Submissions for variant NM_006767.4(LZTR1):c.1616-1G>C

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002400972	SCV002707980	likely pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2023-11-15	criteria provided, single submitter	clinical testing	The c.1616-1G>C intronic variant results from a G to C substitution one nucleotide upstream from coding exon 15 of the LZTR1 gene. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site; however, direct evidence is insufficient at this time (Ambry internal data). This nucleotide position is highly conserved in available vertebrate species. 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 unknown.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003738247	SCV004553279	likely pathogenic	not provided	2024-12-09	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 14 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 (rs777908919, gnomAD 0.002%). Disruption of this splice site has been observed in individual(s) with clinical features of Noonan syndrome (internal data). ClinVar contains an entry for this variant (Variation ID: 1776484). 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.