17-80110938-C-G

Variant names:

• chr17-80110938-C-G
• rs375470378
• NM_000152.5:c.1552-3C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PP3 PS3_Moderate PM2_Supporting PM3 PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.1552-3C>G variant in GAA is an intronic variant which occurs within intron 10 and is predicted to impact splicing by disrupting the acceptor splice site (PP3). Experimental studies in fibroblasts from a patient that was homozygous for the variant demonstrated that the variant results in the full inclusion of intron 10, which is predicted to introduce a premature termination codon. However, there was some evidence of normal splicing (PMID 6838077, 25243733) (PS3_Moderate). At least 3 patients with Pompe disease have been reported with this variant including 2 patients with documented GAA deficiency (PP4_Moderate) (PMID 16838077, 28196920, 23430949). Of these patients, one is homozygous for the variant (PMID 16838077) and one is compound heterozygous for the variant and c.-32-13T>G, phase unknown (PMID 16838077) (PM3). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0002713 (35/129024 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). There is a ClinVar entry for this variant (Variation ID: 419722, 2 star review status) with 10 submitters classifying as likely pathogenic or pathogenic and 1 submitter classifying as a variant of uncertain significance. In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease. GAA-specific ACMG/Amp criteria met, as specified by the ClinGen LSD VCEP: PM3, PS3_Moderate, PP4_Moderate, PP3, PM2_Supporting.Classification approved by the ClinGen LSD VCEP on May 16, 2022. LINK:https://erepo.genome.network/evrepo/ui/classification/CA8815383/MONDO:0009290/010

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: GAA NM_000152.5 splice_region, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Likely pathogenic reviewed by expert panel P:17
• Conservation: PhyloP100: 0.179
• Publications: 7 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: Likely_pathogenic. The variant received 8 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAA	NM_000152.5	c.1552-3C>G		splice_region_variant, intron_variant	Intron 10 of 19	ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8	c.1552-3C>G		splice_region_variant, intron_variant	Intron 10 of 19	1	NM_000152.5	ENSP00000305692.3

Frequencies

GnomAD3 genomes AF: 0.0000788 AC: 12 AN: 152216 Hom.: 0 Cov.: 33

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: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000135 AC: 34 AN: 251292 AF XY: 0.000132

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000273

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000104 AC: 152 AN: 1461624 Hom.: 0 Cov.: 36 AF XY: 0.000105 AC XY: 76 AN XY: 727102

African (AFR) AF: 0.0000597 AC: 2 AN: 33478

American (AMR) AF: 0.0000671 AC: 3 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.0000563 AC: 3 AN: 53242

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000126 AC: 140 AN: 1111946

Other (OTH) AF: 0.0000662 AC: 4 AN: 60390

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152216 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74358

African (AFR) AF: 0.00 AC: 0 AN: 41458

American (AMR) AF: 0.0000654 AC: 1 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000184 Hom.: 0

Bravo AF: 0.000102

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:17

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:11

Nov 06, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The GAA c.1552-3C>G variant involves the alteration of a non-conserved intronic nucleotide and 5/5 splice prediction tools predict an impact on normal splicing. Multiple functional studies support these predictions with findings indicating that the variant does affect splicing (Kroos_2006, Bergsma_2015). This variant was found in 38/277142 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.000276 (35/126638), which does not exceed the estimated maximal expected allele frequency of a pathogenic GAA variant (0.0042205). Multiple publications have cited the variant in homozygous affected individuals. In addition, a clinical diagnostic laboratory classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

May 11, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The GAA c.1552-3C>G variant (rs375470378) is reported in the literature in at least one homozygous individual affected with glycogen storage disease II, also called Pompe disease (Bergsma 2015, Kroos 2006). This variant is found in the non-Finnish European population with an overall allele frequency of 0.03% (35/129024 alleles) in the Genome Aggregation Database. This is an intronic variant in a moderately conserved nucleotide, and computational analyses (Alamut v.2.11) predict that this variant impacts splicing by weakening the nearby canonical acceptor splice site. Consistent with these predictions, analyses of patient cDNAs show production of aberrantly spliced mRNAs and reduced mRNA levels compared to those in healthy individuals (Bergsma 2015, Kroos 2006). In addition, fibroblasts from a homozygous individual with this variant exhibited decreased GAA protein levels and substantially reduced GAA enzymatic activity (Bergsma 2015, Kroos 2006). Based on available information, this variant is considered to be likely pathogenic. References: Bergsma AJ et al. Identification and characterization of aberrant GAA pre-mRNA splicing in pompe disease using a generic approach. Hum Mutat. 2015 Jan;36(1):57-68. Kroos M et al. Seven cases of Pompe disease from Greece. J Inherit Metab Dis. 2006 Aug;29(4):556-63. -

Feb 01, 2024

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

May 03, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 09, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PP3. -

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 10 of the GAA gene. It does not directly change the encoded amino acid sequence of the GAA protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (rs375470378, gnomAD 0.03%). This variant has been observed in individual(s) with glycogen storage disease (PMID: 16838077, 23430949, 25243733, 28196920). ClinVar contains an entry for this variant (Variation ID: 419722). 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 multiple aberrant transcripts, the most prominent of which (~80% of total transcript pool) includes all of intron 10, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 16838077, 25243733). For these reasons, this variant has been classified as Pathogenic. -

