ClinVar Miner

Submissions for variant NM_006767.4(LZTR1):c.1426C>T (p.Gln476Ter)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV002391939 SCV002698435 pathogenic Hereditary cancer-predisposing syndrome; Cardiovascular phenotype 2022-03-10 criteria provided, single submitter clinical testing The p.Q476* variant (also known as c.1426C>T), located in coding exon 13 of the LZTR1 gene, results from a C to T substitution at nucleotide position 1426. This changes the amino acid from a glutamine to a stop codon within coding exon 13. 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 RCV003774324 SCV004639983 pathogenic not provided 2023-10-09 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln476*) 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 (rs764446835, gnomAD 0.0009%). 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: 1772377). For these reasons, this variant has been classified as Pathogenic.

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