17-80105899-G-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PP3PM2_SupportingPM3_StrongPP4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.692+5G>T variant in GAA is located in intron 3 and is predicted to disrupt the 5' donor splice site of the intron. At least 6 individuals have been reported with this variant and late-onset Pompe disease, including individuals with documented GAA enzyme deficiency and symptoms consistent with LOPD and receiving enzyme replacement therapy (PMIDs: 24384324, 26873529,27408821,29181627, 30155607). At least three individuals with confirmed Pompe disease are compound heterozygous for this variant and a second pathogenic variant (phase unconfirmed) including c.1076-22T>G (PMID:27408821 ), c.953T>C (PMIDs: 3015560 and 29181627), and c.482_483del (PMID:26873529) (PM3_strong). One individual with LOPD was reported to have this variant and c.1211A>G, classified as likely pathogenic by the ClinGen Lysosomal Diseases VCEP; however, points were not given for PP4 or PM3 to avoid circular logic as data from this publication were used to support the classification of c.1211A>G (PMID:2438432). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00001195 (14/1171164 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). The computational splicing predictor SpliceAI gives a score of 0.54 for donor loss, predicting that the variant disrupts the donor splice site of intron 3 of GAA (PP3). There is a ClinVar entry for this variant (Variation ID: 526532 , 2-star review status) with 4 submitters classifying the variant as pathogenic (n=2) or likely pathogenic (n=2). In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (Specifications Version 2.0.0): PP4_moderate, PM3_strong, PM2_supporting, PP3.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on April 15, 2025) LINK:https://erepo.genome.network/evrepo/ui/classification/CA8814966/MONDO:0009290/010

Frequency

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

Exomes 𝑓: 0.0000090 ( 0 hom. )

Consequence

GAA
NM_000152.5 splice_region, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Likely pathogenic reviewed by expert panel P:5

Conservation

PhyloP100: 9.68

Publications

1 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: Likely_pathogenic. The variant received 8 ACMG points.

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAA	NM_000152.5 link	c.692+5G>T		splice_region_variant, intron_variant	Intron 3 of 19	ENST00000302262.8	NP_000143.2	P10253

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8 link	c.692+5G>T		splice_region_variant, intron_variant	Intron 3 of 19	1	NM_000152.5	ENSP00000305692.3		P10253

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152260

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000418

AC:

AN:

239172

AF XY:

0.00000767

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:

0.00000900

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000904

AC:

AN:

1437700

Hom.:

Cov.:

AF XY:

0.00000981

AC XY:

AN XY:

713446

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33250

American (AMR)

AF:

0.00

AC:

AN:

44432

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25802

East Asian (EAS)

AF:

0.00

AC:

AN:

39418

South Asian (SAS)

AF:

0.00

AC:

AN:

85912

European-Finnish (FIN)

AF:

0.00

AC:

AN:

41376

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4696

European-Non Finnish (NFE)

AF:

0.0000118

AC:

AN:

1103118

Other (OTH)

AF:

0.00

AC:

AN:

59696

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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:

0.00000657

AC:

AN:

152260

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74386

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41472

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68046

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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

Alfa

AF:

0.0000409

Hom.:

Bravo

AF:

0.00000378

EpiCase

AF:

0.0000546

EpiControl

AF:

0.0000593

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:5

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Glycogen storage disease, type II

Pathogenic:4

Apr 15, 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.692+5G>T variant in GAA is located in intron 3 and is predicted to disrupt the 5' donor splice site of the intron. At least 6 individuals have been reported with this variant and late-onset Pompe disease, including individuals with documented GAA enzyme deficiency and symptoms consistent with LOPD and receiving enzyme replacement therapy (PMIDs: 24384324, 26873529,27408821,29181627, 30155607). At least three individuals with confirmed Pompe disease are compound heterozygous for this variant and a second pathogenic variant (phase unconfirmed) including c.1076-22T>G (PMID: 27408821 ), c.953T>C (PMIDs: 3015560 and 29181627), and c.482_483del (PMID: 26873529) (PM3_strong). One individual with LOPD was reported to have this variant and c.1211A>G, classified as likely pathogenic by the ClinGen Lysosomal Diseases VCEP; however, points were not given for PP4 or PM3 to avoid circular logic as data from this publication were used to support the classification of c.1211A>G (PMID: 2438432). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00001195 (14/1171164 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). The computational splicing predictor SpliceAI gives a score of 0.54 for donor loss, predicting that the variant disrupts the donor splice site of intron 3 of GAA (PP3). There is a ClinVar entry for this variant (Variation ID: 526532 , 2-star review status) with 4 submitters classifying the variant as pathogenic (n=2) or likely pathogenic (n=2). In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (Specifications Version 2.0.0): PP4_moderate, PM3_strong, PM2_supporting, PP3. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on April 15, 2025) -

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 heterozygous c.692+5G>T variant in GAA has been reported in the compound heterozygous state in 2 individuals of northwestern European descent with Glycogen Storage Disease II (PMID: 24384324, 26873529). This variant has been identified in 0.001% (1/111074) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs763027848). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported as a VUS by Invitae in ClinVar (Variation ID: 526532). In vitro RT-PCR with patient muscle cell RNA provides some evidence that the c.692+5G>T variant may impact mRNA expression levels (PMID: 24384324). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The presence of this variant in combination with a reported pathogenic variant and in an individual with Glycogen Storage Disease II increases the likelihood that the c.692+5G>T variant is pathogenic (PMID: 24384324). The phenotype of 2 individuals with the variant in the heterozygous state is highly specific for Glycogen Storage Disease II based on reduced GAA activity compared to controls in relevant tissue (PMID: 24384324, 26873529). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM3, PM2, PP3, PS3_Supporting, PP4 (Richards 2015). -

Dec 20, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change falls in intron 3 of the GAA gene. It does not directly change the encoded amino acid sequence of the GAA protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs763027848, gnomAD 0.0009%). This variant has been observed in individual(s) with Pompe disease (PMID: 24384324, 26873529, 29181627). 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: 526532). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Feb 17, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:1

Jan 23, 2023

Revvity Omics, Revvity

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.37

CADD

Uncertain

(source)

DANN

Benign

0.92

PhyloP100

9.7

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.99

SpliceAI score (max)

0.54

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.45

Position offset: -40

DS_DL_spliceai

0.54

Position offset: -5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over