GAA

protein-coding

alpha glucosidase, the group of Glycoside hydrolase family 31

Gene summary

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]

MANE transcript

NM_000152.5

Inheritance

ClinVar variants

P:957U:1053B:777

Top phenotype

Pompe disease (Glycogen storage disease II)

gnomAD constraint

pLI —, LoF o/e 0.74

Max pathogenic AF

—

Genomic locus

chr17:80,101,533-80,119,881

External References & Databases

Ensembl (ENSG00000171298)

Transcript & Mutation Effects

hg38 • Region Span ~18.3 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

glycogen storage disease IIDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009290

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

glycogen storage disease IIDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009290

Submitter: G2P

glycogen storage disease due to acid maltase deficiency, late-onsetSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018485

Submitter: Orphanet

glycogen storage disease IISTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009290

Submitter: Labcorp Genetics (formerly Invitae)

glycogen storage disease due to acid maltase deficiency, infantile onsetSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0017694

Submitter: Orphanet

glycogen storage disease IISTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009290

Submitter: Genomics England PanelApp

glycogen storage disease IISTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009290

Submitter: PanelApp Australia

glycogen storage disease IIDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009290

Submitter: Natera

glycogen storage disease IIDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009290

Submitter: ClinGen

The relationship between GAA and glycogen storage disease type II (GSD II; Pompe disease; acid maltase deficiency) was evaluated using the ClinGen Clinical Validity Framework as of June 26, 2017. Deficiency of the gene product, acid alpha-glucosidase (acid maltase) was first reported in individuals with GSD II by Hers in 1963, and variants in GAA were first associated with this disease 1991 (Hermans et al, MID 8401535; Zhong et al, 1652892; Martinuik et al, 1684505). Over 800 unique variants, including missense, nonsense, splice site, in frame insertions and deletions, frameshift, large deletions, and complex rearrangements have been reported in humans (http://cluster15.erasmusmc.nl/klgn/pompe/mutations.html?lang=en). Evidence supporting this gene-disease relationship includes case-level data and experimental data. Fourteen variants were curated in 10 probands in 9 publications (Zhong et al, 1991, PMID 1652892; Hermans et al, 1993, PMID 8094613; Huie et al, 1994, PMID 7981676; Boerkoel et al, 1995, PMID 7717400; Huie et al, 1998, PMID 9535769; Pipo et al, 2003, PMID 14643388; Palmer et al, 2007, PMID 17056254; Oba-Shinjo et al, 2009, PMID 19588081; Rohrbach et al, 2010, PMID 20882352 ). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism for disease is loss of function. This gene-disease association is supported by the function of the gene product (Brown et al, 1965, PMID 4286143), abnormal synthesis, transport and processing, and deficient activity of acid alpha-glucosidase in cells from patients and non-patient cells expressing GAA variants (Hermans et al, 1991, PMID 1856189; Reuser et al, 1997, PMID 3108320; Umapathysivam et al, 2000, PMID 10973860; Bali et al, 2011, PMID 21484825), animal models (Raben et al, 1998, PMID 9668092), gene therapy in animal models (Fraites et al, 2002, PMID 11991748) and studies of the clinical impact of enzyme replacement therapy in humans (Kishnani et al, 2006, PMID 1680134). In summary, GAA is definitively associated with glycogen storage disease type II. This association has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

glycogen storage disease IIDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009290

Submitter: G2P

Clinical Genomic Database (CGD)

Pompe disease (Glycogen storage disease II)AR

Manifestation: Biochemical; Cardiovascular; Musculoskeletal; Neurologic; Pulmonary

Intervention: Biochemical; Cardiovascular; Pharmacogenomic

Rationale: Enzyme therapy is available; Disease-specific care of cardiomyopathy may be beneficial (eg, some standard drugs are contraindicated, and there is high risk for arrhythmias and sudden cardiac death)

