NM_000152.5:c.2242dupG

Variant names:

• chr17-80117014-T-TG
• rs777275355
• NM_000152.5:c.2242dupG

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PP4 PM2 PVS1

This summary comes from the ClinGen Evidence Repository: This variant, c.2242dup (p.Glu748Glyfs), is a frameshift variant predicted to cause a premature termination codon, nonsense mediated decay, and lack of gene product, meeting PVS1. The highest population minor allele frequency in gnomAD is 0.00001767 in the European, non-Finnish, population, meeting PM2. This variant has been reported in at least 2 individuals with Pompe disease and deficient GAA activity meeting the ClinGen LSD VCEP’s PP4 specifications (PMIDs 9535769, 21484825). Both of these individuals are compound heterozygous for the variant and a unique variant, phase unknown; either c.1933G>A (p.Asp645Asn) (PMID 9535769) or c.1195-8G>A (PMID 21484825). In both cases, the in trans data from these patients will be used in the assessment of the second variant and was not included here in order to avoid a circular argument. There is a ClinVar entry for this variant (Variation ID 370651; 2 star review status) with three submitters classifying the variant and pathogenic, and one as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe Disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1, PM2, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA8815662/MONDO:0009290/010

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000043 (0 hom.)
• Consequence: GAA NM_000152.5 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:11
• Conservation: PhyloP100: 9.45
• Publications: 2 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 11 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.
• 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.2242dupG	p.Glu748GlyfsTer48	frameshift	Exon 16 of 20	NP_000143.2
	GAA	NM_001079803.3		c.2242dupG	p.Glu748GlyfsTer48	frameshift	Exon 17 of 21	NP_001073271.1
	GAA	NM_001079804.3		c.2242dupG	p.Glu748GlyfsTer48	frameshift	Exon 16 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.2242dupG	p.Glu748GlyfsTer48	frameshift	Exon 16 of 20	ENSP00000305692.3
	GAA	ENST00000390015.7	TSL:1	c.2242dupG	p.Glu748GlyfsTer48	frameshift	Exon 17 of 21	ENSP00000374665.3
	GAA	ENST00000570803.6	TSL:5	c.2242dupG	p.Glu748GlyfsTer48	frameshift	Exon 16 of 20	ENSP00000460543.2

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152154 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000798 AC: 2 AN: 250780 AF XY: 0.00000737

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: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000431 AC: 63 AN: 1461388 Hom.: 0 Cov.: 30 AF XY: 0.0000399 AC XY: 29 AN XY: 727004

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

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

European-Finnish (FIN) AF: 0.0000567 AC: 3 AN: 52938

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

European-Non Finnish (NFE) AF: 0.0000504 AC: 56 AN: 1111996

Other (OTH) AF: 0.0000497 AC: 3 AN: 60392

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152154 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74328

African (AFR) AF: 0.0000241 AC: 1 AN: 41434

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000302

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:7

May 04, 2020

ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

This variant, c.2242dup (p.Glu748Glyfs), is a frameshift variant predicted to cause a premature termination codon, nonsense mediated decay, and lack of gene product, meeting PVS1. The highest population minor allele frequency in gnomAD is 0.00001767 in the European, non-Finnish, population, meeting PM2. This variant has been reported in at least 2 individuals with Pompe disease and deficient GAA activity meeting the ClinGen LSD VCEP's PP4 specifications (PMIDs 9535769, 21484825). Both of these individuals are compound heterozygous for the variant and a unique variant, phase unknown; either c.1933G>A (p.Asp645Asn) (PMID 9535769) or c.1195-8G>A (PMID 21484825). In both cases, the in trans data from these patients will be used in the assessment of the second variant and was not included here in order to avoid a circular argument. There is a ClinVar entry for this variant (Variation ID 370651; 2 star review status) with three submitters classifying the variant and pathogenic, and one as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe Disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1, PM2, PP4.

