rs192044702

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000158.4(GBE1):c.691+2T>C variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00101 in 1,502,074 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.00076 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0010 ( 0 hom. )

Consequence

GBE1
NM_000158.4 splice_donor

Scores

Splicing: ADA: 0.9964

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:30

Conservation

PhyloP100: 8.95

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 18 ACMG points.

PVS1

Splicing variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 3-81648854-A-G is Pathogenic according to our data. Variant chr3-81648854-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 208584.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-81648854-A-G is described in Lovd as [Pathogenic]. Variant chr3-81648854-A-G is described in Lovd as [Pathogenic]. Variant chr3-81648854-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GBE1	NM_000158.4 linkuse as main transcript	c.691+2T>C		splice_donor_variant		ENST00000429644.7
GBE1	XR_007095662.1 linkuse as main transcript	n.819+2T>C		splice_donor_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Appris
GBE1	ENST00000429644.7 linkuse as main transcript	c.691+2T>C	splice_donor_variant	1	NM_000158.4	P1
GBE1	ENST00000489715.1 linkuse as main transcript	c.568+2T>C	splice_donor_variant	2
GBE1	ENST00000498468.1 linkuse as main transcript	n.219+2T>C	splice_donor_variant, non_coding_transcript_variant	3

Frequencies

GnomAD3 genomes

AF:

0.000756

AC:

115

AN:

152098

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00141

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000895

AC:

173

AN:

193326

Hom.:

AF XY:

0.000797

AC XY:

AN XY:

106636

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000999

Gnomad ASJ exome

AF:

0.000259

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000971

Gnomad NFE exome

AF:

0.00152

Gnomad OTH exome

AF:

0.00117

GnomAD4 exome

AF:

0.00103

AC:

1396

AN:

1349858

Hom.:

Cov.:

AF XY:

0.000989

AC XY:

661

AN XY:

668278

show subpopulations

Gnomad4 AFR exome

AF:

0.0000713

Gnomad4 AMR exome

AF:

0.0000668

Gnomad4 ASJ exome

AF:

0.000300

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000831

Gnomad4 NFE exome

AF:

0.00125

Gnomad4 OTH exome

AF:

0.000501

GnomAD4 genome

AF:

0.000756

AC:

115

AN:

152216

Hom.:

Cov.:

AF XY:

0.000605

AC XY:

AN XY:

74402

show subpopulations

Gnomad4 AFR

AF:

0.000240

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000377

Gnomad4 NFE

AF:

0.00141

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000770

Hom.:

Bravo

AF:

0.000654

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00160

AC:

ExAC

AF:

0.000936

AC:

113

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:30

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:14

Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Mar 05, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 21, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 27, 2022	Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 23352160, 19813197, 23218673, 25489661, 26166723, 28507268, 30569318, 31980526, 31862442, 29379554, 31589614, 33726816, 32528171, 33332610, 31127727, 32668698, 34426522) -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 27, 2021	PVS1, PS3, PS4_moderate, PP1, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 02, 2016	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 04, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	GBE1: PVS1, PM2, PM3 -

Glycogen storage disease, type IV

Pathogenic:9

Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 19, 2020	Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with glycogen storage disease IV (GSD-IV) (MIM#232500) and adult form polyglucosan body disease (MIM#263570). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0211 - Canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (194 heterozygotes, 0 homozygotes). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0704 - Another splice variant comparable to the one identified in this case has limited previous evidence for pathogenicity. This splice variant (c.691+5G>C) has been reported as pathogenic and in a homozygous patient with GSD-IV (ClinVar, PMID: 17662246). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic in multiple patients with either GSD-IV or adult form polyglucosan body disease (LOVD, ClinVar, PMID: 29379554). (SP) 1201 - Heterozygous variant detected in trans with a second likely pathogenic heterozygous variant (p.(Gln236His)) in a recessive disease. (SP) 1205 - This variant has been shown to be maternally inherited (PathWest). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Aug 22, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 27, 2021	Variant summary: GBE1 c.691+2T>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: four predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00089 in 193326 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in GBE1 causing Glycogen Storage Disease, Type IV (0.00089 vs 0.0013), allowing no conclusion about variant significance. c.691+2T>C has been reported in the literature in several compound heterozygous individuals affected with Glycogen Storage Disease, Type IV (e.g. Fernandez_2010, Ravenscroft_2013, Bendroth-Asmussen_2016, Schene_2018, Szymanska_2018). These data indicate that the variant is likely to be associated with disease. Several publications also reported severely reduced enzyme activities in patient derived cells (e.g. Fernandez_2010, Ravenscroft_2013, Schene_2018, Szymanska_2018). 13 submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, and all of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Feb 03, 2020	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP5. -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 27, 2022	The c.691+2T>C variant in GBE1 has been reported in at least 10 individuals with GBE1-related disorders (PMID: 19813197, 23218673, 25489661, 26166723, 26886200, 28507268, 29379554, 30569318, Akman 2015, Thomsen 2016) and has been identified in 0.1% (160/110918) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs192044702). 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. Of the many affected individuals, 1 was a compound heterozygote that carried a reported likely pathogenic variant in trans, and 2 were compound heterozygotes that carried a reported pathogenic variant with unknown phase, which increases the likelihood that the c.691+2T>C variant is pathogenic (Variation ID#: 2777; PMID: 25489661, 28507268, Akman 2015). This variant has also been reported in ClinVar (Variation ID#: 208584) and has been interpreted as pathogenic by multiple submitters. The phenotype of individuals homozygous or compound heterozygous for this variant is highly specific for GBE1-related disorders based on strict biochemical investigations consistent with disease (PMID: 19813197, 23218673). This variant is located in the 3' splice region. Computational tools predict a splicing impact, though this information is not predictive enough to determine pathogenicity. Loss of function of the GBE1 gene is an established disease mechanism in autosomal recessive GBE1-related disorders. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive GBE1-related disorders. ACMG/AMP Criteria applied: PVS1, PM3_strong, PP4 (Richards 2015). -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	Dec 06, 2018	This variant affects the canonical splice donor site of intron 5 of 15, and is therefore predicted to interfere with splicing and result in loss of normal protein function. This variant has been previously reported as a compound heterozygous change in patients with GBE1 glycogen storage disease (PMID: 23218673, 19813197). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.082% (183/223430; max AF: 0.0013 in European populations) and thus is presumed to be rare. Multiple splice prediction tools suggest this variant is likely to interfere with normal splicing. Based on the available evidence, the c.691+2T>C variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Aug 03, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 13, 2023	- -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 10, 2022

- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 20, 2024

The c.691+2T>C intronic alteration results from a T to C substitution two nucleotides after coding exon 5 of the GBE1 gene. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay; however, +2T>C alterations are capable of generating wild-type transcripts in some genomic contexts and should be interpreted with caution (Lin, 2019). Based on data from gnomAD, the C allele has an overall frequency of 0.086% (194/224704) total alleles studied. The highest observed frequency was 0.144% (160/110918) of European (non-Finnish) alleles. This variant has been identified in the homozygous state and likely in trans with another GBE1 variant in multiple individuals and fetuses with features consistent with neuromuscular subtypes of GBE1-related glycogen storage disease, including biochemical or histological confirmation (Fernandez, 2010; Ravenscroft, 2013; Bendroth-Asmussen, 2016; Schene, 2019; Lefèvre, 2023). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the available evidence, this alteration is classified as pathogenic. -

Glycogen storage disease

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 16, 2020

The c.691+2T>C variant in GBE1 has been reported in at least 3 compound heterozygous individuals with glycogen storage disease IV and segregated with disease in at least 2 affected relatives from 1 family (Fernandez 2010 PMID:19813197, Ravenscroft 2013 PMID:23218673, Schene 2018 PMID:30569318). It has also been reported in ClinVar (Variation ID 208584) and has been identified in 0.14% (160/110918) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. Loss of function of the GBE1 gene is an established disease mechanism in autosomal recessive glycogen storage disease IV. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive glycogen storage disease IV. ACMG/AMP Criteria applied: PVS1, PM3_Strong, PP1_Moderate. -

Adult polyglucosan body disease

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Sep 28, 2023

Criteria applied: PVS1,PM3_VSTR,PM2_SUP -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

This sequence change affects a donor splice site in intron 5 of the GBE1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in GBE1 are known to be pathogenic (PMID: 15452297, 20058079). This variant is present in population databases (rs192044702, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. Disruption of this splice site has been observed in individual(s) with glycogen storage disease type IV (PMID: 19813197, 23218673, 26166723, 30569318). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 208584). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

GBE1-related condition

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 01, 2023

The GBE1 c.691+2T>C variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant has been reported in the compound heterozygous state in two presumably unrelated families, one of which included siblings initially diagnosed with lethal multiple pterygium syndrome (Fernandez et al. 2010. PubMed ID: 19813197; Ravenscroft et al. 2013. PubMed ID: 23218673). More recently, this variant was identified in the compound heterozygous state with a second pathogenic GBE1 variant in tissue from a fetus lost in a first trimester miscarriage. Histopathological findings in the fetal tissue were consistent with glycogen storage disease type IV (GSD IV) (Bendroth-Asmussen et al. 2016. PubMed ID: 26166723). At PreventionGenetics, we have observed this variant in combination with a second pathogenic variant in at least two unrelated affected patients. This variant is reported in 0.14% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-81698005-A-G). Variants that disrupt the consensus splice donor site in GBE1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

GBE1-Related Disorders

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Oct 13, 2017

The GBE1 c.691+2T>C splice donor variant has been reported in a total of seven individuals, including five with glycogen storage disease type IV (GSD IV) and two with adult polyglucosan body disease (APBD) (Fernandez et al. 2010; Ravenscroft et al. 2013; Bendroth-Asmussen et al. 2016; Kuhn et al. 2016; Franco-Palacios et al. 2016; Lopez Chiriboga 2017). All five individuals with GSD IV and one individual with APBD were compound heterozygous for the variant. In addition, one individual with APBD was heterozygous for the c.691+2T>C variant and homozygous for another intronic variant in the GBE1 gene (Franco-Palacios et al. 2016). The c.691+2T>C variant was also identified in a heterozygous state in two unaffected individuals (Ravenscroft et al. 2013; Dainese et al. 2014). Control data are unavailable for this variant, which is reported at a frequency of 0.00196 in the European (non-Finnish) population of the Exome Aggregation Consortium. Two studies noted significantly reduced GBE enzyme activity in individual fibroblasts (Fernandez et al. 2010; Ravenscroft et al. 2013). Based on the evidence and due to the potential impact of splice donor variants, the p.691+2T>C 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.082

BayesDel_noAF

Pathogenic

0.32

Cadd

Pathogenic

Dann

Uncertain

0.99

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.1

FATHMM_MKL

Pathogenic

0.99

MutationTaster

Benign

1.0

D;D

GERP RS

6.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Benign

0.69

SpliceAI score (max)

0.94

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.94

Position offset: 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