ClinVar Miner

Submissions for variant NM_006767.4(LZTR1):c.994-1G>A

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV002382902 SCV002690097 likely pathogenic Hereditary cancer-predisposing syndrome; Cardiovascular phenotype 2023-10-03 criteria provided, single submitter clinical testing The c.994-1G>A intronic alteration results from a G to A substitution one nucleotide before coding exon 10 of the LZTR1 gene. 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. Based on data from gnomAD, the A allele has an overall frequency of 0.001% (3/281580) total alleles studied. The highest observed frequency was 0.012% (3/24922) of African alleles. 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, and RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the available evidence, this alteration is classified as likely pathogenic.
PreventionGenetics, part of Exact Sciences RCV004534077 SCV004114518 likely pathogenic LZTR1-related disorder 2022-10-26 criteria provided, single submitter clinical testing The LZTR1 c.994-1G>A variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/22-21346502-G-A). Variants that disrupt the consensus splice acceptor site in LZTR1 are expected to be pathogenic. This variant is interpreted as likely pathogenic.
Baylor Genetics RCV003464505 SCV004193693 likely pathogenic Schwannomatosis 2 2022-12-06 criteria provided, single submitter clinical testing
Invitae RCV003730160 SCV004524689 likely pathogenic not provided 2024-01-18 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 9 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 0.01%). 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: 1768685). 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.

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