rs869320698

Variant names:

• chr3-81493813-CCACCACAC-ACCTGTAATGTAAAAAACA
• NM_000158.4:c.2053-3358_2053-3350delGTGTGGTGGinsTGTTTTTTACATTACAGGT

Your query was ambiguous. Multiple possible variants found:

• chr3-81493812-GCCACCACAC-GACCTGTAATGTAAAAAACA
• chr3-81493812-GCCACCACAC-GACCTGTCATGTAAAAAACA

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_000158.4(GBE1):​c.2053-3358_2053-3350delGTGTGGTGGinsTGTTTTTTACATTACAGGT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: GBE1 NM_000158.4 intron
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 0.749

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 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-81493813-CCACCACAC-ACCTGTAATGTAAAAAACA is Pathogenic according to our data. Variant chr3-81493813-CCACCACAC-ACCTGTAATGTAAAAAACA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2635394.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.2053-3358_2053-3350delGTGTGGTGGinsTGTTTTTTACATTACAGGT		intron_variant	Intron 15 of 15	ENST00000429644.7	NP_000149.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GBE1	ENST00000429644.7	c.2053-3358_2053-3350delGTGTGGTGGinsTGTTTTTTACATTACAGGT		intron_variant	Intron 15 of 15	1	NM_000158.4	ENSP00000410833.2
GBE1	ENST00000489715.1	c.1930-3358_1930-3350delGTGTGGTGGinsTGTTTTTTACATTACAGGT		intron_variant	Intron 15 of 15	2		ENSP00000419638.1

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycogen storage disease, type IV Pathogenic:1

Jan 24, 2025

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.2053-3358_2053-3350delinsTGTTTTTTACATTACAGGT is located at a deep intronic position not widely known to affect splicing, however several computational tools predict a significant impact on normal splicing: four predict the variant creates a 3' acceptor site. At least one publication reported RNA sequencing studies that a similar variant (differing by one nucleotide) resulted in an aberrant transcript in patient derived cells with the insertion of a poison exon that introduced a frameshift (Akman_2015). A similar variant allele was found at a frequency of 0.0001 in 149516 control chromosomes, predominantly at a frequency of 0.0035 within the Ashkenazi Jewish (ASJ) subpopulation in the gnomAD database (v4.1 dataset). The variant has been reported in the literature in individuals affected with GBE1-Related Disorders (Grunseich_2021). In addition, a similar variant (differing by one nucleotide, i.e. c.2053-3358_2053-3350delinsTGTTTTTTACATGACAGGT) has been also reported in the literature in several ASJ individuals affected with GBE1-Related Disorders (Akman_2015), and in two affected siblings in a recent whole exome sequencing study (Laquerriere_2022). These data indicate that the variant is likely associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 34103343, 25665141, 33820833). ClinVar contains an entry for this variant (Variation ID: 2635394). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

GBE1-related disorder Pathogenic:1

Dec 27, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The GBE1 c.2053-3358_2053-3350delinsTGTTTTTTACATTACAGGT variant is predicted to result in an in-frame deletion and insertion. This variant is predicted to create a novel splice acceptor site (Alamut Visual Plus v1.6.1). This variant has been reported in the compound heterozygous sate in two siblings with Adult Polyglucosan Body Disease (APBD; Grunseich et al. 2021. PubMed ID: 34103343). A similar variant has been reported in the literature as being causative for APBD, although the reported insertion/deletion (indel) variant differed by one nucleotide compared to that identified in this patient (Akman et al. 2015. PubMed ID: 25665141, c.2053-3358_2053-3350delinsTGTTTTTTACATGACAGGT; variant reported by Akman et al. as GBE1-IVS15+5289_5297del GTGTGGTGGinsTGTTTTTTACATGACAGGT). At PreventionGenetics, we have observed this variant in several APBD patients in conjunction with a second pathogenic variant. We classify this variant as likely pathogenic. -

not provided Pathogenic:1

Dec 18, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; No data available from control populations to assess the frequency of this variant; This variant is associated with the following publications: (PMID: 25665141) -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-81542964;