rs552929702

Variant names:

• chr17-80107809-A-G
• rs552929702
• NM_000152.5:c.868A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PM2_Supporting BS3_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.868A>G variant in GAA is predicted to result in the substitution of asparagine by aspartate at amino acid 290 (p.Asn290Asp). It has been identified in six individuals by newborn screening, none with clinical features consistent with Pompe disease (PMID:32064362, 37414610; Essawi et al. 2021, Egypt J Med Hum Genet 22:87). Four of these individuals are homozygous for the variant and have African ancestry (PMID:37414610), and two patients are compound heterozygous for the variant and a variant that has been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP, either c.2105G>A (p.Arg702His), phase unconfirmed, (ClinVar Variation ID: 426278, SCV004809068.1) (PMID:32064362) or c.2238G>C (p.Trp746Cys) (ClinVar Variation ID: 265160, SCV002032122.1). In the latter, patient, the variants were confirmed to be in trans, and the father, who was described as "completely normal" but with reduced GAA activity, is homozygous for c.868A>G (p.Asn290Asp). Additional cases have been reported (PMID:22644586, 33073007) but the second variant and clinical details were not provided. Due to the lack of evidence for clinical symptoms in the patients with this variant, PP4 and PM3 were not applied. The highest population minor allele frequency in gnomAD v2.1.1. is 0.00004 (1/24356, no homozygotes) in the African population, which is lower than the ClinGen Lysosomal Diseases VCEP's threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). When expressed in COS cells, this variant was classified as Class E ("presumably nonpathogenic") by Kroos et al, 2012 (PMID:22644586). This includes 71% GAA activity in cells and 38% in medium, with synthesis and processing on Western blot (BS3_Supporting). The computational predictor REVEL gives a score of 0.561 which is neither above nor below the thresholds predicting a damaging (>0.7) or benign (<0.5) impact on GAA function. There is a ClinVar entry for this variant (Variation ID: 498117). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Pompe disease. The classification was first approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on October 21, 2022. Since then, the data for this variant have been re-evaluated and new data have been included but the classification remains the same. The classification of variant of uncertain significance was reapproved on April 16, 2024. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PM2_Supporting, BS3_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA8815078/MONDO:0009290/010

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000022 (2 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:2 U:7
• Conservation: PhyloP100: 6.09
• Publications: 17 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• BS3: 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.868A>G	p.Asn290Asp	missense_variant	Exon 5 of 20	ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8	c.868A>G	p.Asn290Asp	missense_variant	Exon 5 of 20	1	NM_000152.5	ENSP00000305692.3

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152122 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000408 AC: 1 AN: 245126 AF XY: 0.00

Gnomad AFR exome AF: 0.0000638

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000219 AC: 32 AN: 1459490 Hom.: 2 Cov.: 56 AF XY: 0.0000275 AC XY: 20 AN XY: 726058

African (AFR) AF: 0.000658 AC: 22 AN: 33458

American (AMR) AF: 0.00 AC: 0 AN: 44554

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39654

South Asian (SAS) AF: 0.00 AC: 0 AN: 86144

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52192

Middle Eastern (MID) AF: 0.000355 AC: 2 AN: 5626

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111548

Other (OTH) AF: 0.0000830 AC: 5 AN: 60242

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152240 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74442

African (AFR) AF: 0.000120 AC: 5 AN: 41536

American (AMR) AF: 0.00 AC: 0 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68000

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000825 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2 Uncertain:7

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:2 Uncertain:3

Feb 13, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 05, 2025

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.868A>G (p.Asn290Asp) results in a conservative amino acid change located in the Glycoside hydrosylase family 31, N-terminal domain (IPR025887) of the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 4.1e-06 in 245126 control chromosomes. c.868A>G has been observed in multiple individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) (example: Hall_2020, internal data). These data indicate that the variant is very likely to be associated with disease. The following publications has been ascertained in the context of this evaluation (PMID: 32064362). ClinVar contains an entry for this variant (Variation ID: 498117). Based on the evidence outlined above, the variant was classified as pathogenic. -

Dec 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 290 of the GAA protein (p.Asn290Asp). This variant is present in population databases (rs552929702, gnomAD 0.004%), including at least one homozygous and/or hemizygous individual. To date, this missense change has only been observed in individual(s) with abnormal newborn screening for Pompe disease (PMID: 32064362; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 498117). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt GAA protein function with a positive predictive value of 95%. This variant disrupts the p.Asn290 amino acid residue in GAA. Other variant(s) that disrupt this residue have been observed in individuals with GAA-related conditions (PMID: 22081099; internal data), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Sep 05, 2021

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 16, 2024

ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000152.5:c.868A>G variant in GAA is predicted to result in the substitution of asparagine by aspartate at amino acid 290 (p.Asn290Asp). It has been identified in six individuals by newborn screening, none with clinical features consistent with Pompe disease (PMID: 32064362, 37414610; Essawi et al. 2021, Egypt J Med Hum Genet 22:87). Four of these individuals are homozygous for the variant and have African ancestry (PMID: 37414610), and two patients are compound heterozygous for the variant and a variant that has been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP, either c.2105G>A (p.Arg702His), phase unconfirmed, (ClinVar Variation ID: 426278, SCV004809068.1) (PMID: 32064362) or c.2238G>C (p.Trp746Cys) (ClinVar Variation ID: 265160, SCV002032122.1). In the latter, patient, the variants were confirmed to be in trans, and the father, who was described as "completely normal" but with reduced GAA activity, is homozygous for c.868A>G (p.Asn290Asp). Additional cases have been reported (PMID: 22644586, 33073007) but the second variant and clinical details were not provided. Due to the lack of evidence for clinical symptoms in the patients with this variant, PP4 and PM3 were not applied. The highest population minor allele frequency in gnomAD v2.1.1. is 0.00004 (1/24356, no homozygotes) in the African population, which is lower than the ClinGen Lysosomal Diseases VCEP's threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). When expressed in COS cells, this variant was classified as Class E ("presumably nonpathogenic") by Kroos et al, 2012 (PMID:22644586). This includes 71% GAA activity in cells and 38% in medium, with synthesis and processing on Western blot (BS3_Supporting). The computational predictor REVEL gives a score of 0.561 which is neither above nor below the thresholds predicting a damaging (>0.7) or benign (<0.5) impact on GAA function. There is a ClinVar entry for this variant (Variation ID: 498117). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Pompe disease. The classification was first approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on October 21, 2022. Since then, the data for this variant have been re-evaluated and new data have been included but the classification remains the same. The classification of variant of uncertain significance was reapproved on April 16, 2024. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PM2_Supporting, BS3_Supporting. -

not provided Uncertain:4

Oct 17, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified with a second variant in the GAA gene in an asymptomatic infant with reduced alpha-glucosidase activity on newborn screening; the variant was apparently homozygous in the father who was clinically asymptomatic, but had significantly reduced alpha-glucosidase activity (Mona Essawi et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22253258, 19343043, 22644586, 32064362, 37414610, Essawi2021) -

Aug 30, 2023

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 30, 2018

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 11, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D;D
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	.;D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.91	D;D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Pathogenic	2.9	M;M
PhyloP100		6.1
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-4.5	D;D
REVEL	Uncertain	0.56
Sift	Uncertain	0.0090	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.94
MutPred		0.39		Gain of phosphorylation at Y292 (P = 0.0793);Gain of phosphorylation at Y292 (P = 0.0793);
MVP		1.0
MPC		0.58
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.90
gMVP		0.95
Mutation Taster		=82/18	polymorphism

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: rs552929702; hg19: chr17-78081608;