ClinVar Genomic variation as it relates to human health

The R102W variant in the GNE gene has been reported previously in the homozygous state in an individual with myopathy (Saechao et al., 2010). The R102W variant is not observed in large population cohorts (Lek et al., 2016). The R102W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret R102W as a variant of uncertain significance.

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 102 of the GNE protein (p.Arg102Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with distal myopathy (PMID: 20059379; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as R71W. ClinVar contains an entry for this variant (Variation ID: 290713). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GNE protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

Variant summary: GNE c.304A>T (p.Arg102Trp) results in a non-conservative amino acid change located in the epimerase domain (IPR003331) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249902 control chromosomes (gnomAD v2.1 Exomes dataset). c.304A>T has been reported in the literature in at least one homozygous individual affected with Inclusion Body Myopathy (e.g., Saechao_2010, Nallamilli_2018). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 20059379, 30564623). Six submitters have reported clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments: five submitters classified the variant as uncertain significance, and one submitter classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.