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, 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: 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAA	NM_000152.5	c.1802C>G	p.Ser601Trp	missense_variant	Exon 13 of 20	ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8	c.1802C>G	p.Ser601Trp	missense_variant	Exon 13 of 20	1	NM_000152.5	ENSP00000305692.3

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

Significance: Likely pathogenic

Submissions summary: Pathogenic:7

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:5

Mar 08, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 p.Ser601Trp variant in GAA has been reported in one Italian individual with Glycogen Storage Disease II (PMID: 17056254) and has also been reported likely pathogenic by EGL in ClinVar (Variation ID: 501793). This variant was absent from large population studies. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. One additional likely pathogenic variant has been reported at the the same position, p.Ser601Leu, slightly supporting that a change at this position may not be tolerated (Variation ID: 194154; PMID: 30023291, 22676651, 22644586). The presence of this variant in combination with a pathogenic variant curated by our study and in an individual with Glycogen Storage Disease II increases the likelihood that the p.Ser601Trp variant is pathogenic (PMID: 17056254). The phenotype of the individual with this variant is highly specific for Glycogen Storage Disease II based on abnormally low GAA activity detected in lymphocytes (PMID: 17056254). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PM5_Supporting, PP3, PM3_Supporting, PP4 (Richards 2015).

May 20, 2025

ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

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)

Mar 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with tryptophan, which is neutral and slightly polar, at codon 601 of the GAA protein (p.Ser601Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Pompe disease (PMID: 17056254, 24158270, 32711049). ClinVar contains an entry for this variant (Variation ID: 501793). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GAA protein function with a positive predictive value of 95%. This variant disrupts the p.Ser601 amino acid residue in GAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22252923, 22644586, 28394184). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

May 01, 2020

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: GAA c.1802C>G (p.Ser601Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 248082 control chromosomes (gnomAD). c.1802C>G has been reported in the literature in individuals (in compound heterozygous state) affected with Glycogen Storage Disease, Type 2 (Pompe Disease) (Angelini_2012, Palmer_2007, DeFilippi_2014, Parini_2018). These data indicate that the variant is likely to be associated with disease. Most of the patients from these reports had late onset phenotype of the disease. In in vitro functional studies, the variant was found to have reduced enzymatic activity (Flanagan_2009). One ClinVar submitter (evaluation after 2014) cite the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

not provided Pathogenic:2

May 10, 2017

Eurofins Ntd Llc (ga)

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 14, 2024

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

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;D
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.0	.;D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	1.0	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	5.0	H;H
PhyloP100		7.7
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-6.9	D;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Vest4		0.99
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;