ClinVar Miner

Submissions for variant NM_006767.4(LZTR1):c.1260+1G>T

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV002430372 SCV002681954 likely pathogenic Hereditary cancer-predisposing syndrome; Cardiovascular phenotype 2022-07-01 criteria provided, single submitter clinical testing The c.1260+1G>T intronic variant results from a G to T substitution one nucleotide after coding exon 11 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; however, direct evidence is insufficient at this time (Ambry internal data). 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.
Clinical Genomics Laboratory, Washington University in St. Louis RCV005051967 SCV005685543 likely pathogenic Noonan syndrome 2 2024-06-07 criteria provided, single submitter clinical testing The LZTR1 c.1260+1G>T variant, to our knowledge, has not been reported in the medical literature. This variant has been reported in the ClinVar database as a likely pathogenic variant in by one submitter. This variant is only observed on 1 out of 220,214 alleles in the general population (gnomAD v.2.1.1), indicating it is not a common variant. This variant occurs within the canonical splice donor site, which is predicted to cause skipping of the exon, leading to an in-frame transcript. Additionally, computational predictors indicate that this variant would alter splicing through an additional donor gain, evidence that correlates to an impact of this variant LZTR1 function. Other variants in the same residue, c.1260+1G>A and c.1260+1G>C, have been submitted to ClinVar as likely pathogenic (Variation ID: 1305284; 2068131). Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as likely pathogenic.

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