rs755272974

Variant names:

• chr17-80116999-G-A
• rs755272974
• NM_000152.5:c.2221G>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PP3 PM2_Supporting PM3_Supporting PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.2221G>A variant in GAA is a missense variant predicted to cause substitution of aspartic acid by asparagine at amino acid 741 (p.Asp741Asn). One proband with symptoms consistent with infantile-onset Pompe disease has been reported with this variant with documented deficiency of GAA activity (PMID:29122469). This proband is compound heterozygous for the variant and a variant classified as pathogenic by the ClinGen Lysosomal Diseases VCEP, c.1978C>T (p.Arg660Cys) (PMID:29122469) (PM3_supporting). Another proband with symptoms consistent with late-onset Pompe disease has been reported with this variant with documented deficiency of GAA activity (Duke University; PMID:31904026, 32518148, 39983297). Additionally, both patients were treated with enzyme replacement therapy (PP4_Moderate). This proband is compound heterozygous for the variant, a variant classified as pathogenic by the ClinGen Lysosomal Diseases VCEP, c.1978C>T (p.Arg660Cys), and a variant classified as liekly pathogenic by the ClinGen Lysosomal Diseases VCEP, c.1477C>T (p.Pro493Ser). The c.2221G>A (p.Asp741Asn) and c.1477C>T (p.Pro493Ser) variants were confirmed in trans with the c.1978C>T (p.Arg660Cys) variant. The variants are confirmed in trans for this patient (Duke University). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00009603 (6/62480 alleles) in the Remaining population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_supporting). The computational predictor REVEL gives a score of 0.828 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3_met). Two other missense variants, c.2222A>T (p.Asp741Val) (ClinVar Variation ID: 291139) and c.2223C>G (p.Asp741Glu) (ClinVar Variation ID: 526539), in the same codon have been reported. However, these variants have not been classified by the ClinGen Lysosomal Diseases VCEP and, therefore, this evidence is not sufficient to meet PM5 at any strength. There is a ClinVar entry for this variant (Variation ID: 571521). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PM3_supporting, PP4_moderate, PM2_supporting, PP3_met). (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on May 6, 2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA8815660/MONDO:0009290/010

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:7
• Conservation: PhyloP100: 9.45
• 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: Uncertain_significance. The variant received 5 ACMG points.

• 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.

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.2221G>A	p.Asp741Asn	missense	Exon 16 of 20	NP_000143.2
	GAA	NM_001079803.3		c.2221G>A	p.Asp741Asn	missense	Exon 17 of 21	NP_001073271.1
	GAA	NM_001079804.3		c.2221G>A	p.Asp741Asn	missense	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.2221G>A	p.Asp741Asn	missense	Exon 16 of 20	ENSP00000305692.3
	GAA	ENST00000390015.7	TSL:1	c.2221G>A	p.Asp741Asn	missense	Exon 17 of 21	ENSP00000374665.3
	GAA	ENST00000570803.6	TSL:5	c.2221G>A	p.Asp741Asn	missense	Exon 16 of 20	ENSP00000460543.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152198 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000797 AC: 2 AN: 250898 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: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461438 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727034

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: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52990

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111994

Other (OTH) AF: 0.0000994 AC: 6 AN: 60392

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152198 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74346

African (AFR) AF: 0.00 AC: 0 AN: 41446

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Uncertain:4

May 06, 2025

ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000152.5:c.2221G>A variant in GAA is a missense variant predicted to cause substitution of aspartic acid by asparagine at amino acid 741 (p.Asp741Asn). One proband with symptoms consistent with infantile-onset Pompe disease has been reported with this variant with documented deficiency of GAA activity (PMID: 29122469). This proband is compound heterozygous for the variant and a variant classified as pathogenic by the ClinGen Lysosomal Diseases VCEP, c.1978C>T (p.Arg660Cys) (PMID: 29122469) (PM3_supporting). Another proband with symptoms consistent with late-onset Pompe disease has been reported with this variant with documented deficiency of GAA activity (Duke University; PMID: 31904026, 32518148, 39983297). Additionally, both patients were treated with enzyme replacement therapy (PP4_Moderate). This proband is compound heterozygous for the variant, a variant classified as pathogenic by the ClinGen Lysosomal Diseases VCEP, c.1978C>T (p.Arg660Cys), and a variant classified as liekly pathogenic by the ClinGen Lysosomal Diseases VCEP, c.1477C>T (p.Pro493Ser). The c.2221G>A (p.Asp741Asn) and c.1477C>T (p.Pro493Ser) variants were confirmed in trans with the c.1978C>T (p.Arg660Cys) variant. The variants are confirmed in trans for this patient (Duke University). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00009603 (6/62480 alleles) in the Remaining population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_supporting). The computational predictor REVEL gives a score of 0.828 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3_met). Two other missense variants, c.2222A>T (p.Asp741Val) (ClinVar Variation ID: 291139) and c.2223C>G (p.Asp741Glu) (ClinVar Variation ID: 526539), in the same codon have been reported. However, these variants have not been classified by the ClinGen Lysosomal Diseases VCEP and, therefore, this evidence is not sufficient to meet PM5 at any strength. There is a ClinVar entry for this variant (Variation ID: 571521). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PM3_supporting, PP4_moderate, PM2_supporting, PP3_met). (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on May 6, 2025).

Oct 01, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 741 of the GAA protein (p.Asp741Asn). This variant is present in population databases (rs755272974, gnomAD 0.01%). This missense change has been observed in individual(s) with Pompe disease (PMID: 29122469, 31904026). ClinVar contains an entry for this variant (Variation ID: 571521). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt GAA protein function with a positive predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Feb 17, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Apr 26, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Uncertain:1

Nov 29, 2022

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: GAA c.2221G>A (p.Asp741Asn) results in a conservative amino acid change located in the Glycosyl hydrolase, all-beta domain (IPR013780) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250898 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2221G>A has been reported in the literature in a case affected with infantile Glycogen Storage Disease, Type 2 (Pompe Disease) (example: Mori_2017). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

not provided Uncertain:1

Dec 12, 2023

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Cardiovascular phenotype Uncertain:1

Dec 31, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.D741N variant (also known as c.2221G>A), located in coding exon 15 of the GAA gene, results from a G to A substitution at nucleotide position 2221. The aspartic acid at codon 741 is replaced by asparagine, an amino acid with highly similar properties. This variant has been identified in the homozygous state and/or in conjunction with other GAA variant(s) in individual(s) with features consistent with glycogen storage disease II (Mori M et al. Mol Genet Metab, 2017 Dec;122:189-197; Korlimarla A et al. Neurology, 2020 Aug;95:e718-e732). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.019	T
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.93	D
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.86	D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		9.5
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Pathogenic	0.83
Sift	Benign	0.034	D
Sift4G	Uncertain	0.041	D
Polyphen		0.99	D
Vest4		0.92
MutPred		0.79		Loss of phosphorylation at T739 (P = 0.1546)
MVP		0.99
MPC		0.52
ClinPred		0.95	D
GERP RS		5.1
Varity_R		0.92
gMVP		0.78
Mutation Taster		=5/95	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs755272974; hg19: chr17-78090798;