ClinVar

Description

The c.27delG pathogenic mutation, located in coding exon 1 of the LZTR1 gene, results from a deletion of one nucleotide at nucleotide position 27, causing a translational frameshift with a predicted alternate stop codon (p.Q10Rfs*15). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This alteration has been reported in multiple individuals with schwannomatosis, as well as in trans with LZTR1 c.1149+1G>A in an individual with autosomal recessive Noonan syndrome (Piotrowski A et al. Nat. Genet., 2014 Feb;46:182-7; Smith MJ et al. Neurology, 2015 Jan;84:141-7; Johnston JJ et al. Genet. Med., 2018 10;20:1175-1185; Louvrier C et al. Neuro-oncology, 2018 06;20:917-929). 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.