17-80112625-C-G

Variant names:

• chr17-80112625-C-G
• rs374470794
• NM_000152.5:c.1802C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PP3 PM2_Supporting PS3_Supporting PM3 PM5 PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.1802C>G variant in GAA is a missense variant predicted to cause substitution of serine serine by tryptophan at amino acid 601 (p.Ser601Trp). The highest population minor allele frequency in gnomAD v4.1.0 is 0.0000008475 (1/1179962 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). The computational predictor REVEL gives a score of 0.964 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). When expressed in COS-7 cells, the variant resulted in <2% wild type activity indicating that this variant may impact protein function (PMID:19862843) (PS3_supporting). Another missense variant (c.1802C>T, p.Ser601Leu) in the same codon has been classified as pathogenic for Pompe disease by the ClinGen Lysosomal Diseases VCEP (ClinVar Variation ID: 194154; Accession: SCV002032130.1) (PM5). This variant has been detected in at least 11 individuals with Pompe disease. Of those individuals, 9 were compound heterozygous for the variant and the c.-32-13T>G variant (classified as pathogenic by the ClinGen LD VCEP). One individual was compound heterozygous for the variant and the c.1935C>A (p.Asp645Glu) variant (classified as pathogenic by the ClinGen LD VCEP). One individual was compound heterozygous for the variant and c.2800-1G>C (not classified by the ClinGen LD VCEP). Zero individuals were homozygous for the variant. (PM3). At least 3 patients with this variant had documented GAA deficiency with <10% of normal mean control level of GAA activity in leukocytes, lymphocytes, or muscle samples (PMID:17056254, 22958975, 24158270) and 2 patients were reported to be on enzyme replacement therapy for Pompe disease (PMID:22081099, 29422078). This meets the criteria for PP4_moderate. There is a ClinVar entry for this variant (Variation ID: 501793). In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PP4_moderate, PM3, PM5, PP3, PM2_supporting, PS3_supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on May 20, 2025) LINK:https://erepo.genome.network/evrepo/ui/classification/CA294896338/MONDO:0009290/010

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:7
• Conservation: PhyloP100: 7.75
• Publications: 29 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

Our verdict: Likely_pathogenic. The variant received 9 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.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: 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.1802C>G	p.Ser601Trp	missense	Exon 13 of 20	NP_000143.2	P10253
	GAA	NM_001079803.3		c.1802C>G	p.Ser601Trp	missense	Exon 14 of 21	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.1802C>G	p.Ser601Trp	missense	Exon 13 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.1802C>G	p.Ser601Trp	missense	Exon 13 of 20	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.1802C>G	p.Ser601Trp	missense	Exon 14 of 21	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.1817C>G	p.Ser606Trp	missense	Exon 13 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460668 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726684

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52328

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111938

Other (OTH) AF: 0.00 AC: 0 AN: 60372

GnomAD4 genome Cov.: 33

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
5	-	-	Glycogen storage disease, type II (5)
2	-	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.97	D
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	5.0	H
PhyloP100		7.7
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-6.9	D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.93		Loss of glycosylation at S601 (P = 0.0225)
MVP		1.0
MPC		0.63
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.96
gMVP		0.97
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs374470794; hg19: chr17-78086424;