ClinVar Miner

Submissions for variant NM_006767.4(LZTR1):c.2070-2A>G

dbSNP: rs774954465
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001562920 SCV001785766 likely pathogenic not provided 2019-10-22 criteria provided, single submitter clinical testing Canonical splice site variant predicted to result in an in-frame deletion of a critical region; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 31182298)
Ambry Genetics RCV002421199 SCV002727701 likely pathogenic Hereditary cancer-predisposing syndrome; Cardiovascular phenotype 2022-09-07 criteria provided, single submitter clinical testing The c.2070-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 18 in the LZTR1 gene. This variant has been confirmed in trans with another LZTR1 variant in an individual diagnosed with Noonan syndrome (Perin F et al. Rev Esp Cardiol (Engl Ed), 2019 Nov;72:978-980). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. 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.
Invitae RCV001562920 SCV004559052 likely pathogenic not provided 2023-12-09 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 17 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 (rs774954465, gnomAD 0.003%). Disruption of this splice site has been observed in individual(s) with clinical features of Noonan syndrome (PMID: 31182298). ClinVar contains an entry for this variant (Variation ID: 1198685). 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.

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