Submissions for variant NM_006767.4(LZTR1):c.321-2del

dbSNP: rs2518612397

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002324612	SCV002610721	pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2024-12-09	criteria provided, single submitter	clinical testing	The c.321-2delA intronic pathogenic mutation, located in intron 3 of the LZTR1 gene, results from a deletion of one nucleotide within intron 3 of the LZTR1 gene. This mutation has been detected in multiple individuals with schwannomatosis (Hutter S et al. Acta Neuropathol, 2014 Sep;128:449-52; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 exon skipping, leading to out-of-frame transcript (Hutter S et al. Acta Neuropathol, 2014 Sep;128:449-52; 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	RCV003660925	SCV004373679	likely pathogenic	not provided	2023-05-26	criteria provided, single submitter	clinical testing	This sequence change affects a splice site in intron 3 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). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 1728959). This variant has not been reported in the literature in individuals affected with LZTR1-related conditions.
GeneDx	RCV003660925	SCV005331610	pathogenic	not provided	2024-03-06	criteria provided, single submitter	clinical testing	Canonical splice site variant demonstrated to result in aberrant splicing resulting in a null allele in a gene for which loss of function is a known mechanism of disease (PMID: 25008767); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25008767)