ClinVar Miner

Submissions for variant NM_006767.4(LZTR1):c.1943-1G>A

gnomAD frequency: 0.00004  dbSNP: rs1189015572
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV002023238 SCV002303735 likely pathogenic not provided 2024-01-19 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 16 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 (no rsID available, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with LZTR1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1512851). 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.
Ambry Genetics RCV002407299 SCV002722780 likely pathogenic Hereditary cancer-predisposing syndrome; Cardiovascular phenotype 2023-05-17 criteria provided, single submitter clinical testing The c.1943-1G>A intronic variant results from a G to A substitution one nucleotide upstream from coding exon 17 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 acceptor site and will result in the creation or strengthening of a novel splice acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (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. 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 unlikely.
Fulgent Genetics, Fulgent Genetics RCV002507803 SCV002810475 likely pathogenic Noonan syndrome 2; Schwannomatosis 2; Noonan syndrome 10 2021-08-31 criteria provided, single submitter clinical testing
Baylor Genetics RCV003471272 SCV004193688 likely pathogenic Schwannomatosis 2 2024-02-29 criteria provided, single submitter clinical testing

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