ClinVar Genomic variation as it relates to human health

For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with LZTR1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser327Glnfs*7) 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).

ACMG Criteria: PVS1, PM2, PP5; Variant was found in heterozygous state

The c.978_985delCAGCTCCG variant, located in coding exon 9 of the LZTR1 gene, results from a deletion of 8 nucleotides at nucleotide positions 978 to 985, causing a translational frameshift with a predicted alternate stop codon (p.S327Qfs*7). Cohort studies of patients with schwannomatosis have identified this variant in affected individuals (Farschtschi SC et al. Int J Mol Sci, 2020 May;21; Godel T et al. Diagnostics (Basel), 2022 Mar;12:). This mutation was also identified in one individual from a cohort of healthy volunteers; this individual lacked LZTR1-associated disease on deep phenotype analysis (Hou YC et al. Proc Natl Acad Sci U S A, 2020 02;117:3053-3062). 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.