rs137852887

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.771T>A(p.Phe257Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000314 in 1,594,282 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. F257S) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

GBE1
NM_000158.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7U:1

Conservation

PhyloP100: 3.33

Publications

6 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 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 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 chr3-81646404-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 801988.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.961

PP5

Variant 3-81646403-A-T is Pathogenic according to our data. Variant chr3-81646403-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2780.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GBE1	NM_000158.4 link	c.771T>A	p.Phe257Leu	missense_variant	Exon 6 of 16	ENST00000429644.7	NP_000149.4	Q04446Q59ET0
GBE1	XR_007095662.1 link	n.899T>A		non_coding_transcript_exon_variant	Exon 6 of 15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GBE1	ENST00000429644.7 link	c.771T>A	p.Phe257Leu	missense_variant	Exon 6 of 16	1	NM_000158.4	ENSP00000410833.2	Q04446
GBE1	ENST00000489715.1 link	c.648T>A	p.Phe216Leu	missense_variant	Exon 6 of 16	2		ENSP00000419638.1	E9PGM4
GBE1	ENST00000498468.1 link	n.321T>A		non_coding_transcript_exon_variant	Exon 3 of 4	3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000424

AC:

AN:

236032

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000913

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000277

AC:

AN:

1442054

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

717038

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32434

American (AMR)

AF:

0.00

AC:

AN:

41116

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25812

East Asian (EAS)

AF:

0.00

AC:

AN:

39424

South Asian (SAS)

AF:

0.00

AC:

AN:

81854

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53318

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5738

European-Non Finnish (NFE)

AF:

0.00000363

AC:

AN:

1102598

Other (OTH)

AF:

0.00

AC:

AN:

59760

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

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:

0.00000657

AC:

AN:

152228

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41464

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68042

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.00000756

EpiCase

AF:

0.00

EpiControl

AF:

0.0000599

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Glycogen storage disease, type IV

Pathogenic:3

Jan 27, 2022

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.Phe257Leu variant in GBE1 has been reported in 1 individual, in the compound heterozygous state, with glycogen storage disease type IV (GSD IV) (PMID: 8613547) and has been identified in 0.004% (1/23832) of African/African American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs137852887). 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#: 2780) and has been interpreted as pathogenic by OMIM, GeneDx, and GeneReviews. In vitro functional studies provide some evidence that the p.Phe257Leu variant may slightly impact protein function (PMID: 8613547). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein. 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, PM3, PM2, PS3_supporting (Richards 2015). -

Jun 05, 2023

Baylor Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 02, 2009

GeneReviews

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:curation

- -

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

Pathogenic:1

May 03, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Glycogen storage disease IV, classic hepatic

Pathogenic:1

Feb 15, 1996

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not provided

Pathogenic:1

Dec 08, 2016

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The F257L variant in the GBE1 gene has previously been reported in association with glycogen storage disorder type IV in a individual who was also compound heterozygous for a nonsense variant (Bao et al., 1996). Functional analysis of F257L found that it is associated with significantly reduced enzyme activity (Bao et al., 1996). Therefore we interpret F257L to be a pathogenic variant. -

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

Pathogenic:1

Jan 07, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 257 of the GBE1 protein (p.Phe257Leu). This variant is present in population databases (rs137852887, gnomAD 0.004%). This missense change has been observed in individual(s) with glycogen storage disease IV (PMID: 8613547). 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: 2780). 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). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

not specified

Uncertain:1

Jun 20, 2025

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.771T>A (p.Phe257Leu) results in a non-conservative amino acid change located in the Glycosyl hydrolase, family 13, catalytic domain (IPR006047) of the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.771T>A has been observed in at least one individual affected with Glycogen Storage Disease, Type IV (example: Bao_1996). This data does not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect resulted in ~27% of normal activity (example: Bao_1996). The following publication has been ascertained in the context of this evaluation (PMID: 8613547). ClinVar contains an entry for this variant (Variation ID: 2780). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.35

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.89

D;D

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Uncertain

0.27

MetaRNN

Pathogenic

0.96

D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.7

M;.

PhyloP100

3.3

PrimateAI

Pathogenic

0.81

PROVEAN

Pathogenic

-5.3

D;D

REVEL

Pathogenic

0.90

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

1.0

D;D

Vest4

0.98

MutPred

0.86

Loss of glycosylation at S261 (P = 0.1019);.;

MVP

0.93

MPC

0.24

ClinPred

0.99

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.97

gMVP

0.86

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over