ClinVar

Description

The c.372C>T pathogenic mutation (also known as p.V124V), located in coding exon 4 of the LZTR1 gene, results from a C to T substitution at nucleotide position 372. This nucleotide substitution does not change the valine at codon 124. This variant has been detected with another LZTR1 pathogenic variant in three individuals who were diagnosed with autosomal recessive Noonan syndrome; two LZTR1 variants were confirmed to be in trans in two individuals (Uluda Alkaya D et al. Am J Med Genet A, 2021 Dec;185:3623-3633; personal communication). This nucleotide position is poorly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. However, RNA studies have demonstrated that this mutation results in a marked increase in skipping of exon 4, leading to an out-of-frame transcript (Uluda Alkaya D et al. Am J Med Genet A, 2021 Dec;185:3623-3633; Ambry internal data). 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.