3-81577972-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_000158.4(GBE1):c.1571G>A(p.Arg524Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000756 in 1,455,954 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: not found (cov: 32)

Exomes 𝑓: 0.0000076 ( 0 hom. )

Consequence

GBE1
NM_000158.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6O: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;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.93

PP5

Variant 3-81577972-C-T is Pathogenic according to our data. Variant chr3-81577972-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-81577972-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GBE1	NM_000158.4 link	c.1571G>A	p.Arg524Gln	missense_variant	Exon 12 of 16	ENST00000429644.7	NP_000149.4	Q04446Q59ET0
GBE1	XR_007095662.1 link	n.1699G>A		non_coding_transcript_exon_variant	Exon 12 of 15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GBE1	ENST00000429644.7 link	c.1571G>A	p.Arg524Gln	missense_variant	Exon 12 of 16	1	NM_000158.4	ENSP00000410833.2	Q04446
GBE1	ENST00000489715.1 link	c.1448G>A	p.Arg483Gln	missense_variant	Exon 12 of 16	2		ENSP00000419638.1	E9PGM4
GBE1	ENST00000484687.1 link	n.-29G>A		upstream_gene_variant		2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000164

AC:

AN:

243710

Hom.:

AF XY:

0.0000227

AC XY:

AN XY:

132376

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:

0.0000338

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000269

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000756

AC:

AN:

1455954

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

724096

show subpopulations

Gnomad4 AFR exome

AF:

0.0000302

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000118

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000721

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000222

Hom.:

ExAC

AF:

0.0000331

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glycogen storage disease, type IV

Pathogenic:3Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Jan 29, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 31, 2023

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.1571G>A (p.Arg524Gln) results in a conservative amino acid change to a highly conserved residue (HGMD) located in the Glycosyl hydrolase, family 13, catalytic domain (IPR006047) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 243710 control chromosomes (gnomAD). c.1571G>A has been reported in the literature in multiple individuals affected with Glycogen Storage Disease, Type IV (Bruno_2004, Ziemssen_2000, Ban_2009, Derks_2021, Stranneheim_2021, Sindern_2003, Westra_2019), and some were reported as compound heterozygous with other (likely) pathogenic variants. These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 15452297, 10762170, 20479904, 33332610, 33726816, 12874416, 31127727). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

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.Arg524Gln variant in GBE1 has been reported in 6 individuals with GBE1-related disorders (PMID: 10762170, 15452297, 20479904, 33332610, 33726816, Pan 2017) and has been identified in 0.004% (1/23800) of African/African American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs80338673). 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 6 affected individuals, 1 was a compound heterozygotes that carried a reported likely pathogenic variants in trans, 1 was a homozygote, and 1 was a compound heterozygote that carried a reported pathogenic variant with unknown phase, which increases the likelihood that the p.Arg524Gln variant is pathogenic (VariationID: 2789, 208584; PMID: 15452297, 33726816). This variant has also been reported in ClinVar (Variation ID#: 2782) and has been interpreted as pathogenic by Invitae, OMIM, and GeneReviews. 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 GBE1-related disorders. ACMG/AMP Criteria applied: PP3, PM3_strong, PM2_supporting (Richards 2015). -

Glycogen storage disease IV, combined hepatic and myopathic

Pathogenic:1

Sep 28, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Adult polyglucosan body neuropathy

Pathogenic:1

Sep 28, 2004

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

Jan 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 524 of the GBE1 protein (p.Arg524Gln). This variant is present in population databases (rs80338673, gnomAD 0.007%). This missense change has been observed in individual(s) with glycogen storage disease IV (PMID: 10545044, 10762170, 12874416, 15452297, 20479904). 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: 2782). 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) performed at Invitae indicates that this missense variant is expected to disrupt GBE1 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.57

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.48

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.83

D;T

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.93

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

1.0

D;D

M_CAP

Pathogenic

0.46

MetaRNN

Pathogenic

0.93

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.0

H;.

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-3.7

D;D

REVEL

Pathogenic

0.91

Sift

Uncertain

0.0050

D;D

Sift4G

Uncertain

0.0060

D;D

Polyphen

1.0

D;D

Vest4

0.95

MutPred

0.79

Loss of glycosylation at K521 (P = 0.0429);.;

MVP

0.97

MPC

0.25

ClinPred

0.93

GERP RS

5.8

Varity_R

0.80

gMVP

0.94

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