3-81642787-T-G

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 13P and 1B. PM2PM5PP3PP5_Very_StrongBP4

The NM_000158.4(GBE1):c.986A>C(p.Tyr329Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000172 in 1,597,294 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y329C) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00017 ( 0 hom. )

Consequence

GBE1
NM_000158.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:21O:1

Conservation

PhyloP100: 7.55

Publications

52 publications found

Variant links:

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

GBE1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-81642787-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 371439.

PP3

Multiple lines of computational evidence support a deleterious effect 11: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Eigen, M_CAP, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

PP5

Variant 3-81642787-T-G is Pathogenic according to our data. Variant chr3-81642787-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 2777.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.28169453). . Strength limited to SUPPORTING due to the PP5.

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.986A>C	p.Tyr329Ser	missense	Exon 7 of 16	NP_000149.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GBE1	ENST00000429644.7	TSL:1 MANE Select	c.986A>C	p.Tyr329Ser	missense	Exon 7 of 16	ENSP00000410833.2
GBE1	ENST00000489715.1	TSL:2	c.863A>C	p.Tyr288Ser	missense	Exon 7 of 16	ENSP00000419638.1
GBE1	ENST00000498468.1	TSL:3	n.536A>C		non_coding_transcript_exon	Exon 4 of 4

Frequencies

GnomAD3 genomes

AF:

0.000191

AC:

AN:

151990

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00693

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000318

AC:

AN:

248464

AF XY:

0.000341

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00648

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000800

Gnomad OTH exome

AF:

0.000831

GnomAD4 exome

AF:

0.000170

AC:

246

AN:

1445304

Hom.:

Cov.:

AF XY:

0.000176

AC XY:

127

AN XY:

720130

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33136

American (AMR)

AF:

0.00

AC:

AN:

44660

Ashkenazi Jewish (ASJ)

AF:

0.00708

AC:

184

AN:

26002

East Asian (EAS)

AF:

0.00

AC:

AN:

39594

South Asian (SAS)

AF:

0.00

AC:

AN:

85914

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53316

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5728

European-Non Finnish (NFE)

AF:

0.0000273

AC:

AN:

1097146

Other (OTH)

AF:

0.000535

AC:

AN:

59808

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000191

AC:

AN:

151990

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74236

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41392

American (AMR)

AF:

0.00

AC:

AN:

15246

Ashkenazi Jewish (ASJ)

AF:

0.00693

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10580

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

67982

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.516

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000571

Hom.:

Bravo

AF:

0.000219

ExAC

AF:

0.000257

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:21Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glycogen storage disease, type IV

Pathogenic:5Other:1

Sep 16, 2020

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

Oct 31, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

Dec 20, 2019

Myriad Genetics, Inc.

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NM_000158.3(GBE1):c.986A>C(Y329S) is classified as pathogenic in the context of GBE1-related disorders and may be associated with adult polyglucosan body disease. Sources cited for classification include the following: 25665141, 8613547, 26385640, 26199317 and 23607684. Classification of NM_000158.3(GBE1):c.986A>C(Y329S) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.

Aug 27, 2021

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: GBE1 c.986A>C (p.Tyr329Ser) results in a non-conservative amino acid change located in the Glycosyl hydrolase, family 13, 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 0.00032 in 248464 control chromosomes (gnomAD). c.986A>C has been reported in the literature in multiple compound heterozygous and homozygous individuals affected with Adult Polyglucosan Body Disease (APBD) and Glycogen Storage Disease, Type IV (e.g. Bao_1996, Roe_2010, Mochel_2012). APBD occurs most frequently in patients of Ashkenazi Jewish origin due to partial deficiency of the glycogen brancher enzyme, which is most commonly caused by the p.Tyr329Ser mutation (Roe_2010). These data indicate that the variant is very likely to be associated with disease. Experimental evidence demonstrated the variant results in protein destabilization and in reduced enzyme activity compared to wild-type (Bao_1996, Akman_2015, Froese_2015). Eleven ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Mar 25, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Adult polyglucosan body disease

