GeneBe

chr17-80113281-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PP3PM2_SupportingPM3_StrongPS3_SupportingPM5PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.2104C>T variant in GAA is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 702 (p.Arg702Cys). At least 1 patient with this variant had documented GAA deficiency with <30% of normal mean control level of GAA activity in cultured fibroblasts (PMID:14972326). At least 1 patient with this variant was reported to be on enzyme replacement therapy for Pompe disease (PMID:25687148). Other patients with this variant who were noted to have Pompe disease were found in the literature, but enzyme activity was not discussed (PMID:20308911, 31086307) (PP4_Moderate). This variant has been detected in at least 5 individuals with Pompe disease. Of those individuals, 2 were compound heterozygous for the variant and -32-13T>G a pathogenic variant by the ClinGen Lysosomal Diseases VCEP (phase unknown)(PMID:20308911, 24158270) and 1 individual was compound heterozygous for the variant and c.2481+110_2646+39del (confirmed in trans by parental/family testing)(PMID:14972326). Two individuals were homozygous for the variant (PMID:25687148, 31086307), meetings the criteria for PM3_Strong. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00004 (1/254192 alleles) in the African population, which is lower than the ClinGen LSD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). Expression of the variant in COS resulted in less than 2% wild type GAA activity and evidence of abnormal GAA synthesis and processing, indicating that this variant may impact protein function (PMID:14972326, 19862843)(PS3_Supporting). The computational predictor REVEL gives a score of 0.985 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Two different missense variants [c.2105G>T (p.Arg702Leu, ClinVar Variation ID: 92472) and c.2105G>A (p.Arg702His, ClinVar Variation ID: 426278)], in the same codon have been classified as pathogenic for Pompe disease by the ClinGen Lysosomal Diseases VCEP (PM5). There is a ClinVar entry for this variant (Variation ID: 189040). In summary, this variant meets the criteria to be classified as 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_Strong, PM2_Supporting, PS3_Supporting, PP3, PM5. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on January 11, 2025) LINK:https://erepo.genome.network/evrepo/ui/classification/CA274304/MONDO:0009290/010

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 34)
Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

GAA
NM_000152.5 missense

Scores

17
1

Clinical Significance

Pathogenic reviewed by expert panel P:13

Conservation

PhyloP100: 5.87

Publications

13 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, 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 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.
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
GAA
NM_000152.5
MANE Select
c.2104C>Tp.Arg702Cys
missense
Exon 15 of 20NP_000143.2P10253
GAA
NM_001079803.3
c.2104C>Tp.Arg702Cys
missense
Exon 16 of 21NP_001073271.1P10253
GAA
NM_001079804.3
c.2104C>Tp.Arg702Cys
missense
Exon 15 of 20NP_001073272.1P10253

Ensembl Transcripts

Sel.
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
GAA
ENST00000302262.8
TSL:1 MANE Select
c.2104C>Tp.Arg702Cys
missense
Exon 15 of 20ENSP00000305692.3P10253
GAA
ENST00000390015.7
TSL:1
c.2104C>Tp.Arg702Cys
missense
Exon 16 of 21ENSP00000374665.3P10253
GAA
ENST00000933406.1
c.2119C>Tp.Arg707Cys
missense
Exon 15 of 20ENSP00000603465.1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152164
Hom.:
0
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.0000483
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:
0.00
AC:
0
AN:
222816
AF XY:
0.00
Gnomad AFR exome
AF:
0.00
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:
0.00000414
AC:
6
AN:
1448162
Hom.:
0
Cov.:
35
AF XY:
0.00000278
AC XY:
2
AN XY:
719058
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33244
American (AMR)
AF:
0.00
AC:
0
AN:
43062
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25740
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39002
South Asian (SAS)
AF:
0.0000239
AC:
2
AN:
83616
European-Finnish (FIN)
AF:
0.0000193
AC:
1
AN:
51938
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5746
European-Non Finnish (NFE)
AF:
0.00000271
AC:
3
AN:
1105962
Other (OTH)
AF:
0.00
AC:
0
AN:
59852
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.450
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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:
0.0000131
AC:
2
AN:
152164
Hom.:
0
Cov.:
34
AF XY:
0.0000135
AC XY:
1
AN XY:
74316
show subpopulations
African (AFR)
AF:
0.0000483
AC:
2
AN:
41436
American (AMR)
AF:
0.00
AC:
0
AN:
15292
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5180
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4834
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10622
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68018
Other (OTH)
AF:
0.00
AC:
0
AN:
2082
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.500
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00
Hom.:
0

ClinVar

ClinVar submissions
Significance:Pathogenic
Revision:reviewed by expert panel
View on ClinVar
Pathogenic
VUS
Benign
Condition
9
-
-
Glycogen storage disease, type II (9)
4
-
-
not provided (4)

Computational scores

Source: dbNSFP v4.9

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.69
BayesDel_addAF
Pathogenic
0.57
D
BayesDel_noAF
Pathogenic
0.58
CADD
Pathogenic
32
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.98
D
Eigen
Pathogenic
0.93
Eigen_PC
Pathogenic
0.80
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.99
D
M_CAP
Pathogenic
0.82
D
MetaRNN
Pathogenic
1.0
D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
4.8
H
PhyloP100
5.9
PrimateAI
Uncertain
0.62
T
PROVEAN
Pathogenic
-7.9
D
REVEL
Pathogenic
0.98
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
1.0
MutPred
0.98
Gain of methylation at K697 (P = 0.0334)
MVP
1.0
MPC
0.63
ClinPred
1.0
D
GERP RS
4.9
Varity_R
0.98
gMVP
0.97
Mutation Taster
=14/86
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

Publications

Other links and lift over

dbSNP: rs786204645; hg19: chr17-78087080; API
Feedback | API | Annotate VCF | Sitemap | About | Privacy & Terms
For research and educational, non-commercial use only. Not for clinical or diagnostic use. GeneBe does not provide medical advice. Data use for AI modeling is prohibited: if used, the cost is $0.001 per byte of downloaded uncompressed data.