ClinVar Genomic variation as it relates to human health

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Has not been observed in patients with schwannomatosis to our knowledge, but has been reported in an individual with features of Noonan syndrome and her unaffected father (Umeki et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30368668, 33895855)

This sequence change creates a premature translational stop signal (p.Met202Valfs*57) 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 (rs776788495, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with clinical features of Noonan syndrome (PMID: 30368668). ClinVar contains an entry for this variant (Variation ID: 1751239). For these reasons, this variant has been classified as Pathogenic.

The c.604_605delAT pathogenic mutation, located in coding exon 7 of the LZTR1 gene, results from a deletion of two nucleotides at nucleotide positions 604 to 605, causing a translational frameshift with a predicted alternate stop codon (p.M202Vfs*57). This alteration was identified as heterozygous in a patient with suspected Noonan syndrome (NS), who's mother was homozygous wild type and father was heterozygous for this alteration with no clinical NS features (Umeki I et al. Hum Genet, 2019 Jan;138:21-35). 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 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. 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.