3-81642787-T-G

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 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 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:19O:1

Conservation

PhyloP100: 7.55

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 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 Lovd as [Pathogenic].

PP3

Multiple lines of computational evidence support a deleterious effect 10: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Eigen, M_CAP, MutationAssessor, phyloP100way_vertebrate, PROVEAN, 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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GBE1	NM_000158.4 link	c.986A>C	p.Tyr329Ser	missense_variant	Exon 7 of 16	ENST00000429644.7	NP_000149.4	Q04446Q59ET0
GBE1	XR_007095662.1 link	n.1114A>C		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.986A>C	p.Tyr329Ser	missense_variant	Exon 7 of 16	1	NM_000158.4	ENSP00000410833.2	Q04446
GBE1	ENST00000489715.1 link	c.863A>C	p.Tyr288Ser	missense_variant	Exon 7 of 16	2		ENSP00000419638.1	E9PGM4
GBE1	ENST00000498468.1 link	n.536A>C		non_coding_transcript_exon_variant	Exon 4 of 4	3

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

GnomAD3 exomes

AF:

0.000318

AC:

AN:

248464

Hom.:

AF XY:

0.000341

AC XY:

AN XY:

134792

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 SAS 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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00708

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000273

Gnomad4 OTH exome

AF:

0.000535

GnomAD4 genome

AF:

0.000191

AC:

AN:

151990

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74236

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00693

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000747

Hom.:

Bravo

AF:

0.000219

ExAC

AF:

0.000257

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:19Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glycogen storage disease, type IV

Pathogenic:5Other:1

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. -

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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. -

Mar 25, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

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

- -

not provided

Pathogenic:5

Jan 27, 2017

Eurofins Ntd Llc (ga)

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) -

Jan 09, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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 -

Adult polyglucosan body disease

Pathogenic:4

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

- -

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). -

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). -

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

- -

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.84

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.77

D;T

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Pathogenic

0.50

MetaRNN

Benign

0.28

T;T

MetaSVM

Pathogenic

0.99

MutationAssessor

Pathogenic

3.6

H;.

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-8.4

D;D

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over