NM_000152.5:c.868A>G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PM2_SupportingBS3_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

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:2U:7

Conservation

PhyloP100: 6.09

Publications

17 publications found

Variant links:

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

GAA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GAA	NM_000152.5	MANE Select	c.868A>G	p.Asn290Asp	missense	Exon 5 of 20	NP_000143.2
GAA	NM_001079803.3		c.868A>G	p.Asn290Asp	missense	Exon 6 of 21	NP_001073271.1
GAA	NM_001079804.3		c.868A>G	p.Asn290Asp	missense	Exon 5 of 20	NP_001073272.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GAA	ENST00000302262.8	TSL:1 MANE Select	c.868A>G	p.Asn290Asp	missense	Exon 5 of 20	ENSP00000305692.3
GAA	ENST00000390015.7	TSL:1	c.868A>G	p.Asn290Asp	missense	Exon 6 of 21	ENSP00000374665.3
GAA	ENST00000933406.1		c.868A>G	p.Asn290Asp	missense	Exon 5 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152122

Hom.:

Cov.:

show subpopulations

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:

AN:

245126

AF XY:

0.00

show subpopulations

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:

AN:

1459490

Hom.:

Cov.:

AF XY:

0.0000275

AC XY:

AN XY:

726058

show subpopulations

African (AFR)

AF:

0.000658

AC:

AN:

33458

American (AMR)

AF:

0.00

AC:

AN:

44554

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26072

East Asian (EAS)

AF:

0.00

AC:

AN:

39654

South Asian (SAS)

AF:

0.00

AC:

AN:

86144

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52192

Middle Eastern (MID)

AF:

0.000355

AC:

AN:

5626

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1111548

Other (OTH)

AF:

0.0000830

AC:

AN:

60242

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152240

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

41536

American (AMR)

AF:

0.00

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68000

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000825

AC:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Glycogen storage disease, type II (5)

not provided (4)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.83

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

-0.050

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.92

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

M_CAP

Pathogenic

0.36

MetaRNN

Pathogenic

0.91

MetaSVM

Uncertain

0.78

MutationAssessor

Pathogenic

2.9

PhyloP100

6.1

PrimateAI

Uncertain

0.63

PROVEAN

Pathogenic

-4.5

REVEL

Uncertain

0.56

Sift

Uncertain

0.0090

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.94

MutPred

0.39

Gain of phosphorylation at Y292 (P = 0.0793)

MVP

1.0

MPC

0.58

ClinPred

0.99

GERP RS

5.3

Varity_R

0.90

gMVP

0.95

Mutation Taster

=82/18

polymorphism

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over