ClinVar Genomic variation as it relates to human health

The GBE1 c.708G>C variant is predicted to result in the amino acid substitution p.Gln236His. This variant has been reported in the compound heterozygous states in individuals with glycogen storage disease type 4 (Burrow et al. 2006. PubMed ID: 16528737; Malfatti et al. 2016. PubMed ID: 27546458; Table S2, Ravenscroft et al. 2020. PubMed ID: 33060286; Table 1, Magoulas et al. 2012. PubMed ID: 22305237). This variant is reported in 0.0070% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-81695617-C-G). This variant is interpreted as likely pathogenic.

This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 236 of the GBE1 protein (p.Gln236His). This variant is present in population databases (rs137852892, gnomAD 0.007%). This missense change has been observed in individual(s) with GBE1-related conditions (PMID: 16528737, 27546458, 33060286). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 2790). 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 GBE1 protein function. For these reasons, this variant has been classified as Pathogenic.

Variant summary: GBE1 c.708G>C (p.Gln236His) results in a non-conservative amino acid change located in the 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 2.1e-05 in 240712 control chromosomes (i.e. 5 heterozygous carriers) in the gnomAD database. The variant, c.708G>C, has been reported in the literature in at least 3 compound heterozygous individuals affected with Glycogen Storage Disease, Type IV (Burrow_2006, Malfatti_2016, Ravenscroft_2021), and in two of these cases biochemical- or electron microscopy studies confirmed the diagnosis in patient derived samples (Burrow_2006, Malfatti_2016). These data indicate that the variant is likely associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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; This variant is associated with the following publications: (PMID: 31589614, 16528737, 27546458)

The p.Gln236His variant in GBE1 has been reported in 4 individuals with glycogen storage disease type IV (GSD IV) (PMID: 16528737, 27546458, 33060286, 37598009) and has been identified in 0.003% (3/88322) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs137852892). 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. Of the 4 affected individuals, 2 were compound heterozygotes that carried a reported pathogenic variant in trans or with unknown phase which increases the likelihood that the p.Gln236His variant is pathogenic (VariationID: 208584; PMID: 33060286, 37598009). This variant has also been reported in ClinVar (Variation ID#: 2790) and has been interpreted as pathogenic by OMIM and Invitae, and likely pathogenic by Nilou-Genome Lab, Women's Health and Genetics/Laboratory Corporation of America (LabCorp), MGZ Medical Genetics Center, GeneDx, and PreventionGenetics (PreventionGenetics). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The phenotype of an individual compound heterozygous for this variant is highly specific for GSD IV based on strict biochemical investigations consistent with disease (PMID: 16528737). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive GSD IV. ACMG/AMP Criteria applied: PP3, PM2_supporting, PM3_strong, PP4 (Richards 2015).