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
Consequence
NM_000152.5 splice_donor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 37
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Glycogen storage disease, type II Pathogenic:4
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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. -
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) -
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.