Nov 08, 2021

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_000152.3(GAA):c.1552-3C>G is an intronic variant classified as likely pathogenic in the context of Pompe disease. c.1552-3C>G has been observed in cases with relevant disease (PMID: 28196920, 16838077, 23430949, 33202836). Functional assessments of this variant are available in the literature (PMID: 16838077, 25243733, 27623443). c.1552-3C>G has been observed in population frequency databases (gnomAD: NFE 0.03%). In summary, NM_000152.3(GAA):c.1552-3C>G is an intronic variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -

Mar 24, 2024

Baylor Genetics

Significance: Likely 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.1552-3C>G variant in GAA has been reported in 3 individuals with Glycogen Storage Disease II (PMID: 16838077, 25243733, 28196920) and has also been reported likely pathogenic by Counsyl, Invitae, and EGL Genetic Diagnostics and pathogenic by GeneDx and Integrated Genetics in ClinVar (Variation ID: 419722). This variant has been identified in 0.027% (35/129024) of European (non-Finnish) chromosomes and 0.008% (3/35432) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs375470378). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies provide some evidence that the c.1552-3C>G variant may cause an impact on splicing in individuals homozygous for this variant with less than 9% of mRNA spliced correctly (PMID: 25243733, 16838077). However, these types of assays may not accurately represent biological function. This variant is located in the 3' splice region. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein, though some splice predictors do suggest an impact on a splice site. The presence of this variant in the homozygous state and in combination with a reported pathogenic variant, and in individuals with Glycogen Storage Disease II increases the likelihood that the c.1552-3C>G variant is pathogenic (PMID: 28196920, 16838077). The phenotype of individuals homozygous and heterozygous with this variant is highly specific for Glycogen Storage Disease II with abnormally low GAA activity detected in their leukocytes and the absence of known pseudodeficiency alleles in one individual (PMID: 28196920, 16838077). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PP4_Moderate, PM3, PM2, PS3_Supporting (Richards 2015). -

Jun 03, 2022

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.1552-3C>G variant in GAA is an intronic variant which occurs within intron 10 and is predicted to impact splicing by disrupting the acceptor splice site (PP3). Experimental studies in fibroblasts from a patient that was homozygous for the variant demonstrated that the variant results in the full inclusion of intron 10, which is predicted to introduce a premature termination codon. However, there was some evidence of normal splicing (PMID 6838077, 25243733) (PS3_Moderate). At least 3 patients with Pompe disease have been reported with this variant including 2 patients with documented GAA deficiency (PP4_Moderate) (PMID 16838077, 28196920, 23430949). Of these patients, one is homozygous for the variant (PMID 16838077) and one is compound heterozygous for the variant and c.-32-13T>G, phase unknown (PMID 16838077) (PM3). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0002713 (35/129024 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). There is a ClinVar entry for this variant (Variation ID: 419722, 2 star review status) with 10 submitters classifying as likely pathogenic or pathogenic and 1 submitter classifying as a variant of uncertain significance. In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease. GAA-specific ACMG/Amp criteria met, as specified by the ClinGen LSD VCEP: PM3, PS3_Moderate, PP4_Moderate, PP3, PM2_Supporting. Classification approved by the ClinGen LSD VCEP on May 16, 2022. -

Jul 22, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:5

Sep 16, 2021

AiLife Diagnostics, AiLife Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 28, 2023

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 16, 2017

Eurofins Ntd Llc (ga)

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 30, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RNA studies demonstrate a damaging effect; the c.1552-3 C>G variant causes aberrant gene splicing and reduced GAA expression (PMID: 16838077, 25243733); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 25525159, 16838077, 28196920, 34426522, 33202836, 23430949, 25243733, 34691145, 33717985, 35123877, 37670900, 27623443, 39678382, 40136631, 39033325) -

Jan 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GAA: PM2, PM3, PP3, PS3:Supporting -

Cardiovascular phenotype Pathogenic:1

Jul 17, 2023

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1552-3C>G intronic variant results from a C to G substitution 3 nucleotides upstream from coding exon 10 in the GAA gene. This alteration has been reported as homozygous and compound heterozygous in individuals with Pompe disease, including those with low enzyme activity (Kroos M et al. J Inherit Metab Dis, 2006 Aug;29:556-63; Wittmann J et al. JIMD Rep, 2012 Mar;6:117-25; Lin N et al. Clin Chem, 2017 Apr;63:842-851; Ficicioglu C et al. Int J Neonatal Screen, 2020 Nov;6:[ePub ahead of print]). Additionally, aberrant splicing was observed in an in vitro study (Kroos M et al. J Inherit Metab Dis, 2006 Aug;29:556-63). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and may result in the creation or strengthening of a novel splice acceptor site. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.30
CADD	Benign	18
DANN	Benign	0.92
PhyloP100		0.18
Mutation Taster		=5/95	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.95
SpliceAI score (max)		0.87		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.34		Position offset: -27
DS_AL_spliceai		0.87		Position offset: 3

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

Other links and lift over

dbSNP: rs375470378; hg19: chr17-78084737;