17-80105132-G-C

Variant names:

• chr17-80105132-G-C
• rs143523371
• NM_000152.5:c.546G>C

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM2_Supporting PM3_Strong PVS1_Strong PS1_Moderate PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.546G>C variant alters that last nucleotide of exon 2 of GAA, but does not result in an amino acid change (p.Thr182=). Study using minigene analysis showed that the variant disrupts normal splicing, resulting in skipping of exon 2, with a low proportion of normal transcripts produced (PMID:31301153). In addition, deletion of exon 2 results in complete loss of enzyme activity when expressed in heterologous cells (PMID:7881425, 7717400). As this variant appears to allow a low level of normal splicing to occur, PVS1 was applied at the strong level (PVS1_Strong). At least 4 late-onset Pompe Disease patient with this variant had documented GAA deficiency or activity in the affected range in any appropriate tissue (PMID:17616415, clinical lab data) (PP4_Moderate). One patient is compound heterozygous for the variant and c.-32-13T>G that has been classified as pathogenic by the ClinGen LD VCEP, phase not confirmed (PMID:17616415). This variant has also been detected in a Pompe disease patient who was heterozygous with c.2608C>T (p.Arg870*, Pathogenic by LD VCEP), and in 3 additional patients with homozygous (Revvity Omics and Duke lab data) (PM3_Strong). The highest population minor allele frequency in gnomAD v4.1.0 is 0.000008496 (10/1177056 alleles) in the European Non-Finnish population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). Other variants at the same nucleotide position (c.546G>T, c.546G>A), and in the same splice region (c.546+1G>T, c.546+2T>C, c.546+5G>T, and c.546del2‐5) have been reported in individuals with Pompe disease (https://www.pompevariantdatabase.nl/). All of these variants have been shown to result in skipping of exon 2 using a minigene assay (PMID:31301153, 39905333). c.546G>T and c.546G>A have been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP (PS1_Moderate).The computational splicing predictor SpliceAI gives a score of 0.84 for donor loss, predicting that the variant disrupts the donor splice site of intron 2 of GAA. But PP3 was not applied as PVS1 was applied. There is a ClinVar entry for this variant (Variation ID: 281056; 2 star review status) with 4 submitters classifying the variant as pathogenic, and 4 submitters classifying it as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, based in the specification of the ClinGen Lysosomal Diseases VCEP: PVS1_Strong, PS1_Moderate, PM3_Strong, PP4_Moderate, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on April 1, 2025) LINK:https://erepo.genome.network/evrepo/ui/classification/CA10603795/MONDO:0009290/010

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: GAA NM_000152.5 splice_region, synonymous
• Scores: Splicing: ADA: 0.9995
• Clinical Significance: Pathogenic reviewed by expert panel P:9
• Conservation: PhyloP100: 0.305
• Publications: 40 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, ClinGen, Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine
• 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

Specifications for GAA are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

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: NM_000152.5. 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
	GAA	NM_000152.5	MANE Select	c.546G>C	p.Thr182Thr	splice_region synonymous	Exon 2 of 20	NP_000143.2	P10253
	GAA	NM_001079803.3		c.546G>C	p.Thr182Thr	splice_region synonymous	Exon 3 of 21	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.546G>C	p.Thr182Thr	splice_region synonymous	Exon 2 of 20	NP_001073272.1	P10253

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAA	ENST00000302262.8	TSL:1 MANE Select	c.546G>C	p.Thr182Thr	splice_region synonymous	Exon 2 of 20	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.546G>C	p.Thr182Thr	splice_region synonymous	Exon 3 of 21	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.546G>C	p.Thr182Thr	splice_region synonymous	Exon 2 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000846 AC: 2 AN: 236410 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000188

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000689 AC: 10 AN: 1451670 Hom.: 0 Cov.: 36 AF XY: 0.00000832 AC XY: 6 AN XY: 721554

African (AFR) AF: 0.00 AC: 0 AN: 33410

American (AMR) AF: 0.00 AC: 0 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26072

East Asian (EAS) AF: 0.00 AC: 0 AN: 39578

South Asian (SAS) AF: 0.00 AC: 0 AN: 86202

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46842

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5728

European-Non Finnish (NFE) AF: 0.00000902 AC: 10 AN: 1109026

Other (OTH) AF: 0.00 AC: 0 AN: 60144

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
6	-	-	Glycogen storage disease, type II (6)
3	-	-	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	19
DANN	Benign	0.79
PhyloP100		0.30
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=16/84	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.97
SpliceAI score (max)		0.84		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.24		Position offset: 40
DS_DL_spliceai		0.84		Position offset: 0

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

Other links and lift over

dbSNP: rs143523371; hg19: chr17-78078931;