ClinVar Genomic variation as it relates to human health

Variant summary: LZTR1 c.848G>A (p.Arg283Gln) results in a conservative amino acid change located in the Kelch repeat type 1 domain (IPR006652) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 230510 control chromosomes (gnomAD). c.848G>A has been reported in the literature in individuals affected with Noonan Syndrome, including two individuals were the variant arose de novo (Umeki_2019, Quaio_2020) and one individual via maternal inheritance (Maron_2021). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Umeki_2019). Four ClinVar submitters have assessed the variant since 2014: one classified the variant as of uncertain significance, two as likely pathogenic, and one as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].

Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 30368668, 33258288, 33792302)

This missense variant results in a change from arginine to glutamine at amino acid position 283. It has been reported previously in individuals with Noonan syndrome (PMIDs: 30368668, 33587123) or neurological anomaly (precise phenotype not specified – PMID: 33258288). This variant was reported to have occurred de novo in at least one individual. This variant is observed at an allele frequency of 0.000062% in population controls of the Genome Aggregation Database (gnomAD). In silico prediction programs predict this variant to impact protein function. Based on the evidence above, this variant is classified as likely pathogenic (ACMG criteria - PS4_Moderate, PM6, PP3, PP5).

The variant is not observed in the gnomAD v2.1.1 dataset. Protein truncation variants are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.61; 3Cnet: 0.69). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000561716). The variant has been previously reported as de novo in a similarly affected individual (PMID: 30368668). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

For these reasons, this variant has been classified as Pathogenic. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on LZTR1 function (PMID: 30368668). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt LZTR1 protein function. ClinVar contains an entry for this variant (Variation ID: 561716). This missense change has been observed in individual(s) with clinical features of Noonan syndrome (PMID: 30368668, 33258288; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 283 of the LZTR1 protein (p.Arg283Gln).

The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. This variant segregates with disease in multiple families. This variant appears to occur de novo in one individual with clinical features associated with this gene.

The LZTR1 c.848G>A variant is predicted to result in the amino acid substitution p.Arg283Gln. This variant was reported de novo in two individuals with Noonan syndrome (Umeki et al. 2019. PubMed ID: 30368668; supplementary material, Quaio et al. 2020. PubMed ID: 33258288). This variant was also reported as maternally-inherited in an individual with Noonan syndrome (eTable 2, Maron et al. 2021. PubMed ID: 33587123). In vitro functional studies showed that this variant does not induce the activation of ERK- or ELK-mediated transactivation (Figure S2, Umeki et al. 2019. PubMed ID: 30368668). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as likely pathogenic.