ClinVar Miner

Submissions for variant NM_006767.4(LZTR1):c.238dup (p.Ile80fs)

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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 RCV003183923 SCV003864248 pathogenic Hereditary cancer-predisposing syndrome; Cardiovascular phenotype 2023-02-06 criteria provided, single submitter clinical testing The c.238dupA pathogenic mutation, located in coding exon 2 of the LZTR1 gene, results from a duplication of A at nucleotide position 238, causing a translational frameshift with a predicted alternate stop codon (p.I80Nfs*15). This mutation has been reported in an individual with two schwannomas whose tumors both demonstrated loss of heterozygosity (LOH) of LZTR1 (Piotrowski A et al. Nat Genet, 2014 Feb;46:182-7). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or 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 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 RCV003561213 SCV004298834 pathogenic not provided 2023-12-27 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Ile80Asnfs*15) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with LZTR1-related conditions (PMID: 24362817). ClinVar contains an entry for this variant (Variation ID: 2457590). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV004572879 SCV005060679 pathogenic Schwannomatosis 2 2023-12-21 criteria provided, single submitter clinical testing

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