ClinVar Genomic variation as it relates to human health

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

The p.Arg565Trp variant in GBE1 has been reported in 1 individual in the homozygous state with glycogen storage disease type IV (GSD IV) (PMID: 31680123) and has been identified in 0.004% (1/27172) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs552094593). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID#: 425301) and has been interpreted as likely pathogenic by Cirak Lab (University Hospital Cologne), CeGaT Praxis fuer Humangenetik Tuebingen, Baylor Genetics, and a variant of uncertain significance by Mayo Clinic Laboratories. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Arg565Trp variant is uncertain. ACMG/AMP Criteria applied: PP3, PM3_supporting, PM2_supporting (Richards 2015).

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 565 of the GBE1 protein (p.Arg565Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with glycogen storage disease (PMID: 31680123; Invitae). ClinVar contains an entry for this variant (Variation ID: 425301). 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 expected to disrupt GBE1 protein function. 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.

Variant summary: GBE1 c.1693C>T (p.Arg565Trp) results in a non-conservative amino acid change located in the Glycosyl hydrolase, family 13, catalytic domain (IPR006047) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.9e-06 in 224694 control chromosomes. c.1693C>T has been reported in the literature in and individual affected with fetal akinesia (Pergande_2020). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 31680123). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as VUS (n=3) and likely pathogenic (n=3). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.