17-80105132-G-C

Variant names:

• chr17-80105132-G-C
• rs143523371
• NM_000152.5:c.546G>C

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM2_Supporting PM3_Strong PVS1_Strong PS1_Moderate PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.546G>C variant alters that last nucleotide of exon 2 of GAA, but does not result in an amino acid change (p.Thr182=). Study using minigene analysis showed that the variant disrupts normal splicing, resulting in skipping of exon 2, with a low proportion of normal transcripts produced (PMID:31301153). In addition, deletion of exon 2 results in complete loss of enzyme activity when expressed in heterologous cells (PMID:7881425, 7717400). As this variant appears to allow a low level of normal splicing to occur, PVS1 was applied at the strong level (PVS1_Strong). At least 4 late-onset Pompe Disease patient with this variant had documented GAA deficiency or activity in the affected range in any appropriate tissue (PMID:17616415, clinical lab data) (PP4_Moderate). One patient is compound heterozygous for the variant and c.-32-13T>G that has been classified as pathogenic by the ClinGen LD VCEP, phase not confirmed (PMID:17616415). This variant has also been detected in a Pompe disease patient who was heterozygous with c.2608C>T (p.Arg870*, Pathogenic by LD VCEP), and in 3 additional patients with homozygous (Revvity Omics and Duke lab data) (PM3_Strong). The highest population minor allele frequency in gnomAD v4.1.0 is 0.000008496 (10/1177056 alleles) in the European Non-Finnish population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). Other variants at the same nucleotide position (c.546G>T, c.546G>A), and in the same splice region (c.546+1G>T, c.546+2T>C, c.546+5G>T, and c.546del2‐5) have been reported in individuals with Pompe disease (https://www.pompevariantdatabase.nl/). All of these variants have been shown to result in skipping of exon 2 using a minigene assay (PMID:31301153, 39905333). c.546G>T and c.546G>A have been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP (PS1_Moderate).The computational splicing predictor SpliceAI gives a score of 0.84 for donor loss, predicting that the variant disrupts the donor splice site of intron 2 of GAA. But PP3 was not applied as PVS1 was applied. There is a ClinVar entry for this variant (Variation ID: 281056; 2 star review status) with 4 submitters classifying the variant as pathogenic, and 4 submitters classifying it as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, based in the specification of the ClinGen Lysosomal Diseases VCEP: PVS1_Strong, PS1_Moderate, PM3_Strong, PP4_Moderate, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on April 1, 2025) LINK:https://erepo.genome.network/evrepo/ui/classification/CA10603795/MONDO:0009290/010

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: GAA NM_000152.5 splice_region, synonymous
• Scores: Splicing: ADA: 0.9995
• Clinical Significance: Pathogenic reviewed by expert panel P:9
• Conservation: PhyloP100: 0.305
• Publications: 40 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS1: 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.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAA	NM_000152.5	MANE Select	c.546G>C	p.Thr182Thr	splice_region synonymous	Exon 2 of 20	NP_000143.2
	GAA	NM_001079803.3		c.546G>C	p.Thr182Thr	splice_region synonymous	Exon 3 of 21	NP_001073271.1
	GAA	NM_001079804.3		c.546G>C	p.Thr182Thr	splice_region synonymous	Exon 2 of 20	NP_001073272.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAA	ENST00000302262.8	TSL:1 MANE Select	c.546G>C	p.Thr182Thr	splice_region synonymous	Exon 2 of 20	ENSP00000305692.3
	GAA	ENST00000390015.7	TSL:1	c.546G>C	p.Thr182Thr	splice_region synonymous	Exon 3 of 21	ENSP00000374665.3
	GAA	ENST00000570803.6	TSL:5	c.546G>C	p.Thr182Thr	splice_region synonymous	Exon 2 of 20	ENSP00000460543.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000846 AC: 2 AN: 236410 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: 0.0000188

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000689 AC: 10 AN: 1451670 Hom.: 0 Cov.: 36 AF XY: 0.00000832 AC XY: 6 AN XY: 721554

African (AFR) AF: 0.00 AC: 0 AN: 33410

American (AMR) AF: 0.00 AC: 0 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26072

