathogenic (PMID: 24362817, 25335493, 25480913, 25795793, 29469822, 30442762, 30442766, 30481304, 30859559). |
Baylor Genetics | RCV003475419 | SCV004193683 | likely pathogenic | LZTR1-related schwannomatosis | 2023-02-27 | criteria provided, single submitter | clinical testing | |
Neuberg Centre For Genomic Medicine, |
RCV004786744 | SCV005400775 | likely pathogenic | Noonan syndrome 10 | 2023-06-22 | criteria provided, single submitter | clinical testing | The observed splice donor c.200+1G>C variant in LZTR1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is absent in gnomAD Exomes. This variant has been reported to the ClinVar database as Likely Pathogenic. The variant affects the GT donor splice site downstream of exon 1. This variant is predicted to cause loss of normal protein function through protein truncation. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function, and loss-of-function variants in LZTR1 are known to be pathogenic (Pagnamenta et al., 2019). The spliceAI tool predicts that this splice site variant is damaging. For these reasons, this variant has been classified as Likely Pathogenic. |
Ambry Genetics | RCV004990860 | SCV005616226 | likely pathogenic | Hereditary cancer-predisposing syndrome; Cardiovascular phenotype | 2024-07-10 | criteria provided, single submitter | clinical testing | The c.200+1G>C intronic variant results from a G to C substitution one nucleotide after coding exon 1 of the LZTR1 gene. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to 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 likely 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. |