Submissions for variant NM_006767.4(LZTR1):c.594-2A>G

gnomAD frequency: 0.00001  dbSNP: rs1374011263

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001552275	SCV001772934	pathogenic	not provided	2020-11-03	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); Has not been previously published as pathogenic or benign to our knowledge
Baylor Genetics	RCV003463049	SCV004191200	likely pathogenic	LZTR1-related schwannomatosis	2023-10-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004995942	SCV005616169	pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2024-11-22	criteria provided, single submitter	clinical testing	The c.594-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 7 in 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 acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Another variant impacting the same acceptor site (c.594-3C>G) has been shown to have a similar impact on splicing in an individual with features consistent with LZTR1-related schwannomatosis (Piotrowski A et al. Nat Genet, 2014 Feb;46:182-7; 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 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	RCV001552275	SCV005717236	likely pathogenic	not provided	2024-05-14	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 6 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 not present in population databases (gnomAD no frequency). 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: 1191273). 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.