ClinVar Miner

Submissions for variant NM_006767.4(LZTR1):c.200+1dup

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV002417164 SCV002719583 likely pathogenic Hereditary cancer-predisposing syndrome; Cardiovascular phenotype 2021-11-04 criteria provided, single submitter clinical testing The c.200+1dupG intronic variant, results from a duplication of two nucleotides at nucleotide position 200 after intron 1 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 will 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. 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.
Invitae RCV003100998 SCV003497004 pathogenic not provided 2023-10-13 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (Splice site) in the LZTR1 gene. It is expected to result in an absent or disrupted protein product. 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 0.01%). This variant has not been reported in the literature in individuals affected with LZTR1-related conditions. This variant is also known as c.200+1dup. ClinVar contains an entry for this variant (Variation ID: 1784227). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV004572456 SCV005060612 likely pathogenic Schwannomatosis 2 2024-03-11 criteria provided, single submitter clinical testing

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