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 NM_000152.5 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAA	NM_000152.5	c.1551+1G>T		splice_donor_variant, intron_variant	Intron 10 of 19	ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8	c.1551+1G>T		splice_donor_variant, intron_variant	Intron 10 of 19	1	NM_000152.5	ENSP00000305692.3

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

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:9

Jun 22, 2023

Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The homozygous splice site variant c.1551+1G>T has been identified in the proband with phenotypes: respiratory distress, muscle weakness, proximal and distal muscles weakness in lower and upper extremities. This variant has been identified in a proband in a compound heterozygous state with c.1861T>C (p.Trp621Arg) presented with symptoms at 7 months with cardiomegaly, respiratory distress, muscle weakness. -

Jan 22, 2020

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The c.1551+1G>T variant in GAA has been reported in five individuals with glycogen storage disease II, segregated with disease in two affected relatives from one family (PMID: 25703594) and has been identified in 0.003% (1/34580) of Latino chromosomes and 0.001% (1/113512) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs770780848). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar as pathogenic by Counsyl (VariationID: 555986). This variant occurs in the invariant region (+/- 1/2) of the splice consensus sequence and is predicted to cause in-frame exon skipping and a leaky splice site leading to an abnormal or absent protein. There is an in-frame cryptic splice site 6 bases from the intron-exon boundary, providing evidence that this variant may add 2 amino acids instead of causing loss of function. However, this information is not predictive enough to determine pathogenicity. Loss of function of the GAA gene is an established disease mechanism in autosomal recessive glycogen storage disease II. The phenotype of individuals that are compound heterozygous for this variant is highly specific for glycogen storage disease II based on GAA enzyme activity in fibroblasts being <10% of wild type, consistent with disease (PMID: 25703594, 25243733). Additionally, the presence of this variation in combination with reported pathogenic variant c.-32-13T>G (VariationID: 4027, PMID: 30155607, 25703594) and likely pathogenic variant p.Asp419Val (PMID: 25243733) and in individuals with glycogen storage disease II increases the likelihood that the c.1551+1G>T variant is pathogenic. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PVS1_moderate, PM3, PM2, PP4 (Richards 2015). -

Jul 27, 2021

Kariminejad - Najmabadi Pathology & Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2, PVS1, PP5 -

Jan 05, 2018

Counsyl

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Apr 01, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in skipping of exon 10, but is expected to preserve the integrity of the reading-frame (PMID: 25243733). ClinVar contains an entry for this variant (Variation ID: 555986). Disruption of this splice site has been observed in individual(s) with Pompe disease (PMID: 25243733, 31086307). This variant is present in population databases (rs770780848, gnomAD 0.003%). This sequence change affects a donor splice site in intron 10 of the GAA gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. -

May 20, 2025

ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

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) -

Jul 23, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 03, 2022

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1551+1G>T variant in GAA has been reported in at least five individuals with glycogen storage disease II (3 in the compound heterozygous state) and segregated with disease in 1 family member (Gesquière-Dando 2015 PMID: 25703594, Bali 2012 PMID: 22252923, Bergsma 2015 PMID: 25243733, Kishnani 2019 PMID: 31086307). It has been reported in ClinVar (Variation ID 555986) and was absent from large population databases. This variant occurs in the invariant region (+/- 1/2) of the splice consensus sequence, and in vitro functional studies suggest it causes in-frame exon 10 skipping and a leaky wild-type splice site leading to an abnormal or absent protein (Gesquière-Dando 2015 PMID: 25703594, Bergsma 2015 PMID: 25243733). Loss of function of the GAA gene is an established disease mechanism in autosomal recessive glycogen storage disease II. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive glycogen storage disease II. ACMG/AMP Criteria applied: PM3_Strong, PM2_Supporting, PS3_Moderate, PM4. -

Apr 08, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: GAA c.1551+1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5 splicing donor site. Bergsma et al, 2014 report that the variant causes in-frame exon 10 skipping and a leaky wild-type splicing (Bergsma_2014). The variant allele was found at a frequency of 8e-06 in 251156 control chromosomes (gnomAD). c.1551+1G>T has been reported in the literature in multiple individuals (both homozygous and compound heterozygous patients) affected with Glycogen Storage Disease, Type 2 (Pompe Disease) (Bergsma_2014, Gupta_2020, Kishnani_2019, Semplicini_2018, Thomas_2021). Several of these patients had juvenile and infantile onset of the disease. These data indicate that the variant is very likely to be associated with disease. Patient homozygous for the variant show reduced alpha-glucosidase activity (Thomas_2021). Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

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;