ClinVar Miner

Submissions for variant NM_006767.4(LZTR1):c.401-2_401-1del

gnomAD frequency: 0.00001  dbSNP: rs769200796
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Centre for Mendelian Genomics, University Medical Centre Ljubljana RCV001196403 SCV001367010 pathogenic Schwannomatosis 2 2020-03-31 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP1.
Invitae RCV001377465 SCV001574802 likely pathogenic not provided 2023-12-12 criteria provided, single submitter clinical testing This sequence change affects a splice site in intron 4 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, 30368668, 30442762, 30442766, 30481304, 30859559). This variant is present in population databases (rs769200796, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with LZTR1-related conditions. ClinVar contains an entry for this variant (Variation ID: 930614). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
Ambry Genetics RCV002356868 SCV002622196 likely pathogenic Hereditary cancer-predisposing syndrome; Cardiovascular phenotype 2023-04-20 criteria provided, single submitter clinical testing The c.401-2_401-1delAG intronic variant results from a deletion of AG nucleotides between positions c.401-2 and c.401-1 and involves the canonical splice acceptor site before coding exon 5 of the LZTR1 gene. These nucleotide positions are highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor 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, and RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). 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.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden RCV001377465 SCV004026078 likely pathogenic not provided 2021-06-08 criteria provided, single submitter clinical testing PVS1
PreventionGenetics, part of Exact Sciences RCV004528408 SCV004110188 likely pathogenic LZTR1-related disorder 2023-03-24 criteria provided, single submitter clinical testing The LZTR1 c.401-2_401-1delAG variant is predicted to result in a deletion affecting a canonical splice site. To our knowledge, this variant has not been reported in any affected individuals. This variant is reported in 0.0055% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/22-21342296-CAG-C). This variant is predicted to abolish a canonical splice donor site. Canonical splice altering variants in LZTR1 are expected to be pathogenic for autosomal dominant susceptibility to schwannomatosis. This variant is interpreted as likely pathogenic for susceptibility to autosomal dominant schwannomatosis. In relation to autosomal dominant and recessive Noonan syndrome, this is a variant of uncertain significance, and based on variant type, it is not predicted to cause autosomal dominant Noonan.

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