Mar 26, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 15, 2016

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Oct 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Glu748Glyfs*48) in the GAA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GAA are known to be pathogenic (PMID: 18425781, 22252923). This variant is present in population databases (rs777275355, gnomAD 0.002%). This premature translational stop signal has been observed in individuals with glycogen storage disease type II (PMID: 9535769, 16917947, 21484825, 29122469). This variant is also known as insGnt2243 and insG2242. ClinVar contains an entry for this variant (Variation ID: 370651). For these reasons, this variant has been classified as Pathogenic.

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jan 22, 2020

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The p.Glu748GlyfsTer48 variant in GAA has been reported in at least 5 individuals (including 2 from the UK, and 1 Italian individuals) with Glycogen Storage Disease II (PMID: 16917947, 9535769, 10206684, 21484825), and has also been reported likely pathogenic by Counsyl and pathogenic by GeneDx and EGL in ClinVar (Variation ID: 370651). This variant has been identified in 0.0018% (2/113202) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1057516659). 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 predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 748 and leads to a premature termination codon 48 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the GAA gene is an established disease mechanism in autosomal recessive Glycogen Storage Disease II. The presence of this variant in combination with at least 2 pathogenic variants curated by our study and in individuals with Glycogen Storage Disease II increases the likelihood that the p.Glu748GlyfsTer48 variant is pathogenic (PMID: 9535769, 29122469). The phenotype of two individuals heterozygous for this variant is highly specific for Glycogen Storage Disease II with abnormally low GAA activity detected in fibroblasts (PMID: 9535769, 21484825). In summary, this variant meets criteria to be classified as pathogenic for Glycogen Storage Disease II in an autosomal recessive manner based on the predicted impact of the variant and multiple occurrences with pathogenic GAA variants in individuals with Glycogen Storage Disease II. ACMG/AMP Criteria applied: PVS1, PM3, PM2, PP4 (Richards 2015).

Dec 27, 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.2242dupG (p.Glu748GlyfsX48) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (c.2501_2502delCA p.Thr834ArgfsX49; c.2544delC p.Lys849ArgfsX38). The variant allele was found at a frequency of 8e-06 in 250780 control chromosomes. c.2242dupG has been reported in the literature in multiple individuals affected with both infantile (example: Beesley_1998, Huie_1998) and late/adult (example: Montalvo_2006, Stepien_2016) onset forms of Glycogen Storage Disease, Type 2 (Pompe Disease). 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: fibroblasts cultured from a patient with the variant of interest alongside a null variant showed <0.1% normal enzymatic activity (Huie_1998). Eight ClinVar submitters, including one expert panel (ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel) have assessed the variant since 2014: seven have classified the variant as pathogenic and one as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

not provided Pathogenic:4

Jul 24, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in multiple patients with GSDII in published literature, including at least one patient who had biochemical testing that was diagnostic and consistent with the results seen in other patients with pathogenic variants in this gene (PMID: 10206684, 16917947, 21484825); Not observed at significant frequency in large population cohorts (gnomAD); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 17915575, 29122469, 26873529, 31254424, 34501319, 10206684, 16917947, 22644586, 9535769, 36046397, 21484825)

Jan 31, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 21, 2025

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 29, 2024

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This is a single base pair duplication in exon 16, c.2242dup. This sequence change results in an amino acid frameshift and creates a premature stop codon 47 amino acids downstream of the change, p.Glu748Glyfs*48. This sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated GAA protein with potentially abnormal function. This sequence change has been described in the gnomAD database with a frequency of 0.005% in the European subpopulation (dbSNP rs777275355). This sequence change has previously been described in individuals with glycogen storage disease type II (PMID: 9535769, 16917947, 21484825, 29122469, 10206684, 36046397, 31254424). Collectively, this evidence indicates that this sequence change is pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.5
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs777275355; hg19: chr17-78090813; COSMIC: COSV100162834; COSMIC: COSV100162834;