ClinVar Miner

Submissions for variant NM_000158.4(GBE1):c.1571G>A (p.Arg524Gln)

gnomAD frequency: 0.00003  dbSNP: rs80338673
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001043400 SCV001207144 pathogenic Glycogen storage disease, type IV; Glycogen storage disease IV, classic hepatic 2019-11-15 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 524 of the GBE1 protein (p.Arg524Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs80338673, ExAC 0.006%). This variant has been observed in individual(s) with glycogen storage disease IV (PMID: 12874416, 10762170, 20479904, 15452297, 10545044). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 2782). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). For these reasons, this variant has been classified as Pathogenic.
Broad Institute Rare Disease Group, Broad Institute RCV000020162 SCV002097090 likely pathogenic Glycogen storage disease, type IV 2022-01-27 criteria provided, single submitter curation The p.Arg524Gln variant in GBE1 has been reported in 6 individuals with GBE1-related disorders (PMID: 10762170, 15452297, 20479904, 33332610, 33726816, Pan 2017) and has been identified in 0.004% (1/23800) of African/African American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs80338673). 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 6 affected individuals, 1 was a compound heterozygotes that carried a reported likely pathogenic variants in trans, 1 was a homozygote, and 1 was a compound heterozygote that carried a reported pathogenic variant with unknown phase, which increases the likelihood that the p.Arg524Gln variant is pathogenic (VariationID: 2789, 208584; PMID: 15452297, 33726816). This variant has also been reported in ClinVar (Variation ID#: 2782) and has been interpreted as pathogenic by Invitae, OMIM, and GeneReviews. 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, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for GBE1-related disorders. ACMG/AMP Criteria applied: PP3, PM3_strong, PM2_supporting (Richards 2015).
OMIM RCV000002915 SCV000023073 pathogenic Glycogen storage disease IV, combined hepatic and myopathic 2004-09-28 no assertion criteria provided literature only
GeneReviews RCV000020162 SCV000040489 pathologic Glycogen storage disease, type IV 2009-04-02 no assertion criteria provided curation Converted during submission to Pathogenic.
OMIM RCV000150107 SCV000196931 pathogenic Adult polyglucosan body neuropathy 2004-09-28 no assertion criteria provided literature only

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