ClinVar Genomic variation as it relates to human health

Reported as a heterozygous variant in a patient with features suggestive of Noonan syndrome in the published literature; however, a second variant in LZTR1 was not reported (Ghedira et al., 2017); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function

Variant summary: LZTR1 c.347C>T (p.Ala116Val) results in a non-conservative amino acid change located in the Kelch repeat type 1 (IPR006652) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250768 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.347C>T has been reported in the literature in at least one individual affected with Noonan Syndrome, where the variant was confirmed to have occured de novo (Farncombe_2022). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 35840934). Two ClinVar submitters have assessed this variant since 2014: both classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

This variant has not been reported in the literature in individuals affected with LZTR1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 116 of the LZTR1 protein (p.Ala116Val). This variant is not present in population databases (gnomAD no frequency).

The p.A116V variant (also known as c.347C>T), located in coding exon 4 of the LZTR1 gene, results from a C to T substitution at nucleotide position 347. The alanine at codon 116 is replaced by valine, an amino acid with similar properties. This alteration has been detected in an individual with multiple schwannomas as well as in an individual with features of Noonan syndrome, reportedly in the heterozygous state (Ambry internal data; Ghedira N et al. Biol Med (Aligarh), 2017 9(6)). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly 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 alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the supporting evidence, this variant is likely pathogenic for an increased risk of LZTR1-related schwannomatosis (SWN). This alteration is also likely to cause autosomal recessive Noonan syndrome when present along with a second pathogenic variant on the other allele; however, the clinical significance for autosomal dominant Noonan syndrome is unclear.

LZTR1: PM2