17-80110841-G-A

Variant names:

• chr17-80110841-G-A
• rs770780848
• NM_000152.5:c.1551+1G>A

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM2_Supporting PM3 PP4_Moderate PVS1

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.1551+1G>A variant alters the canonical donor splice site of intron 10 of GAA. RT-PCR and sequencing using cells from an individual who is compound heterozygous for this variant show that the predominant effect is skipping of exon 10 (GAA has 20 exons). Additionally, an immunoblot from a patient homozygous for this variant showed a specific band at ~105.8 kD, which is consistent with the size of the 110 kD precursor GAA protein minus 4.2 kD, caused by an in-frame skip of exon 10 (PMID:25243733, 29428273). Skipping of exon 10 results in an in-frame deletion of amino acids 480-517. This region forms part of the GAA catalytic barrel (amino acids 347-727) including two residues, Trp481 and Trp516, which are important in active site architecture and substrate binding (Kroos et al, 2012, PMID 22253258; Deming et al, 2017; DOI 10.1101/212837; Roig-Zamboni et al, 2017, PMID:29061980). Therefore, loss of this exon is expected to abolish GAA activity (PVS1). At least 5 patients with findings consistent with Pompe disease have been reported with this variant. GAA activity was reported for 5 patients and was deficient (<10% residual activity) (PMID:29428273, 21550241, 27189384, 37542277) (PP4_Moderate). At least one patient is homozygous for the variant, 0.5 points (PMID:29428273). One patient is compound heterozygous for the variant and c.1561G>A, p.E521K (PMID:37542277, pathogenic by ClinGen LD VCEP, phase unknown), 0.5 points. Two patients are compound heterozygous for the variant and GAA variant c.-32-3C>G (PMID:27189384). The allelic data from these patients will be used in the assessment of the second variant and is not included here to avoid circular logic. 1 point (PM3). This variant is absent in gnomAD v2.1.1 and gnomAD v4.1.0 (PM2_Supporting). Other variants at the same canonical donor splice site have been reported in patients with Pompe disease, including c.1551+1G>C, c.1551+1G>T, and c.1551+2T>G (www.pompevariantdatabase.nl). One of these variants, c.1551+1G>C, has been classified as Pathogenic by the ClinGen LD VCEP. There is a ClinVar entry for this variant (Variation ID: 1065143). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PVS1, PM3, PP4_Moderate, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on January 21, 2025) LINK:https://erepo.genome.network/evrepo/ui/classification/CA401367166/MONDO:0009290/010

• Frequency: Genomes: not found (cov: 33)
• Consequence: GAA NM_000152.5 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic reviewed by expert panel P:5
• Conservation: PhyloP100: 9.39
• Publications: 2 publications found

Genes affected

GAA (HGNC:4065): (alpha glucosidase) This gene encodes lysosomal alpha-glucosidase, which is essential for the degradation of glycogen to glucose in lysosomes. The encoded preproprotein is proteolytically processed to generate multiple intermediate forms and the mature form of the enzyme. Defects in this gene are the cause of glycogen storage disease II, also known as Pompe's disease, which is an autosomal recessive disorder with a broad clinical spectrum. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

GAA Gene-Disease associations (from GenCC):

• glycogen storage disease II

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen, G2P
• glycogen storage disease due to acid maltase deficiency, infantile onset

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• glycogen storage disease due to acid maltase deficiency, late-onset

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000152.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAA	NM_000152.5	MANE Select	c.1551+1G>A		splice_donor intron	N/A	NP_000143.2
	GAA	NM_001079803.3		c.1551+1G>A		splice_donor intron	N/A	NP_001073271.1
	GAA	NM_001079804.3		c.1551+1G>A		splice_donor intron	N/A	NP_001073272.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAA	ENST00000302262.8	TSL:1 MANE Select	c.1551+1G>A		splice_donor intron	N/A	ENSP00000305692.3
	GAA	ENST00000390015.7	TSL:1	c.1551+1G>A		splice_donor intron	N/A	ENSP00000374665.3
	GAA	ENST00000570803.6	TSL:5	c.1551+1G>A		splice_donor intron	N/A	ENSP00000460543.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
4	-	-	Glycogen storage disease, type II (4)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	33
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		9.4
GERP RS		5.4
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.21		Position offset: -25
DS_DL_spliceai		0.99		Position offset: -1

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

Other links and lift over

dbSNP: rs770780848; hg19: chr17-78084640;