rs770780848

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PP4_ModeratePVS1PM3PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.1551+1G>A variant alters the canonical donor splice site of intron 10 of GAA. RT-PCR and sequencing using cells from an individual who is compound heterozygous for this variant show that the predominant effect is skipping of exon 10 (GAA has 20 exons). Additionally, an immunoblot from a patient homozygous for this variant showed a specific band at ~105.8 kD, which is consistent with the size of the 110 kD precursor GAA protein minus 4.2 kD, caused by an in-frame skip of exon 10 (PMID:25243733, 29428273). Skipping of exon 10 results in an in-frame deletion of amino acids 480-517. This region forms part of the GAA catalytic barrel (amino acids 347-727) including two residues, Trp481 and Trp516, which are important in active site architecture and substrate binding (Kroos et al, 2012, PMID 22253258; Deming et al, 2017; DOI 10.1101/212837; Roig-Zamboni et al, 2017, PMID:29061980). Therefore, loss of this exon is expected to abolish GAA activity (PVS1). At least 5 patients with findings consistent with Pompe disease have been reported with this variant. GAA activity was reported for 5 patients and was deficient (<10% residual activity) (PMID:29428273, 21550241, 27189384, 37542277) (PP4_Moderate). At least one patient is homozygous for the variant, 0.5 points (PMID:29428273). One patient is compound heterozygous for the variant and c.1561G>A, p.E521K (PMID:37542277, pathogenic by ClinGen LD VCEP, phase unknown), 0.5 points. Two patients are compound heterozygous for the variant and GAA variant c.-32-3C>G (PMID:27189384). The allelic data from these patients will be used in the assessment of the second variant and is not included here to avoid circular logic. 1 point (PM3). This variant is absent in gnomAD v2.1.1 and gnomAD v4.1.0 (PM2_Supporting). Other variants at the same canonical donor splice site have been reported in patients with Pompe disease, including c.1551+1G>C, c.1551+1G>T, and c.1551+2T>G (www.pompevariantdatabase.nl). One of these variants, c.1551+1G>C, has been classified as Pathogenic by the ClinGen LD VCEP. There is a ClinVar entry for this variant (Variation ID: 1065143). 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 Diseases Variant Curation Expert Panel (Specifications Version 2.0): PVS1, PM3, PP4_Moderate, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on January 21, 2025) LINK:https://erepo.genome.network/evrepo/ui/classification/CA401367166/MONDO:0009290/010

Frequency

Genomes: not found (cov: 33)

Consequence

GAA
NM_000152.5 splice_donor, intron

Scores

5
1
1
Splicing: ADA: 1.000
2

Clinical Significance

Pathogenic reviewed by expert panel P:4

Conservation

PhyloP100: 9.39
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PVS1
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.
PP4
For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GAANM_000152.5 linkc.1551+1G>A splice_donor_variant, intron_variant Intron 10 of 19 ENST00000302262.8 NP_000143.2 P10253

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GAAENST00000302262.8 linkc.1551+1G>A splice_donor_variant, intron_variant Intron 10 of 19 1 NM_000152.5 ENSP00000305692.3 P10253

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
37
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:4
Apr 20, 2020
Natera, Inc.
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Apr 07, 2021
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.1551+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing resulting in exon 10 skipping (Bergsma_2015). The variant was absent in 251156 control chromosomes. c.1551+1G>A has been reported in the literature in multiple individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) (example, Mechler_2012, Bergsma_2015, Figueroa-Bonaparte_2016, Papadopoulos_2017, Poelman_2018, Semplicini_2018). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity in fibroblasts and leukocytes from a patient homozygous for this variant (example, Poelman_2018). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. -

Jan 21, 2025
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel
Significance: Pathogenic
Review Status: reviewed by expert panel
Collection Method: curation

The NM_000152.5:c.1551+1G>A variant alters the canonical donor splice site of intron 10 of GAA. RT-PCR and sequencing using cells from an individual who is compound heterozygous for this variant show that the predominant effect is skipping of exon 10 (GAA has 20 exons). Additionally, an immunoblot from a patient homozygous for this variant showed a specific band at ~105.8 kD, which is consistent with the size of the 110 kD precursor GAA protein minus 4.2 kD, caused by an in-frame skip of exon 10 (PMID: 25243733, 29428273). Skipping of exon 10 results in an in-frame deletion of amino acids 480-517. This region forms part of the GAA catalytic barrel (amino acids 347-727) including two residues, Trp481 and Trp516, which are important in active site architecture and substrate binding (Kroos et al, 2012, PMID 22253258; Deming et al, 2017; DOI 10.1101/212837; Roig-Zamboni et al, 2017, PMID: 29061980). Therefore, loss of this exon is expected to abolish GAA activity (PVS1). At least 5 patients with findings consistent with Pompe disease have been reported with this variant. GAA activity was reported for 5 patients and was deficient (<10% residual activity) (PMID: 29428273, 21550241, 27189384, 37542277) (PP4_Moderate). At least one patient is homozygous for the variant, 0.5 points (PMID: 29428273). One patient is compound heterozygous for the variant and c.1561G>A, p.E521K (PMID: 37542277, pathogenic by ClinGen LD VCEP, phase unknown), 0.5 points. Two patients are compound heterozygous for the variant and GAA variant c.-32-3C>G (PMID: 27189384). The allelic data from these patients will be used in the assessment of the second variant and is not included here to avoid circular logic. 1 point (PM3). This variant is absent in gnomAD v2.1.1 and gnomAD v4.1.0 (PM2_Supporting). Other variants at the same canonical donor splice site have been reported in patients with Pompe disease, including c.1551+1G>C, c.1551+1G>T, and c.1551+2T>G (www.pompevariantdatabase.nl). One of these variants, c.1551+1G>C, has been classified as Pathogenic by the ClinGen LD VCEP. There is a ClinVar entry for this variant (Variation ID: 1065143). 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 Diseases Variant Curation Expert Panel (Specifications Version 2.0): PVS1, PM3, PP4_Moderate, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on January 21, 2025) -

May 12, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This sequence change affects a donor splice site in intron 10 of the GAA gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in GAA are known to be pathogenic (PMID: 18425781, 22252923). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with Pompe disease (PMID: 22133539, 25243733, 28648663). ClinVar contains an entry for this variant (Variation ID: 1065143). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.32
CADD
Pathogenic
33
DANN
Uncertain
1.0
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
0.98
FATHMM_MKL
Pathogenic
0.99
D
GERP RS
5.4

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.93
SpliceAI score (max)
0.99
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.21
Position offset: -25
DS_DL_spliceai
0.99
Position offset: -1

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-78084640; API