3-81577972-C-T

Position:

• chr3-81577972-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6 O:1
• 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 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/exons	MANE	Protein	UniProt
GBE1	NM_000158.4	c.1571G>A	p.Arg524Gln	missense_variant	12/16	ENST00000429644.7	NP_000149.4
GBE1	XR_007095662.1	n.1699G>A		non_coding_transcript_exon_variant	12/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GBE1	ENST00000429644.7	c.1571G>A	p.Arg524Gln	missense_variant	12/16	1	NM_000158.4	ENSP00000410833	P1
GBE1	ENST00000489715.1	c.1448G>A	p.Arg483Gln	missense_variant	12/16	2		ENSP00000419638
GBE1	ENST00000484687.1			upstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000164 AC: 4 AN: 243710 Hom.: 0 AF XY: 0.0000227 AC XY: 3 AN XY: 132376

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: 11 AN: 1455954 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9 AN XY: 724096

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.: 32

Alfa AF: 0.0000222 Hom.: 0

ExAC AF: 0.0000331 AC: 4

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycogen storage disease, type IV Pathogenic:3 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 31, 2023	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. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Likely pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 27, 2022	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). -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 29, 2024	- -

Glycogen storage disease IV, combined hepatic and myopathic Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 28, 2004

- -

Adult polyglucosan body neuropathy Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 28, 2004

- -

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

Jan 02, 2024

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	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.83	D;T
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.0	H;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.76	T
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	D
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

Other links and lift over

dbSNP: rs80338673; hg19: chr3-81627123; COSMIC: COSV70099315; COSMIC: COSV70099315;