3-81578051-C-T

Variant names:

• chr3-81578051-C-T
• rs201758548
• NM_000158.4:c.1492G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM1

The NM_000158.4(GBE1):​c.1492G>A​(p.Glu498Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000943 in 1,607,986 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. E498E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00068 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00097 (0 hom.)
• Consequence: GBE1 NM_000158.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:18
• Conservation: PhyloP100: 7.55
• Publications: 3 publications found

Genes affected

GBE1 (HGNC:4180): (1,4-alpha-glucan branching enzyme 1) The protein encoded by this gene is a glycogen branching enzyme that catalyzes the transfer of alpha-1,4-linked glucosyl units from the outer end of a glycogen chain to an alpha-1,6 position on the same or a neighboring glycogen chain. Branching of the chains is essential to increase the solubility of the glycogen molecule and, consequently, in reducing the osmotic pressure within cells. Highest level of this enzyme are found in liver and muscle. Mutations in this gene are associated with glycogen storage disease IV (also known as Andersen's disease). [provided by RefSeq, Jul 2008]

GBE1 Gene-Disease associations (from GenCC):

• glycogen storage disease due to glycogen branching enzyme deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Laboratory for Molecular Medicine, Ambry Genetics, G2P, ClinGen
• adult polyglucosan body disease

  Inheritance: AR Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000158.4

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000158.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GBE1	NM_000158.4	MANE Select	c.1492G>A	p.Glu498Lys	missense	Exon 12 of 16	NP_000149.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GBE1	ENST00000429644.7	TSL:1 MANE Select	c.1492G>A	p.Glu498Lys	missense	Exon 12 of 16	ENSP00000410833.2
	GBE1	ENST00000489715.1	TSL:2	c.1369G>A	p.Glu457Lys	missense	Exon 12 of 16	ENSP00000419638.1
	GBE1	ENST00000484687.1	TSL:2	n.-108G>A		upstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.000678 AC: 103 AN: 151858 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.000759

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00128

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000728 AC: 175 AN: 240226 AF XY: 0.000875

Gnomad AFR exome AF: 0.000135

Gnomad AMR exome AF: 0.0000918

Gnomad ASJ exome AF: 0.000304

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00141

Gnomad NFE exome AF: 0.000972

Gnomad OTH exome AF: 0.000690

GnomAD4 exome AF: 0.000970 AC: 1412 AN: 1456010 Hom.: 0 Cov.: 31 AF XY: 0.00101 AC XY: 728 AN XY: 723864

African (AFR) AF: 0.0000602 AC: 2 AN: 33238

American (AMR) AF: 0.000114 AC: 5 AN: 43850

Ashkenazi Jewish (ASJ) AF: 0.000308 AC: 8 AN: 25996

East Asian (EAS) AF: 0.00 AC: 0 AN: 39450

South Asian (SAS) AF: 0.000904 AC: 77 AN: 85136

European-Finnish (FIN) AF: 0.000977 AC: 52 AN: 53240

Middle Eastern (MID) AF: 0.000521 AC: 3 AN: 5756

European-Non Finnish (NFE) AF: 0.00111 AC: 1232 AN: 1109124

Other (OTH) AF: 0.000548 AC: 33 AN: 60220

GnomAD4 genome AF: 0.000684 AC: 104 AN: 151976 Hom.: 0 Cov.: 32 AF XY: 0.000538 AC XY: 40 AN XY: 74292

African (AFR) AF: 0.000121 AC: 5 AN: 41450

American (AMR) AF: 0.00 AC: 0 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4806

European-Finnish (FIN) AF: 0.000759 AC: 8 AN: 10542

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00128 AC: 87 AN: 67988

Other (OTH) AF: 0.00 AC: 0 AN: 2106

Alfa AF: 0.000861 Hom.: 1

Bravo AF: 0.000646

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000605 AC: 5

ExAC AF: 0.000695 AC: 84

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:18

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:9

Sep 19, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in trans with a GBE1 splicing variant in a patient with an unusual manifestation of adult polyglucosan body disease, whose GBE enzyme activity in blood leukocytes was 7% of normal levels (PMID: 26789422); 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: 34426522, 36628840, 26789422, 34946936, 37152446)

Feb 27, 2025

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Clinical Genetics, Academic Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Feb 15, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BS1, PP3, PP4, PM3

