ClinVar Miner

Submissions for variant NM_000158.4(GBE1):c.1883A>G (p.His628Arg)

gnomAD frequency: 0.00001  dbSNP: rs137852891
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services,Illumina RCV000056098 SCV000915065 uncertain significance Glycogen storage disease, type IV 2018-03-29 criteria provided, single submitter clinical testing The GBE1 c.1883A>G (p.His628Arg) missense variant has been reported in two studies and is found in a compound heterozygous state in two individuals with glycogen storage disease type IV (Bruno et al. 2004; Kuhn et al. 2016). These individuals exhibited reduced glycogen branching enzyme activity at 15% and 35% respectively, when compared to controls. The p.His628Arg variant was absent from 96 control chromosomes (Bruno et al. 2004) and is reported at a frequency of 0.000015 in the European (non-Finnish) population of the Exome Aggregation Consortium, but this is based on one allele so the variant is presumed to be rare. Based on the evidence, the p.His628Arg variant is classified as a variant of unknown significance but suspicious for pathogenicity for glycogen storage disease type IV. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
CeGaT Center for Human Genetics Tuebingen RCV001092351 SCV001248810 pathogenic not provided 2017-04-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000056098 SCV002041497 likely pathogenic Glycogen storage disease, type IV 2021-11-07 criteria provided, single submitter clinical testing Variant summary: GBE1 c.1883A>G (p.His628Arg) results in a non-conservative amino acid change located in the Alpha-amylase/branching enzyme, C-terminal all beta domain (IPR006048) 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 4e-06 in 247212 control chromosomes. c.1883A>G has been reported in the literature as a compound heterozygous genotype in individuals affected with Glycogen Storage Disease, Type IV (example, Bruno_2004, Kuhn_2016, Yubero_2016, Derks_2021). These data indicate that the variant is likely to be associated with disease. To our knowledge, no variant specific experimental evidence demonstrating an impact on protein function has been reported although some of the affected compound heterozygous individuals mentioned above were reported to have a deficiency of branching enzyme activity. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Broad Institute Rare Disease Group, Broad Institute RCV000056098 SCV002097078 likely pathogenic Glycogen storage disease, type IV 2022-01-27 criteria provided, single submitter curation The p.His628Arg variant in GBE1 has been reported in at least 4 individuals with glycogen storage disease type IV (GSD IV) (PMID: 15452297, 26886200, 33332610, 33473341) and has been identified in 0.0009% (1/112290) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs137852891). 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, 1 was a compound heterozygote that carried a likely pathogenic variant in trans, and 2 were compound heterozygotes that carried reported pathogenic variants with unknown phase, which increases the likelihood that the p.His628Arg variant is pathogenic (VariationID: 208584, 2781; PMID: 26886200, 33332610, 15452297). This variant has also been reported in ClinVar (Variation ID#: 2788) and has been interpreted as pathogenic by CeGaT Praxis fuer Humangenetik Tuebingen, OMIM, and GeneReviews and as a variant of uncertain significance by Illumina Clinical Services Laboratory (Illumina). 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: 15452297). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for GSD IV. ACMG/AMP Criteria applied: PP3, PM3_strong, PM2_supporting, PP4 (Richards 2015).
Invitae RCV001851596 SCV002235555 pathogenic Glycogen storage disease, type IV; Glycogen storage disease IV, classic hepatic 2021-08-27 criteria provided, single submitter clinical testing
OMIM RCV000002922 SCV000023080 pathogenic Glycogen storage disease due to glycogen branching enzyme deficiency, childhood neuromuscular form 2004-09-28 no assertion criteria provided literature only
GeneReviews RCV000056098 SCV000087170 pathologic Glycogen storage disease, type IV 2009-04-02 no assertion criteria provided curation Converted during submission to Pathogenic.

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