chr3-81642988-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5

The NM_000158.4(GBE1):c.785G>A(p.Arg262His) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000318 in 1,601,384 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R262C) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000030 ( 0 hom. )

Consequence

GBE1
NM_000158.4 missense, splice_region

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6U:4

Conservation

PhyloP100: 7.45

Publications

4 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 11 ACMG points.

PM1

In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_000158.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-81642989-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2791.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.943

PP5

Variant 3-81642988-C-T is Pathogenic according to our data. Variant chr3-81642988-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 437422.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GBE1	NM_000158.4 link	c.785G>A	p.Arg262His	missense_variant, splice_region_variant	Exon 7 of 16	ENST00000429644.7	NP_000149.4	Q04446Q59ET0
GBE1	XR_007095662.1 link	n.913G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 7 of 15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GBE1	ENST00000429644.7 link	c.785G>A	p.Arg262His	missense_variant, splice_region_variant	Exon 7 of 16	1	NM_000158.4	ENSP00000410833.2	Q04446
GBE1	ENST00000489715.1 link	c.662G>A	p.Arg221His	missense_variant, splice_region_variant	Exon 7 of 16	2		ENSP00000419638.1	E9PGM4
GBE1	ENST00000498468.1 link	n.335G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 4 of 4	3

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

151998

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000725

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000298

AC:

AN:

234522

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.0000686

Gnomad AMR exome

AF:

0.0000620

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000595

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000190

Gnomad OTH exome

AF:

0.000174

GnomAD4 exome

AF:

0.0000297

AC:

AN:

1449386

Hom.:

Cov.:

AF XY:

0.0000236

AC XY:

AN XY:

720640

show subpopulations

African (AFR)

AF:

0.000151

AC:

AN:

33206

American (AMR)

AF:

0.0000231

AC:

AN:

43202

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25940

East Asian (EAS)

AF:

0.0000508

AC:

AN:

39348

South Asian (SAS)

AF:

0.00

AC:

AN:

85116

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53144

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5744

European-Non Finnish (NFE)

AF:

0.0000281

AC:

AN:

1103746

Other (OTH)

AF:

0.0000501

AC:

AN:

59940

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

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:

0.0000526

AC:

AN:

151998

Hom.:

Cov.:

AF XY:

0.0000674

AC XY:

AN XY:

74206

show subpopulations

African (AFR)

AF:

0.0000725

AC:

AN:

41400

American (AMR)

AF:

0.00

AC:

AN:

15230

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10568

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68000

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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:

0.000115

Hom.:

Bravo

AF:

0.0000529

ESP6500AA

AF:

0.000264

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000249

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6Uncertain:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Glycogen storage disease, type IV

Pathogenic:3Uncertain:1

May 03, 2018

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. -

May 18, 2021

Genome-Nilou Lab

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 20, 2024

Baylor Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 05, 2025

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

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

The p.Arg262His variant in GBE1 has been reported in 2 individuals with glycogen storage disease type IV (GSD IV) (PMID: 33332610, 33820833) and has been identified in 0.01% (8/74606) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs369574719). 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. This variant has also been reported in ClinVar (Variation ID#: 437422) and has been interpreted as likely pathogenic/pathogenic by Nilou-Genome lab, Center of Genomic medicine (Geneva, University Hospital of Geneva), Institute of Medical Genetics and Applied Genomics (University Hospital Tübingen), and Baylor Genetics, and as uncertain significance by GeneDx, Women's Health and Genetics/Laboratory Corporation of America, Labcorp Genetics (formerly Invitae), and Counsyl. Of the two affected individuals, both were compound heterozygotes that carried a reported pathogenic/likely pathogenic variant in trans which increases the likelihood that the p.Arg262His variant is pathogenic (Variation ID: 208584, 2792; PMID: 33332610, 33820833). 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 autosomal recessive GSD IV. ACMG/AMP Criteria applied: PP3_moderate, PM3_strong, PM2_supporting (Richards 2015). -

Adult polyglucosan body disease

Pathogenic:3

Feb 08, 2024

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 19, 2025

Institute of Human Genetics, University of Leipzig Medical Center

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Criteria applied: PM1,PM3,PM5,PM2_SUP,PP3; comp-het with c.760A>G, p.(Thr254Ala) -

Nov 15, 2016

Center of Genomic medicine, Geneva, University Hospital of Geneva

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This heterozygous variant in the GBE1 gene (autosomal recessive transmission), inherited from the father, was present in a female patient who also harbours a second variant in the same codon of the same gene inherited by the mother (compound heterozygosity). -

not specified

Uncertain:1

Dec 09, 2022

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: GBE1 c.785G>A (p.Arg262His) results in a non-conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 3e-05 in 234522 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.785G>A in individuals affected with Glycogen Storage Disease, Type IV and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments. Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided

Uncertain:1

May 15, 2019

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge -

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

Uncertain:1

Jun 10, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 262 of the GBE1 protein (p.Arg262His). This variant is present in population databases (rs369574719, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with GBE1-related conditions. ClinVar contains an entry for this variant (Variation ID: 437422). 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: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available"). 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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.46

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.38

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.88

D;D

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

1.0

D;D

M_CAP

Pathogenic

0.33

MetaRNN

Pathogenic

0.94

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.6

M;.

PhyloP100

7.5

PrimateAI

Uncertain

0.76

PROVEAN

Pathogenic

-4.8

D;D

REVEL

Pathogenic

0.90

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;D

Vest4

0.94

MVP

0.97

MPC

0.25

ClinPred

0.94

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.89

gMVP

0.88

Mutation Taster

=4/96

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over