GeneBe

17-80112928-C-G

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 7 ACMG points: 7P and 0B. PP3PM2_SupportingPM3PS3_SupportingPP4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.1941C>G variant in GAA is a missense variant that is predicted to result in substitution of cysteine by tryptophan at amino acid 647 (p.Cys647Trp). At least 10 patients with this variant have been reported to have Pompe disease including two with documented laboratory values showing deficiency of GAA, one of whom also had reported symptoms consistent with infantile onset Pompe disease (PMID:7981676, 9535769, 17723315) (meeting PP4_Moderate), three patients with reported symptoms consistent with infantile onset Pompe disease (PMID:7981676, 19588081, 22658377, 31510962), one patient on enzyme replacement therapy (PMID:31086307) (all meeting PP4). Four patients are compound heterozygous for the variant and a variant in GAA that has been classified as pathogenic for Pompe disease including c.-32-13T>G (PMID:25681614, 31931849; 2 patients), c.2481+110_2646+39del (exon 18 deletion, PMID:7981676), and c.1655T>C (p.Leu552Pro) (PMID:19588081), all phase unconfirmed. In another patient, the variant is confirmed in trans with an allele containing two pathogenic variants, c.1456_1468del (p.Ala486fsTer30) (confirmed de novo) and c.2238G>C (p.Trp746Cys) (PMID:7981676), and two patients are homozygous for the variant (PMID:9535769, 31510962) (PM3_Very Strong). In addition, two patients are compound heterozygous for the variant and either c.1846G>A (p.Asp616Asn) (PMID:31086307) or c.1781G>C (p.Arg594Pro) (PMID:19588081). The allelic data from these patients will be used in the classification of the second variant and is not included here to avoid circular logic. In another patient, no second variant was found (PMID:25681614). When expressed in GAA-deficient SV40 immortalized fibroblasts, the variant resulted in <1% GAA activity compared to the normal control ( PMID:9535769) (PS3_Supporting).The computational predictor REVEL gives a score of 0.802 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). The highest continental population minor allele frequency in gnomAD v2.1.1 is 0.00002 (3/124712 alleles) in the European non-Finnish population, which is lower than the ClinGen LSD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). Of note, the highest population minor allele frequency in gnomAD v2.1.1 is in the "other" population, 0.00014 (1/7006 alleles) which also meets the PM2_Supporting threshold. There is a ClinVar entry for this variant (Variation ID: 550327). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG-AMP criteria met, as specified by the ClinGen Lysosomal Storage Disorders VCEP (Specifications Version 2.0): PM3_Very_Strong, PP4_Moderate, PP3, PS3_Supporting, PM2_Supporting.Classification approved by the ClinGen LSD VCEP on Nov. 15, 2022. LINK:https://erepo.genome.network/evrepo/ui/classification/CA8815554/MONDO:0009290/010

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

GAA
NM_000152.5 missense

Scores

13
2
3

Clinical Significance

Pathogenic reviewed by expert panel P:9

Conservation

PhyloP100: -1.20

Publications

12 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 7 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.
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.1941C>Gp.Cys647Trp
missense
Exon 14 of 20NP_000143.2P10253
GAA
NM_001079803.3
c.1941C>Gp.Cys647Trp
missense
Exon 15 of 21NP_001073271.1P10253
GAA
NM_001079804.3
c.1941C>Gp.Cys647Trp
missense
Exon 14 of 20NP_001073272.1P10253

Ensembl Transcripts

Sel.
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
GAA
ENST00000302262.8
TSL:1 MANE Select
c.1941C>Gp.Cys647Trp
missense
Exon 14 of 20ENSP00000305692.3P10253
GAA
ENST00000390015.7
TSL:1
c.1941C>Gp.Cys647Trp
missense
Exon 15 of 21ENSP00000374665.3P10253
GAA
ENST00000933406.1
c.1956C>Gp.Cys652Trp
missense
Exon 14 of 20ENSP00000603465.1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152188
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
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:
0.0000124
AC:
3
AN:
242552
AF XY:
0.0000227
show subpopulations
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:
0.0000274
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000617
AC:
9
AN:
1458152
Hom.:
0
Cov.:
33
AF XY:
0.00000690
AC XY:
5
AN XY:
725018
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33454
American (AMR)
AF:
0.00
AC:
0
AN:
44444
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26008
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39648
South Asian (SAS)
AF:
0.00
AC:
0
AN:
85566
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
52236
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5750
European-Non Finnish (NFE)
AF:
0.00000810
AC:
9
AN:
1110830
Other (OTH)
AF:
0.00
AC:
0
AN:
60216
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.497
Heterozygous variant carriers
0
1
2
4
5
6
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:
0.00000657
AC:
1
AN:
152188
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74346
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41444
American (AMR)
AF:
0.0000654
AC:
1
AN:
15284
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5188
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4836
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10628
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
314
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68022
Other (OTH)
AF:
0.00
AC:
0
AN:
2090
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
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:
0.0000868
Hom.:
0
Bravo
AF:
0.00000756
ExAC
AF:
0.00000825
AC:
1

ClinVar

ClinVar submissions
Significance:Pathogenic
Revision:reviewed by expert panel
View on ClinVar
Pathogenic
VUS
Benign
Condition
7
-
-
Glycogen storage disease, type II (7)
2
-
-
not provided (2)

Computational scores

Source: dbNSFP v4.9

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.39
D
BayesDel_noAF
Pathogenic
0.39
CADD
Benign
19
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.98
D
Eigen
Benign
-0.10
Eigen_PC
Benign
-0.40
FATHMM_MKL
Benign
0.54
D
LIST_S2
Uncertain
0.94
D
M_CAP
Pathogenic
0.87
D
MetaRNN
Pathogenic
0.99
D
MetaSVM
Pathogenic
0.93
D
MutationAssessor
Pathogenic
4.8
H
PhyloP100
-1.2
PrimateAI
Pathogenic
0.82
D
PROVEAN
Pathogenic
-11
D
REVEL
Pathogenic
0.80
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.93
MutPred
0.92
Gain of loop (P = 0.2045)
MVP
0.99
MPC
0.63
ClinPred
1.0
D
GERP RS
-3.4
Varity_R
0.99
gMVP
0.97
Mutation Taster
=2/98
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: rs776948121; hg19: chr17-78086727; API
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