Pathogenic:5

Jan 06, 2020

Reproductive Health Research and Development, BGI Genomics

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:curation

NM_000158.3:c.986A>C in the GBE1 gene has an allele frequency of 0.006 in Ashkenazi Jewish subpopulation in the gnomAD database. The c.986A>C (p.Tyr329Ser) missense variant has been reported in multiple individuals with glycogen storage disease type IV or adult polyglucosan body disease, both in homozygous state and compound heterozygous state: p.Y329S/p.L224P, p.Y329S/p.R565Q, p.Y329S/c.2003delA, p.Y329C/p.N556Y (PMID: 20655781; 23034915). Functional studies showed the Y329S variant has 50% of GBE activity when compared to wild type (PMID: 8613547). Taken together, we interprete this variant as Pathogenic/Likely pathogenic variant. ACMG/AMP Criteria applied: PS3, PM3_Strong, PP4.

Apr 07, 2021

Undiagnosed Diseases Network, NIH

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mar 28, 2025

Undiagnosed Diseases Network, NIH

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jul 12, 2021

Division Of Personalized Genomic Medicine, Columbia University Irving Medical Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant in the GBE1 gene, c.986A>C is a missense variant, resulting in a tyrosine to serine protein substitution at position 329 (p.Tyr329Ser). This variant localizes to coding exon 7 of the GBE1 gene (16 exons in total; NM_000158.4) and is predicted to damage protein structure and/or function based on in silico analyses (Provean and SIFT). Functional studies show the expression of the recombinant protein carrying the p.Tyr329Ser variant results in drastically reduced protein yield and solubility, suggesting that the variant leads to protein misfolding (PMID: 26199317). The variant has also been shown to result in decreased enzyme activity ranging from undetectable levels to 50% of wild type (PMID: 8613547). This variant has been reported in several studies in either a homozygous or compound heterozygous state with a second known pathogenic variant in unrelated individuals with glycogen storage disease type IV or adult polyglucosan body disease (PMID: 9851430; 20655781; 22106711; 23034915; 25665141; 28265589; 32455116). It is also the most common variant associated with adult polyglucosan body disease in the Ashkenazi Jewish population (PMID: 25665141). This variant is reported in the Genome Aggregation Database (gnomAD) with an allele frequency of 79/248464 (no homozygote), indicating it is not a common benign variant in the populations represented in this database. It has already been interpreted as pathogenic by multiple laboratories in the ClinVar database (variation ID: 2777).

Jan 27, 2022

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

The p.Tyr329Ser variant in GBE1 has been reported in many individuals with GBE1-related disorders (PMID: 8613547, 9851430, 20655781, 23034915, 25133958, 25665141, 33332610), segregated with disease in 4 affected relatives from 3 families (PMID: 9851430, 20655781, 33332610), and has been identified in 0.6% (65/10038) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs80338671). 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. This variant has also been reported in ClinVar (Variation ID#: 2777) and has been interpreted as pathogenic by multiple submitters in ClinVar. Of the many affected individuals, at least 2 of those were homozygotes, which increases the likelihood that the p.Tyr329Ser variant is pathogenic (PMID: 8613547, 9851430, 20655781, 23034915, 25133958, 25665141, 33332610). Animal models in mice have shown that this variant causes GBE1-related disorders (PMID: 26385640). Computational prediction tools and conservation analyses suggest that this variant may impact the protein. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive GBE1-related disorder. ACMG/AMP Criteria applied: PP3, PM3, PP1_strong, PS3 (Richards 2015).

not provided

Pathogenic:5

Apr 11, 2024

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Apr 01, 2017

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jun 03, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate that the variant is associated with 50% of GBE activity when compared to wild type (Bao et al., 1996); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Common pathogenic variant in the Ashkenazi Jewish population (Akman et al., 2015); This variant is associated with the following publications: (PMID: 24082139, 30185673, 20655781, 26385640, 30228975, 25133958, 31692161, 34103343, 31980526, 31589614, 9851430, 32746448, 33332610, 25665141, 8613547)

