Submissions for variant NM_006767.4(LZTR1):c.320+2T>G

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002322977	SCV002609179	likely pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2022-01-18	criteria provided, single submitter	clinical testing	The c.320+2T>G intronic variant results from a T to G substitution two nucleotides after coding exon 3 in the LZTR1 gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; however, direct evidence is insufficient at this time (Ambry internal data). The exact functional effect of the altered amino acid sequence is unknown, but the impacted region is critical for protein function (Ambry internal data).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. Based on the supporting evidence, this variant is likely pathogenic for an increased risk of nerve sheath tumors 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	RCV003099288	SCV003489396	likely pathogenic	not provided	2024-12-09	criteria provided, single submitter	clinical testing	This sequence change affects a donor 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). Disruption of this splice site has been observed in individual(s) with schwannomatosis (PMID: 28365909). ClinVar contains an entry for this variant (Variation ID: 1728809). 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.