17-80110841-G-T

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PP4 PS1_Supporting PM2_Supporting PM3 PVS1

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.1551+1G>T variant alters the donor splice site of intron 10 in GAA. RT-PCR in fibroblasts revealed that this variant results in skipping of exon 10, with low levels of normal splicing (PMID 25243733). Skipping of exon 10 causes and in frame loss of 38 amino acids, encompassing part of the GAA catalytic barrel, and including two residues, Trp481 and Trp516, which are part of the active site (PMIDs 1856189, 22253258; DOI 10.1101/212837). Therefore, loss of this exon is expected to abolish GAA activity (PVS1). At least four probands and one sibling with this variant have been reported; for 3 individuals, documented GAA activity is available in fibroblasts or dried blood spot and is in the affected range (PMID 25243733, 25703594) (PP4_Moderate). Three of these probands, each with late-onset Pompe disease, are compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic for Pompe disease by the ClinGen LD VCEP. The phase is unconfirmed in all cases. The second variant is either c.1942G>A (p.Gly648Ser) (ClinVar Variation ID: 188902) (PMID:31606152, 0.5 points) or c.-32-13T>G (ClinVar Variation ID: 4027) (2 patients and one sibling, PMID:25703594, 30155607; 2 x 0.5 points). Another patient is compound heterozygous for the variant and c.1256A>T (p.Asp419Val) (PMID:25243733, 27623443). The allelic data from this patient will be used in the assessment of p.Asp419Val and is not included here in order to avoid circular logic. Total 1.5 points (PM3). The highest population minor allele frequency in gnomAD v4.1.0. is 0.00002228 in the East Asian population, which is lower than the ClinGen LD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). Additional variants in the same splice region have been classified as pathogenic by the ClinGen LD VCEP including c.1551+1G>A (ClinVar Variation ID: 1065143), c.1551+1G>C (ClinVar Variation ID: 554983), and c.1551+3_1551+6del (aka c.1551+1_1551+4del) (PS1_Supporting; PMID:37352859). There is a ClinVar entry for this variant (Variation ID: 555986). 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 LD VCEP (Specifications Version 2.0.0.): PVS1, PM3, PP4_Moderate, PS1_Supporting, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on May 20, 2025) LINK:https://erepo.genome.network/evrepo/ui/classification/CA8815365/MONDO:0009290/010

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: GAA ENST00000302262.8 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic reviewed by expert panel P:9
• Conservation: PhyloP100: 9.39
• Publications: 3 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.
• PS1: 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: ENST00000302262.8. 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>T		splice_donor intron	N/A	NP_000143.2
	GAA	NM_001079803.3		c.1551+1G>T		splice_donor intron	N/A	NP_001073271.1
	GAA	NM_001079804.3		c.1551+1G>T		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>T		splice_donor intron	N/A	ENSP00000305692.3
	GAA	ENST00000390015.7	TSL:1	c.1551+1G>T		splice_donor intron	N/A	ENSP00000374665.3
	GAA	ENST00000570803.6	TSL:5	c.1551+1G>T		splice_donor intron	N/A	ENSP00000460543.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251156 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1461748 Hom.: 0 Cov.: 37 AF XY: 0.00000963 AC XY: 7 AN XY: 727180

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53362

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1111934

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
9	-	-	Glycogen storage disease, type II (9)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.27
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 (ClinVar)

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		0.22		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;