Sep 03, 2019

Mayo Clinic Laboratories, Mayo Clinic

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PS3, PS4_moderate, PM2, PM3, PP1, PP3, PP4, PP5

Jan 27, 2017

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Pathogenic:1

Feb 13, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Inborn genetic diseases

Pathogenic:1

Mar 21, 2025

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.986A>C (p.Y329S) alteration is located in exon 7 (coding exon 7) of the GBE1 gene. This alteration results from an A to C substitution at nucleotide position 986, causing the tyrosine (Y) at amino acid position 329 to be replaced by a serine (S). Based on data from gnomAD, the C allele has an overall frequency of 0.032% (79/248464) total alleles studied. The highest observed frequency was 0.648% (65/10038) of Ashkenazi Jewish alleles. This variant has been identified in the homozygous state and in conjunction with other GBE1 variants in individuals with features consistent with GBE1-related glycogen storage disease (Bao, 1996; Lossos, 1998; Mochel, 2012; Fogel, 2014). This amino acid position is highly conserved in available vertebrate species. In multiple assays testing GBE1 function, this variant showed functionally abnormal results (Bao, 1996; Lossos, 1998; Mochel, 2012). In addition, an animal model expressing this variant exhibited phenotypes consistent with GBE1-related disease (Orhan Akman, 2015). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.

GBE1-related disorder

Pathogenic:1

Sep 07, 2018

Illumina Laboratory Services, Illumina

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The GBE1 c.986A>C (p.Tyr329Ser) missense variant has been reported in at least six studies in which it is found in a total of 82 individuals with glycogen storage disease type IV or adult polyglucosan body disease, including in 48 in a homozygous state, in 25 in a compound heterozygous state, and in nine in a heterozygous state where a second variant was not detected (Bao et al. 1996; Lossos et al. 1998; Roe et al. 2010; DiMauro and Spiegel 2011; Mochel et al. 2013; Akman et al. 2015). The p.Tyr329Ser variant was absent from 143 controls but is reported at a frequency of 0.00045 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies demonstrated that the expression of recombinant protein carrying the p.Tyr329Ser variant resulted in a drastically reduced protein yield and solubility, suggesting that the variant leads to protein misfolding (Froese et al. 2015). The variant has also been shown to result in decreased enzyme activity ranging from undetectable levels to 50% of wild type (Bao et al. 1996; Lossos et al. 1998; Mochel et al. 2013; Akman et al. 2015). Based on the collective evidence, the p.Tyr329Ser variant is classified as pathogenic for GBE1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

Adult polyglucosan body neuropathy

Pathogenic:1

Dec 01, 1998

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Glycogen storage disease IV, nonprogressive hepatic

Pathogenic:1

Dec 01, 1998

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

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

Pathogenic:1

Dec 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces tyrosine, which is neutral and polar, with serine, which is neutral and polar, at codon 329 of the GBE1 protein (p.Tyr329Ser). This variant is present in population databases (rs80338671, gnomAD 0.6%). This missense change has been observed in individual(s) with adult polyglucosan body disease (PMID: 8613547, 20655781, 24082139, 25133958, 25665141). It is commonly reported in individuals of Ashkenazi Jewish ancestry (PMID: 8613547, 20655781, 24082139, 25133958, 25665141). ClinVar contains an entry for this variant (Variation ID: 2777). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt GBE1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GBE1 function (PMID: 8613547, 26199317, 26385640). For these reasons, this variant has been classified as Pathogenic.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.84

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.77

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.50

MetaRNN

Benign

0.28

MetaSVM

Pathogenic

0.99

MutationAssessor

Pathogenic

3.6

PhyloP100

7.6

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-8.4

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.86

MVP

0.94

MPC

0.27

ClinPred

0.94

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.95

gMVP

0.93

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over