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

dbSNP: rs774954465

Total submissions: 3

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.
Labcorp Genetics (formerly Invitae), Labcorp	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.