ClinVar Miner

Submissions for variant NM_006767.4(LZTR1):c.651+1G>T

gnomAD frequency: 0.00001  dbSNP: rs1450044732
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001378878 SCV001576565 likely pathogenic not provided 2021-12-17 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: 1067576). This variant has not been reported in the literature in individuals affected with LZTR1-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change affects a donor splice site in intron 7 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, 30442762, 30442766, 30481304, 30859559).
GeneDx RCV001378878 SCV002072844 likely pathogenic not provided 2022-12-13 criteria provided, single submitter clinical testing Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Observed in an individual with congenital heart disease in published literature (Morton et al., 2021); Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 33084842)
Ambry Genetics RCV002368216 SCV002658810 likely pathogenic Hereditary cancer-predisposing syndrome; Cardiovascular phenotype 2022-12-19 criteria provided, single submitter clinical testing The c.651+1G>T intronic variant results from a G to T substitution one nucleotide after coding exon 7 of the LZTR1 gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and may result in the creation or strengthening of a novel splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). In addition, 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. 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.

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