rs201958741

chr3-81577999-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_000158.4(GBE1):c.1544G>A(p.Arg515His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000249 in 1,608,922 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/20 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. R515C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: GBE1 NM_000158.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 7.55

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

Verdict is Pathogenic. Variant got 16 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 chr3-81578000-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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.911
• PP5: Variant 3-81577999-C-T is Pathogenic according to our data. 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GBE1	NM_000158.4	c.1544G>A	p.Arg515His	missense_variant	12/16	ENST00000429644.7
GBE1	XR_007095662.1	n.1672G>A		non_coding_transcript_exon_variant	12/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GBE1	ENST00000429644.7	c.1544G>A	p.Arg515His	missense_variant	12/16	1	NM_000158.4	P1
GBE1	ENST00000489715.1	c.1421G>A	p.Arg474His	missense_variant	12/16	2

Frequencies

GnomAD3 genomes AF: 0.0000461 AC: 7 AN: 151966 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

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: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000328 AC: 8 AN: 243796 Hom.: 0 AF XY: 0.0000378 AC XY: 5 AN XY: 132394

Gnomad AFR exome AF: 0.0000662

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000568

Gnomad SAS exome AF: 0.0000339

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000448

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000227 AC: 33 AN: 1456956 Hom.: 0 Cov.: 31 AF XY: 0.0000248 AC XY: 18 AN XY: 724628

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000279

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000461 AC: 7 AN: 151966 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74194

Gnomad4 AFR AF: 0.0000484

Gnomad4 AMR AF: 0.0000656

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000683 Hom.: 0

Bravo AF: 0.0000378

ESP6500AA AF: 0.000256 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000414 AC: 5

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycogen storage disease, type IV Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 14, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	-	This variant has been previously reported as a homozygous or compound heterozygous change in patients with adult onset polyglucosan body disease and glycogen storage disease IV (PMID: 10762170, 12874416, 24248152, 31815882). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.004% (10/275166) and thus is presumed to be rare. The c.1544G>A (p.Arg515His) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. A different missense change at the same codon (p.Arg515Cys) has also been observed in individuals with GBE1-related conditions (PMID: 8613547), which suggests that this may be a clinically significant amino acid residue. Based on the available evidence, the c.1544G>A (p.Arg515His) variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 15, 2023	Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 10762170, 9851430, 12874416, 28716262, 24248152, 31815882, 33141444) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 03, 2016	- -

Adult polyglucosan body disease Pathogenic:1

Likely pathogenic, criteria provided, single submitter

curation

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Jan 27, 2022

The p.Arg515His variant in GBE1 has been reported in 4 individuals with adult polyglucosan body disease (APBD) (PMID: 10762170, 24248152, 31815882) and has been identified in 0.008% (2/23806) of African/African American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs201958741). 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 reported likely pathogenic variants in trans, 1 was a homozygote, and 2 were compound heterozygotes that carried variants of uncertain significance in trans, which increases the likelihood that the p.Arg515His variant is pathogenic (VariationID: 2782; PMID: 10762170, 24248152, 31815882). This variant has also been reported in ClinVar (Variation ID#: 180651) and has been interpreted as pathogenic or likely pathogenic by Invitae, OMIM, GeneDx, EGL Genetic Diagnostics (Eurofins Clinical Diagnostics), and Natera. 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 APBD. ACMG/AMP Criteria applied: PP3, PM3_strong, PM2_supporting (Richards 2015). -

See cases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Jan 12, 2022

ACMG classification criteria: PS4, PM2, PM3, PP3 -

Adult polyglucosan body neuropathy Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 2000

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 17, 2024

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 515 of the GBE1 protein (p.Arg515His). This variant is present in population databases (rs201958741, gnomAD 0.008%). This missense change has been observed in individual(s) with adult polyglucosan body disease or glycogen storage disease IV (PMID: 10762170, 24248152; Invitae). 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: 180651). 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%. This variant disrupts the p.Arg515 amino acid residue in GBE1. Other variant(s) that disrupt this residue have been observed in individuals with GBE1-related conditions (PMID: 8613547, 20058079), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

GBE1-related condition Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 23, 2023

The GBE1 c.1544G>A variant is predicted to result in the amino acid substitution p.Arg515His. This variant has been reported, in the homozygous or compound heterozygous state, in patients with clinical features consistent with later-onset glycogen storage disease type IV (GSD IV) or adult polyglucosan body disease (APBD), and reduced glycogen branching enzyme activity in various tested cell types (Ziemssen et al. 2000. PubMed ID: 10762170; Sindern et al. 2003. PubMed ID: 12874416; Billot et al. 2013. PubMed ID: 23146612; Paradas et al. 2014. PubMed ID: 24248152). It has also been reported, along with the known pathogenic c.986A>C (p.Tyr329Ser) variant, in a patient with features consistent with hereditary spastic paraplegia (Souza et al. 2017. PubMed ID: 28716262). To our knowledge, the c.1544G>A (p.Arg515His) variant has not been reported in patients with infantile onset GSD IV, although a different substitution of the same amino acid (p.Arg515Cys) has been reported in patients with infantile onset GSD IV (Bao et al. 1996. PubMed ID: 8613547; Li et al. 2010. PubMed ID: 20058079). Internally, we have observed the c.1544G>A variant in the compound heterozygous state with a rare GBE1 variant of uncertain significance in a patient with a liver biopsy suggestive of GSD IV. This variant is reported in 0.0084% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-81627150-C-T). This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.40
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.79	D;T
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.91	D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	4.0	H;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-4.9	D;D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.012	D;D
Sift4G	Uncertain	0.0060	D;D
Polyphen		1.0	D;D
Vest4		0.94
MVP		0.97
MPC		0.26
ClinPred		0.92	D
GERP RS		5.8
Varity_R		0.56
gMVP		0.91

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: rs201958741; hg19: chr3-81627150;