rs80338672

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000158.4(GBE1):c.1543C>T(p.Arg515Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000808 in 1,608,504 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R515H) has been classified as Likely pathogenic.

Frequency

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

Exomes 𝑓: 0.0000082 ( 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: 9.58

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 18 ACMG points.

PM1

In a helix (size 19) in uniprot entity GLGB_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) 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 chr3-81577999-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 180651.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.949

PP5

Variant 3-81578000-G-A is Pathogenic according to our data. Variant chr3-81578000-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2779.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GBE1	NM_000158.4 linkuse as main transcript	c.1543C>T	p.Arg515Cys	missense_variant	12/16	ENST00000429644.7
GBE1	XR_007095662.1 linkuse as main transcript	n.1671C>T		non_coding_transcript_exon_variant	12/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GBE1	ENST00000429644.7 linkuse as main transcript	c.1543C>T	p.Arg515Cys	missense_variant	12/16	1	NM_000158.4	P1
GBE1	ENST00000489715.1 linkuse as main transcript	c.1420C>T	p.Arg474Cys	missense_variant	12/16	2

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151886

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:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000370

AC:

AN:

243364

Hom.:

AF XY:

0.0000378

AC XY:

AN XY:

132170

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000123

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:

0.0000449

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000824

AC:

AN:

1456618

Hom.:

Cov.:

AF XY:

0.00000828

AC XY:

AN XY:

724450

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000114

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:

0.00000450

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151886

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74162

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:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000324

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000496

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

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 17, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Mar 30, 2023	This sequence change is predicted to replace arginine with cysteine at codon 515 of the GBE1 protein, p.(Arg515Cys). The arginine residue is highly conserved (100 vertebrates, UCSC), and is located within a helical region in the catalytic domain (PMID: 26199317). There is a large physicochemical difference between arginine and cysteine. The variant is present in a large population cohort at a frequency of 0.004%, which is consistent with recessive disease (rs80338672, 9/243,364 alleles, 0 homozygotes in gnomAD v2.1). It has been identified compound heterozygous with a second pathogenic allele or suspected compound heterozygous in cases with the fatal perinatal neuromuscular form or infantile classic hepatic phenotype of glycogen storage disorder type IV. Further, there was biochemical confirmation of the diagnosis in the cases with the classic hepatic phenotype, through the measurement of branching enzyme activity in patient fibroblasts (PMID: 8613547, 20058079, 26147564). Reduced enzymatic activity of the variant has also been demonstrated in in vitro functional studies (PMID: 8613547). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (7/7 algorithms). Additionally, a different missense change (p.Arg515His) at the same position, determined to be pathogenic has been identified in adult polyglucosan body disease (PMID: 10762170). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PM2, PM3, PM5, PS3_Supporting, PP3, PP4. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 08, 2021	Variant summary: GBE1 c.1543C>T (p.Arg515Cys) results in a non-conservative amino acid change located in the Glycosyl hydrolase, family 13, catalytic domain 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 3.7e-05 in 243364 control chromosomes. c.1543C>T has been reported in the literature in individuals affected with Glycogen Storage Disease, Type IV (Bao_1996, Li_2010, Farwell_2015). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 10%-<30% of normal activity (Bao_1996). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic. In addition, p.R515H has been reported to associate with the disease too. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Glycogen storage disease IV, classic hepatic

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 15, 1996

- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 30, 2013

- -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 05, 2023

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 515 of the GBE1 protein (p.Arg515Cys). This variant is present in population databases (rs80338672, gnomAD 0.01%). This missense change has been observed in individual(s) with glycogen storage disease, also known as polyglucosan body myopathy (PMID: 8613547, 11949934). ClinVar contains an entry for this variant (Variation ID: 2779). 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%. Experimental studies have shown that this missense change affects GBE1 function (PMID: 8613547). This variant disrupts the p.Arg515 amino acid residue in GBE1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10762170, 24248152). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.74

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.44

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Pathogenic

0.87

D;T

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

D;D

M_CAP

Pathogenic

0.42

MetaRNN

Pathogenic

0.95

D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.4

H;.

MutationTaster

Benign

1.0

A;A

PrimateAI

Pathogenic

0.79

PROVEAN

Pathogenic

-7.9

D;D

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.98

MVP

0.98

MPC

0.27

ClinPred

1.0

GERP RS

5.8

Varity_R

0.84

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