3-81493812-GCCACCACAC-GACCTGTCATGTAAAAAACA

Variant names:

• chr3-81493813-CCACCACAC-ACCTGTCATGTAAAAAACA
• rs869320698
• NM_000158.4:c.2053-3358_2053-3350delGTGTGGTGGinsTGTTTTTTACATGACAGGT

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS3 PM2 PP5_Very_Strong

The NM_000158.4(GBE1):​c.2053-3358_2053-3350delGTGTGGTGGinsTGTTTTTTACATGACAGGT 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 (★★). ClinVar reports functional evidence for this variant: "SCV002097125: "In vitro functional studies provide some evidence that the c.2053-3358_2053-3350delinsTGTTTTTTACATGACAGGT variant may impact protein function." PMID:25665141" and additional evidence is available in ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: GBE1 NM_000158.4 intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 0.749
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• glycogen storage disease due to glycogen branching enzyme deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Laboratory for Molecular Medicine, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
• adult polyglucosan body disease

  Inheritance: AR Classification: MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002097125: "In vitro functional studies provide some evidence that the c.2053-3358_2053-3350delinsTGTTTTTTACATGACAGGT variant may impact protein function." PMID:25665141; SCV004190170: PCR analysis showed that this variant caused the splicing of exon 15 into an ectopic splice acceptor site, creating an abnormal exon 16 with a new stop codon. The mean GBE activity in compound heterozygotes was 8% of normal compared to 18% of normal in c.986A>C homozygotes, indicating the truncated protein product is unstable (PMID: 25665141).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-81493813-CCACCACAC-ACCTGTCATGTAAAAAACA is Pathogenic according to our data. Variant chr3-81493813-CCACCACAC-ACCTGTCATGTAAAAAACA is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 225145.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000158.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GBE1	NM_000158.4	MANE Select	c.2053-3358_2053-3350delGTGTGGTGGinsTGTTTTTTACATGACAGGT		intron	N/A	NP_000149.4	Q04446

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GBE1	ENST00000429644.7	TSL:1 MANE Select	c.2053-3358_2053-3350delGTGTGGTGGinsTGTTTTTTACATGACAGGT		intron	N/A	ENSP00000410833.2	Q04446
	GBE1	ENST00000895874.1		c.2047-3358_2047-3350delGTGTGGTGGinsTGTTTTTTACATGACAGGT		intron	N/A	ENSP00000565933.1
	GBE1	ENST00000942742.1		c.2047-3358_2047-3350delGTGTGGTGGinsTGTTTTTTACATGACAGGT		intron	N/A	ENSP00000612801.1

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

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Adult polyglucosan body disease (4)
1	-	-	Adult polyglucosan body neuropathy (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.75
Mutation Taster		=4/96	disease causing

Splicing

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

Other links and lift over

dbSNP: rs869320698; hg19: chr3-81542964;