ClinVar Miner

Submissions for variant NM_006767.4(LZTR1):c.791+1G>T

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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 RCV002416692 SCV002676520 likely pathogenic Hereditary cancer-predisposing syndrome; Cardiovascular phenotype 2023-04-10 criteria provided, single submitter clinical testing The c.791+1G>T intronic variant results from a G to T substitution one nucleotide after coding exon 8 of the LZTR1 gene. 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). In silico splice site analysis predicts that this alteration will weaken the native 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 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 RCV003103453 SCV003472979 pathogenic not provided 2023-12-01 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 8 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 (rs148031742, gnomAD 0.003%). Disruption of this splice site has been observed in individuals with clinical features of LZTR1-related conditions (PMID: 25335493, 28295212; Invitae). ClinVar contains an entry for this variant (Variation ID: 1761188). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV003471360 SCV004191213 likely pathogenic Schwannomatosis 2 2023-10-19 criteria provided, single submitter clinical testing

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