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

gnomAD frequency: 0.00003  dbSNP: rs80338673

Total submissions: 7

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	2024-01-02	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 524 of the GBE1 protein (p.Arg524Gln). This variant is present in population databases (rs80338673, gnomAD 0.007%). This missense change has been observed in individual(s) with glycogen storage disease IV (PMID: 10545044, 10762170, 12874416, 15452297, 20479904). 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: 2782). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	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).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000020162	SCV004030058	pathogenic	Glycogen storage disease, type IV	2023-07-31	criteria provided, single submitter	clinical testing	Variant summary: GBE1 c.1571G>A (p.Arg524Gln) results in a conservative amino acid change to a highly conserved residue (HGMD) located in the Glycosyl hydrolase, family 13, catalytic domain (IPR006047) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 243710 control chromosomes (gnomAD). c.1571G>A has been reported in the literature in multiple individuals affected with Glycogen Storage Disease, Type IV (Bruno_2004, Ziemssen_2000, Ban_2009, Derks_2021, Stranneheim_2021, Sindern_2003, Westra_2019), and some were reported as compound heterozygous with other (likely) pathogenic variants. These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 15452297, 10762170, 20479904, 33332610, 33726816, 12874416, 31127727). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000020162	SCV004198686	pathogenic	Glycogen storage disease, type IV	2023-08-21	criteria provided, single submitter	clinical testing
OMIM	RCV000002915	SCV000023073	pathogenic	Glycogen storage disease IV, combined hepatic and myopathic	2004-09-28	no assertion criteria provided	literature only
GeneReviews	RCV000020162	SCV000040489	not provided	Glycogen storage disease, type IV		no assertion provided	literature only
OMIM	RCV000150107	SCV000196931	pathogenic	Adult polyglucosan body neuropathy	2004-09-28	no assertion criteria provided	literature only