ClinVar Miner

Submissions for variant NM_006767.4(LZTR1):c.1149+1G>T

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV002994987 SCV003293447 pathogenic not provided 2024-01-30 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 10 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 (rs767191322, gnomAD 0.0009%). Disruption of this splice site has been observed in individual(s) with Noonan syndrome (PMID: 31182298, 33407364). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2078744). 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.
Ambry Genetics RCV003170797 SCV003911669 pathogenic Hereditary cancer-predisposing syndrome; Cardiovascular phenotype 2023-09-05 criteria provided, single submitter clinical testing The c.1149+1G>T pathogenic mutation results from a G to T substitution one nucleotide after coding exon 10 of the LZTR1 gene. This alteration has been detected in the compound heterozygous state with pathogenic and likely pathogenic LZTR1 alterations in several individuals with Noonan syndrome phenotypes and familial transmission consistent with autosomal recessive Noonan Syndrome (Pagnamenta AT et al. Clin Genet, 2019 06;95:693-703; Perin F et al. Rev Esp Cardiol (Engl Ed), 2019 Nov;72:978-980). This variant has also been detected in a family with apparent autosomal dominant Noonan syndrome inheritance (Zhao X et al. BMC Endocr Disord, 2021 Jan;21:2). In addition to the clinical data in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and may result in the creation or strengthening of a novel splice donor site, and RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Another alteration impacting the same nucleotide position (c.1149+1G>A) has been detected in trans with a pathogenic LZTR1 frameshift alteration in a patient with Noonan syndrome (Johnston JJ et al. Genet Med, 2018 10;20:1175-1185). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is pathogenic for an increased risk of nerve sheath tumors 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, its clinical significance for autosomal dominant Noonan syndrome is unclear.
Baylor Genetics RCV003464647 SCV004191835 pathogenic Schwannomatosis 2 2022-06-20 criteria provided, single submitter clinical testing

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