rs121907941

Variant names:

• chr17-80110974-TC-GT
• rs121907941
• NM_000152.5:c.1585_1586delTCinsGT

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2_Supporting PM3_Strong PS3_Supporting PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.1585_1586delinsGT variant in GAA is predicted to cause substitution of serine by valine at amino acid 529 (p.Ser529Val). At least 5 patients with this variant had documented GAA deficiency with <10% of normal mean control level of GAA activity in leukocytes, lymphocytes, muscle samples or were noted to have deficient GAA activity but results were not provided(PMIDs: 11053688, 17805474, 21984055) (PP4_Moderate). Of those individuals, 2 were compound heterozygous for the variant and a pathogenic variant as classified by the ClinGen Lysosomal Diseases VCEP (PMIDs 17805474, 11053688). Three individuals were homozygous for the variant (PMIDs: 21984055, 11053688) (PM3_Strong). This variant is absent in gnomAD v4.1.0. (PM2_Supporting). This variant results in 14.1% GAA activity when expressed in COS-1 cells by Tsunoda et al, 1996 (PMID 8834250), 10% GAA activity when expressed in SV40 immortalized fibroblasts (TR4912) by Tsujino S et al, 2000 (PMID 11053688), 9.0% wild-type activity in transiently transfected HEK293T cells by Shimada Y et al, 2014 (PMID 25256446), and 14% in transfected COS-7 cells by Flanagan et al, 2009 (PMID:19862843) (PS3_Supporting). There is a ClinVar entry for this variant (Variation ID: 4026, 0 star review status). In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease based on the GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (Specifications Version 2.0): PM3_Strong, PP4_Moderate, PM2_Supporting, PS3_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on June 17, 2025) LINK:https://erepo.genome.network/evrepo/ui/classification/CA116604/MONDO:0009290/010

• Frequency: Genomes: not found (cov: 33)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2
• Conservation: PhyloP100: 4.92
• Publications: 11 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: Likely_pathogenic. The variant received 8 ACMG points.

• PS3: 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.1585_1586delTCinsGT	p.Ser529Val	missense	N/A	NP_000143.2	P10253
	GAA	NM_001079803.3		c.1585_1586delTCinsGT	p.Ser529Val	missense	N/A	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.1585_1586delTCinsGT	p.Ser529Val	missense	N/A	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.1585_1586delTCinsGT	p.Ser529Val	missense	N/A	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.1585_1586delTCinsGT	p.Ser529Val	missense	N/A	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.1600_1601delTCinsGT	p.Ser534Val	missense	N/A	ENSP00000603465.1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	-	-	Glycogen storage disease due to acid maltase deficiency, late-onset (1)
1	-	-	Glycogen storage disease, type II (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.9
Mutation Taster		=3/97	disease causing

Splicing

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

Other links and lift over

dbSNP: rs121907941; hg19: chr17-78084773;