chr3-81535246-T-C

Position:

chr3-81535246-T-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_000158.4(GBE1):c.1883A>G(p.His628Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000931 in 1,611,390 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 Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

GBE1
NM_000158.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 7.58

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 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.97

PP5

Variant 3-81535246-T-C is Pathogenic according to our data. Variant chr3-81535246-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2788.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GBE1	NM_000158.4 linkuse as main transcript	c.1883A>G	p.His628Arg	missense_variant	14/16	ENST00000429644.7	NP_000149.4
GBE1	XR_007095662.1 linkuse as main transcript	n.2011A>G		non_coding_transcript_exon_variant	14/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
GBE1	ENST00000429644.7 linkuse as main transcript	c.1883A>G	p.His628Arg	missense_variant	14/16	1	NM_000158.4	ENSP00000410833	P1
GBE1	ENST00000489715.1 linkuse as main transcript	c.1760A>G	p.His587Arg	missense_variant	14/16	2		ENSP00000419638
GBE1	ENST00000484687.1 linkuse as main transcript	n.284A>G		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151890

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000405

AC:

AN:

247212

Hom.:

AF XY:

0.00000745

AC XY:

AN XY:

134168

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000891

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000891

AC:

AN:

1459500

Hom.:

Cov.:

AF XY:

0.00000689

AC XY:

AN XY:

726044

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000108

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151890

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74188

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000326

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.00000827

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000594

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glycogen storage disease, type IV

Pathogenic:5

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 05, 2024	- -
Likely pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 27, 2022	The p.His628Arg variant in GBE1 has been reported in at least 4 individuals with glycogen storage disease type IV (GSD IV) (PMID: 15452297, 26886200, 33332610, 33473341) and has been identified in 0.0009% (1/112290) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs137852891). 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. Of the 4 affected individuals, 1 was a compound heterozygote that carried a likely pathogenic variant in trans, and 2 were compound heterozygotes that carried reported pathogenic variants with unknown phase, which increases the likelihood that the p.His628Arg variant is pathogenic (VariationID: 208584, 2781; PMID: 26886200, 33332610, 15452297). This variant has also been reported in ClinVar (Variation ID#: 2788) and has been interpreted as pathogenic by CeGaT Praxis fuer Humangenetik Tuebingen, OMIM, and GeneReviews and as a variant of uncertain significance by Illumina Clinical Services Laboratory (Illumina). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The phenotype of an individual compound heterozygous for this variant is highly specific for GSD IV based on strict biochemical investigations consistent with disease (PMID: 15452297). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for GSD IV. ACMG/AMP Criteria applied: PP3, PM3_strong, PM2_supporting, PP4 (Richards 2015). -
Pathogenic, no assertion criteria provided	curation	GeneReviews	Apr 02, 2009	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 07, 2021	Variant summary: GBE1 c.1883A>G (p.His628Arg) results in a non-conservative amino acid change located in the Alpha-amylase/branching enzyme, C-terminal all beta domain (IPR006048) 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 4e-06 in 247212 control chromosomes. c.1883A>G has been reported in the literature as a compound heterozygous genotype in individuals affected with Glycogen Storage Disease, Type IV (example, Bruno_2004, Kuhn_2016, Yubero_2016, Derks_2021). These data indicate that the variant is likely to be associated with disease. To our knowledge, no variant specific experimental evidence demonstrating an impact on protein function has been reported although some of the affected compound heterozygous individuals mentioned above were reported to have a deficiency of branching enzyme activity. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Sep 05, 2024	- -

not provided

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 24, 2023	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 15452297, 17915577, 26199317, 33473341, 29379554, 20058079, 33332610, 22305237, 27243974, 26886200) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2017	- -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 05, 2023

This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 628 of the GBE1 protein (p.His628Arg). This variant is present in population databases (rs137852891, gnomAD 0.0009%). This missense change has been observed in individual(s) with glycogen storage disease (PMID: 15452297, 26886200, 27243974, 33332610). 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: 2788). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GBE1 protein function. For these reasons, this variant has been classified as Pathogenic. -

Glycogen storage disease due to glycogen branching enzyme deficiency, childhood neuromuscular form

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 28, 2004

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.83

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.37

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.88

D;D

Eigen

Pathogenic

0.96

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Uncertain

0.22

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Uncertain

0.75

MutationAssessor

Pathogenic

4.0

H;.

MutationTaster

Benign

1.0

A;A

PrimateAI

Uncertain

0.57

PROVEAN

Pathogenic

-7.2

D;D

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;D

Vest4

0.97

MutPred

0.86

Gain of glycosylation at Y633 (P = 0.0647);.;

MVP

0.93

MPC

0.26

ClinPred

1.0

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.98

gMVP

0.87

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