ClinVar Miner

Submissions for variant NM_006767.4(LZTR1):c.320+1G>C

dbSNP: rs943939913
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Centogene AG - the Rare Disease Company RCV001809170 SCV002059612 likely pathogenic Noonan syndrome 10 2019-09-10 criteria provided, single submitter clinical testing
Ambry Genetics RCV002324209 SCV002610836 likely pathogenic Hereditary cancer-predisposing syndrome; Cardiovascular phenotype 2021-11-12 criteria provided, single submitter clinical testing The c.320+1G>C intronic variant results from a G to C substitution one nucleotide after coding exon 3 of 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 unavailable. The exact functional effect of the altered amino acid sequence is unknown; however, 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.
Invitae RCV003738099 SCV004561518 likely pathogenic not provided 2022-11-06 criteria provided, single submitter clinical testing 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: 1333955). This variant has not been reported in the literature in individuals affected with LZTR1-related conditions. This variant is not present in population databases (gnomAD no frequency). 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).
Baylor Genetics RCV004571109 SCV005060593 likely pathogenic Schwannomatosis 2 2024-03-27 criteria provided, single submitter clinical testing

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