ClinVar Miner

Submissions for variant NM_006767.4(LZTR1):c.115G>T (p.Glu39Ter)

gnomAD frequency: 0.00001  dbSNP: rs762434811
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001951347 SCV002246486 pathogenic not provided 2024-01-11 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu39*) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 1459953). For these reasons, this variant has been classified as Pathogenic.
MGZ Medical Genetics Center RCV002290824 SCV002580620 likely pathogenic Schwannomatosis 2 2021-12-22 criteria provided, single submitter clinical testing
Ambry Genetics RCV002352656 SCV002621923 pathogenic Hereditary cancer-predisposing syndrome; Cardiovascular phenotype 2022-01-20 criteria provided, single submitter clinical testing The p.E39* pathogenic mutation (also known as c.115G>T), located in coding exon 1 of the LZTR1 gene, results from a G to T substitution at nucleotide position 115. This changes the amino acid from a glutamic acid to a stop codon within coding exon 1. 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.

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