chr3-81578000-G-A

Variant names:

• chr3-81578000-G-A
• rs80338672
• NM_000158.4:c.1543C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_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. 14/23 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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: 9.58

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]

ACMG classification

Our verdict: Pathogenic. The variant received 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 rank	MANE	Protein	UniProt
GBE1	NM_000158.4	c.1543C>T	p.Arg515Cys	missense_variant	Exon 12 of 16	ENST00000429644.7	NP_000149.4
GBE1	XR_007095662.1	n.1671C>T		non_coding_transcript_exon_variant	Exon 12 of 15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GBE1	ENST00000429644.7	c.1543C>T	p.Arg515Cys	missense_variant	Exon 12 of 16	1	NM_000158.4	ENSP00000410833.2
GBE1	ENST00000489715.1	c.1420C>T	p.Arg474Cys	missense_variant	Exon 12 of 16	2		ENSP00000419638.1
GBE1	ENST00000484687.1	n.-57C>T		upstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151886 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.0000370 AC: 9 AN: 243364 AF XY: 0.0000378

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000449

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000824 AC: 12 AN: 1456618 Hom.: 0 Cov.: 31 AF XY: 0.00000828 AC XY: 6 AN XY: 724450

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33142

Gnomad4 AMR exome AF: 0.000114 AC: 5 AN: 43788

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26062

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39360

Gnomad4 SAS exome AF: 0.0000118 AC: 1 AN: 85036

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53318

Gnomad4 NFE exome AF: 0.00000450 AC: 5 AN: 1109926

Gnomad4 Remaining exome AF: 0.0000166 AC: 1 AN: 60226

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151886 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74162

Gnomad4 AFR AF: 0.00 AC: 0 AN: 0

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.000208 AC: 0.000207814 AN: 0.000207814

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.00 AC: 0 AN: 0

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.00000459 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000496 AC: 6

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycogen storage disease, type IV Pathogenic:4 Other:1

Mar 24, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 08, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Mar 30, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

May 05, 2025

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.Arg515Cys variant in GBE1 has been reported in at least 2 individuals with glycogen storage disease type IV (GSD IV) (PMID: 25356970, 20058079, 26147564), and has been identified in 0.008% (5/59026) of Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs80338672). 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 (VCV000002779.18) and has been interpreted as pathogenic/likely pathogenic by multiple submitters. Of the two affected individuals, one was a compound heterozygote that carried reported pathogenic/likely pathogenic variant in trans, which increases the likelihood that the p.Arg515Cys variant is pathogenic (VCV000224994.11;PMID: 26147564). In vitro functional studies provide some evidence that the p.Arg515Cys variant may slightly impact protein function (PMID: 8613547). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Two additional likely pathogenic variants, resulting in a different amino acid change at the same position, Arg515His and p.Arg515Gly, have been reported in association with disease in ClinVar, supporting that a change at this position may not be tolerated (VCV000180651.22, VCV002930057.2). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive GSD IV. ACMG/AMP Criteria applied: PP3_moderate, PM5, PM2_supporting, PM3, PS3_supporting (Richards 2015). -

Glycogen storage disease IV, classic hepatic Pathogenic:1

Feb 15, 1996

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Inborn genetic diseases Pathogenic:1

Aug 30, 2013

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Glycogen storage disease, type IV;C1856301:Glycogen storage disease IV, classic hepatic Pathogenic:1

Nov 05, 2023

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 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	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.87	D;T
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.4	H;.
PrimateAI	Pathogenic	0.79	T
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	D
GERP RS		5.8
Varity_R		0.84
gMVP		0.93
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs80338672; hg19: chr3-81627151;