East Asian (EAS) AF: 0.00 AC: 0 AN: 39578

South Asian (SAS) AF: 0.00 AC: 0 AN: 86202

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46842

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5728

European-Non Finnish (NFE) AF: 0.00000902 AC: 10 AN: 1109026

Other (OTH) AF: 0.00 AC: 0 AN: 60144

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:6

Nov 22, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 24, 2021

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Apr 01, 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.546G>C variant alters that last nucleotide of exon 2 of GAA, but does not result in an amino acid change (p.Thr182=). Study using minigene analysis showed that the variant disrupts normal splicing, resulting in skipping of exon 2, with a low proportion of normal transcripts produced (PMID: 31301153). In addition, deletion of exon 2 results in complete loss of enzyme activity when expressed in heterologous cells (PMID: 7881425, 7717400). As this variant appears to allow a low level of normal splicing to occur, PVS1 was applied at the strong level (PVS1_Strong). At least 4 late-onset Pompe Disease patient with this variant had documented GAA deficiency or activity in the affected range in any appropriate tissue (PMID: 17616415, clinical lab data) (PP4_Moderate). One patient is compound heterozygous for the variant and c.-32-13T>G that has been classified as pathogenic by the ClinGen LD VCEP, phase not confirmed (PMID: 17616415). This variant has also been detected in a Pompe disease patient who was heterozygous with c.2608C>T (p.Arg870*, Pathogenic by LD VCEP), and in 3 additional patients with homozygous (Revvity Omics and Duke lab data) (PM3_Strong). The highest population minor allele frequency in gnomAD v4.1.0 is 0.000008496 (10/1177056 alleles) in the European Non-Finnish population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). Other variants at the same nucleotide position (c.546G>T, c.546G>A), and in the same splice region (c.546+1G>T, c.546+2T>C, c.546+5G>T, and c.546del2‐5) have been reported in individuals with Pompe disease (https://www.pompevariantdatabase.nl/). All of these variants have been shown to result in skipping of exon 2 using a minigene assay (PMID: 31301153, 39905333). c.546G>T and c.546G>A have been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP (PS1_Moderate).The computational splicing predictor SpliceAI gives a score of 0.84 for donor loss, predicting that the variant disrupts the donor splice site of intron 2 of GAA. But PP3 was not applied as PVS1 was applied. There is a ClinVar entry for this variant (Variation ID: 281056; 2 star review status) with 4 submitters classifying the variant as pathogenic, and 4 submitters classifying it as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, based in the specification of the ClinGen Lysosomal Diseases VCEP: PVS1_Strong, PS1_Moderate, PM3_Strong, PP4_Moderate, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on April 1, 2025)

Apr 24, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects codon 182 of the GAA mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the GAA protein. RNA analysis indicates that this variant induces altered splicing and is likely to result in the loss of the initiator methionine. This variant is present in population databases (no rsID available, gnomAD 0.002%). This variant has been observed in individual(s) with Pompe disease (PMID: 17616415). ClinVar contains an entry for this variant (Variation ID: 281056). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of skipping of exon 2, and is expected to result in the loss of the initiator methionine (PMID: 31301153). This variant disrupts the c.546G nucleotide in the GAA gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 14695532, 21484825, 25037089; Invitae). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

Mar 06, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 c.546G>C (p.Thr182=) variant in GAA has been reported in 1 Spanish individual with Glycogen Storage Disease II (PMID: 17616415), and has also been reported pathogenic by EGL in ClinVar (Variation ID: 281056). This variant has been identified in 0.002% (2/106330) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs143523371). 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 is located in the last three bases of the exon, which is part of the 5' splice region. Computational tools do suggest an impact to splicing. The Threonine (Thr) at position 182 is not well conserved in mammals or evolutionary distant species, raising the possibility that a change at this position may be tolerated. However, this information is not predictive enough to determine pathogenicity. The presence of this variant in combination with a pathogenic variant and in an individual with Glycogen Storage Disease II slightly increases the likelihood that the c.546G>C variant is pathogenic (PMID: 17616415). The phenotype of an individual heterozygous for this variant is highly specific for Glycogen Storage Disease II with only 21% of control GAA activity detected in patient fibroblasts (PMID: 17616415). Two additional variants at the same position, c.546G>T and c.546G>A, have been reported as a VUS or likely pathogenic in association with Glycogen Storage Disease II in ClinVar, supporting that a change at this position may not be tolerated (Variation ID: 370637, 280955). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PP3, PP4, PM3_Supporting, PM5_Supporting (Richards 2015).

not provided Pathogenic:3

Sep 26, 2022

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 19, 2021

AiLife Diagnostics, AiLife Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 06, 2015

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	19
DANN	Benign	0.79
PhyloP100		0.30
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=16/84	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.97
SpliceAI score (max)		0.84		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.24		Position offset: 40
DS_DL_spliceai		0.84		Position offset: 0

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

Other links and lift over

dbSNP: rs143523371; hg19: chr17-78078931;