Submissions for variant NM_006767.4(LZTR1):c.594-3C>G

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV003184008	SCV003864354	likely pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2023-03-07	criteria provided, single submitter	clinical testing	The c.594-3C>G intronic variant results from a C to G substitution 3 nucleotides upstream from coding exon 7 in the LZTR1 gene. This variant has been reported in a patient with schwannomatosis (SWN) with loss of heterozygosity at the LZTR1 locus and a somatic NF2 mutation detected in a schwannoma (Piotrowski A et al. Nat Genet, 2014 Feb;46:182-7). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site, and RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data; Piotrowski A et al. Nat Genet, 2014 Feb;46:182-7). 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 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.
GeneDx	RCV004719316	SCV005325190	likely pathogenic	not provided	2023-08-18	criteria provided, single submitter	clinical testing	Non-canonical splice site variant demonstrated to result in loss of function (Piotrowski et al., 2014); Not observed at significant frequency in large population cohorts (gnomAD); Identified in a patient with schwannomas who inherited the variant from an unaffected parent in published literature (Piotrowski et al., 2014); This variant is associated with the following publications: (PMID: 35391499, 24362817)
Labcorp Genetics (formerly Invitae), Labcorp	RCV004719316	SCV005772521	uncertain significance	not provided	2024-02-12	criteria provided, single submitter	clinical testing	This sequence change falls in intron 6 of the LZTR1 gene. It does not directly change the encoded amino acid sequence of the LZTR1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with schwannomatosis (PMID: 24362817). ClinVar contains an entry for this variant (Variation ID: 2457675). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 7 and introduces a premature termination codon (PMID: 24362817). The resulting mRNA is expected to undergo nonsense-mediated decay. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.