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Nov 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GBE1: PM3, PM2:Supporting, PP3

Jul 12, 2017

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Glycogen storage disease, type IV Pathogenic:1 Uncertain:4

May 17, 2017

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Nov 25, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: GBE1 c.1492G>A (p.Glu498Lys) results in a conservative amino acid change 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 0.00073 in 240226 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in GBE1 causing Glycogen Storage Disease, Type IV (0.00073 vs 0.0013), allowing no conclusion about variant significance. c.1492G>A has been reported in the literature as a compound heterozygous genotype in two individuals affected with Adult onset polyglucosan body disease (APBD) (Naddaf_2016, De Winter_2023) and as a homozygous genotype in at-least one individual affected with Glycogen storage disease type IV (Ersoy_2021). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 548007). Based on the evidence outlined above, the variant was classified as likely pathogenic.

Jan 13, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jun 13, 2025

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as VUS-3A. Evidence in support of pathogenic classification: Variant is present in gnomAD <0.01 for a recessive condition (v4: 1516 heterozygote(s), 0 homozygote(s)); Missense variant predicted to be damaging by in silico tool(s) or highly conserved with a major amino acid change. Additional information: Variant is predicted to result in a missense amino acid change from glutamic acid to lysine; This variant is heterozygous; This gene is associated with autosomal recessive disease; Alternative amino acid change(s) at the same position are present in gnomAD (Highest allele count: v4: 2 heterozygote(s), 0 homozygote(s)); Previous reports of pathogenicity for this variant are conflicting. This variant has been classified as VUS by multiple clinical laboratories in ClinVar and has also been classified once as likely pathogenic. In addition, it has been reported in the literature in a compound heterozygous individual with adult polyglucosan body disease and in a homozygous individual with mild developmental delay and early onset peripheral sensory neuropathy (PMIDs: 26789422, 34946936); No published segregation evidence has been identified for this variant; No published functional evidence has been identified for this variant; No comparable missense variants have previous evidence for pathogenicity; Variant is not located in an established domain, motif, hotspot or informative constraint region; Loss of function is a known mechanism of disease in this gene and is associated with glycogen storage disease due to glycogen branching enzyme deficiency (MONDO:0009292), GBE1-related; This variant has been shown to be maternally inherited (by trio analysis).

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Glycogen storage disease, type IV;C1849722:Adult polyglucosan body disease Uncertain:2

Apr 18, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 03, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

Dementia Pathogenic:1

Feb 04, 2020

Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GBE1-related disorder Uncertain:1

Aug 05, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The GBE1 c.1492G>A variant is predicted to result in the amino acid substitution p.Glu498Lys. This variant has been reported in the compound heterozygous state in a patient with adult polyglucosan body disease (Naddaf et al. 2016. PubMed ID: 26789422). Of note, GBE1 exon 12 has previously been reported as a mutation “hotspot” (Moses and Parvari. 2002. PubMed ID: 11949934) and exon 12 mutations have been associated with a wide range of clinical phenotypes (for review, see Li et al. 2010. PubMed ID: 20058079). This variant is reported in 0.13% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-81627202-C-T) and is interpreted as uncertain by many outside laboratories in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/548007/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Adult polyglucosan body disease Uncertain:1

Jan 27, 2022

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

The p.Glu498Lys variant in GBE1 has been reported in 1 individual. in the compound heterozygous state, with adult polyglucosan body disease (APBD) (PMID: 26789422) and has been identified in 0.1% (32/24784) of European (Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs201758548). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. 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.Glu498Lys variant is uncertain. ACMG/AMP Criteria applied: PP3 (Richards 2015).

Glycogen storage disease, type IV;C1856301:Glycogen storage disease IV, classic hepatic Uncertain:1

Oct 24, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 498 of the GBE1 protein (p.Glu498Lys). This variant is present in population databases (rs201758548, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with GBE1-related conditions (PMID: 26789422). ClinVar contains an entry for this variant (Variation ID: 548007). 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.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.40	D
MetaRNN	Uncertain	0.55	D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	4.1	H
PhyloP100		7.6
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.051	T
Polyphen		1.0	D
Vest4		0.97
MVP		0.95
MPC		0.25
ClinPred		0.21	T
GERP RS		5.7
Varity_R		0.78
gMVP		0.83
Mutation Taster		=2/98	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs201758548; hg19: chr3-81627202;