rs772802187

Positions:

• chr3-81535304-C-A
• chr3-81535304-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000158.4(GBE1):​c.1825G>T​(p.Glu609*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000343 in 1,457,218 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 (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: GBE1 NM_000158.4 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 5.68

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-81535304-C-A is Pathogenic according to our data. Variant chr3-81535304-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1341385.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GBE1	NM_000158.4	c.1825G>T	p.Glu609*	stop_gained	14/16	ENST00000429644.7	NP_000149.4
GBE1	XR_007095662.1	n.1953G>T		non_coding_transcript_exon_variant	14/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GBE1	ENST00000429644.7	c.1825G>T	p.Glu609*	stop_gained	14/16	1	NM_000158.4	ENSP00000410833.2
GBE1	ENST00000489715.1	c.1702G>T	p.Glu568*	stop_gained	14/16	2		ENSP00000419638.1
GBE1	ENST00000484687.1	n.226G>T		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000123 AC: 3 AN: 244706 Hom.: 0 AF XY: 0.0000151 AC XY: 2 AN XY: 132812

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000899

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000343 AC: 5 AN: 1457218 Hom.: 0 Cov.: 31 AF XY: 0.00000414 AC XY: 3 AN XY: 724888

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000907

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.0000166 AC: 2

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycogen storage disease, type IV Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 20, 2023	- -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 27, 2022	The p.Glu609Ter variant in GBE1 has not been previously reported in the literature in individuals with GBE1-related disorders but has been identified in 0.009% (3/33374) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs772802187). 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. Animal models in mice have shown that this variant causes GBE1-related disorder (PMID: 21075835). This nonsense variant leads to a premature termination codon at position 609, which is predicted to lead to a truncated or absent protein. Loss of function of the GBE1 gene is an established disease mechanism in autosomal recessive GBE1-related disorders. In summary, this variant meets criteria to be classified as pathogenic for GBE1-related disorders. ACMG/AMP Criteria applied: PVS1, PM2_supporting, PS3 (Richards 2015). -

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

Oct 14, 2023

This sequence change creates a premature translational stop signal (p.Glu609*) in the GBE1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GBE1 are known to be pathogenic (PMID: 15452297, 20058079). This variant is present in population databases (rs772802187, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with GBE1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1341385). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects GBE1 function (PMID: 21075835). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.98	D
Vest4		0.94
GERP RS		5.5

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.32		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.32		Position offset: 21

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs772802187; hg19: chr3-81584455;