Refs: 5217754; 4288232; 5229488; 5247277; 5240358; 6810200; 6401355; 3084996; 3093639; 3090917; 3322184; 3135192; 3282727; 3288378; 2403755; 2243227; 2203258; 1895140; 11071489; 10931430; 11286229; 12601120; 12897283; 15668445; 15985590; 16433701; 17190962; 16917947; 19047571; 19047572; 20301438; 21543987; 21518733; 21637107; 22253258; 22334186; 22353292; 22365055; 22492103; 22538254; 22539577; 22581536; 22616199; 23884227; 24008937; 24011652; 24044919

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GAA variants in ClinVar

26 Conditions Cataloged

Glycogen storage disease, type IITotal: 3258

not providedTotal: 911

Cardiovascular phenotypeTotal: 428

not specifiedTotal: 304

GAA-related disorderTotal: 107

GAA-related disordersTotal: 60

Glycogen storage disease due to acid maltase deficiency, late-onsetTotal: 30

Glycogen storage diseaseTotal: 17

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000152.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous	3 clinvar	4 clinvar	32 clinvar	724 clinvar	10 clinvar	773
missense	67 clinvar	270 clinvar	1006 clinvar	38 clinvar	4 clinvar	1385
nonsense	90 clinvar	41 clinvar	2 clinvar			133
start loss	3 clinvar	3 clinvar				6
frameshift	225 clinvar	135 clinvar	3 clinvar			363
splice donor/acceptor (+/-2bp)	53 clinvar	63 clinvar	10 clinvar	1 clinvar		127
Total	441	516	1053	763	14	2787

Highest pathogenic variant AF is 0.0052548107

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 37 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000152.5	RefSeq	NP_000143.2	19	MANE Select
ENST00000302262.8	Ensembl	ENSP00000305692.3	19	MANE Select
NM_001079803.3	RefSeq	NP_001073271.1	19	Standard
NM_001079804.3	RefSeq	NP_001073272.1	19	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
gaa	Danio rerio	Structure: skeletal muscle Quality: increased amount abnormal

Gene / Model

Organism

Observed Phenotype

gaa

Danio rerio

Structure: skeletal muscle

Quality: increased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Starch and sucrose metabolism - Homo sapiens (human)
Lysosome - Homo sapiens (human)
Galactose metabolism - Homo sapiens (human)
Galactose Metabolism
Galactosemia

Biological Process

maltose metabolic process
regulation of the force of heart contraction
diaphragm contraction
heart morphogenesis
glycogen catabolic process

Molecular Function

alpha-1,4-glucosidase activity
carbohydrate binding
maltose alpha-glucosidase activity
alpha-glucosidase activity

Cellular Component

lysosome
lysosomal membrane
plasma membrane
membrane
azurophil granule membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000302262
Coding exons: 19
Length: 18324
Individuals with no LoFs: 125568
Homozygous LoFs: 0
Heterozygous LoFs: 178
Defined: 125746
p: 0.000708

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.633	646	602	1.07	0.0000408	6128
Missense (PolyPhen)		214	204.02	1.0489		2086
Synonymous	-0.901	290	271	1.07	0.0000207	1986
Loss of Function	1.66	34	46.1	0.737	0.00000236	447

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0027	0.0026	notable
Latino/Admixed American	0.00070	0.00069	rare
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.00076	0.00076	rare
Finnish	0.00037	0.00037	rare
European (Non-Finnish)	0.00071	0.00067	rare
South Asian	0.00040	0.00039	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Essential for the degradation of glycogen in lysosomes (PubMed:1856189, PubMed:7717400, PubMed:14695532, PubMed:18429042). Has highest activity on alpha-1,4-linked glycosidic linkages, but can also hydrolyze alpha-1,6-linked glucans (PubMed:29061980). {ECO:0000269|PubMed:14695532, ECO:0000269|PubMed:18429042, ECO:0000269|PubMed:1856189, ECO:0000269|PubMed:29061980, ECO:0000269|PubMed:7717400}.;
Disease: DISEASE: Glycogen storage disease 2 (GSD2) [MIM:232300]: A metabolic disorder with a broad clinical spectrum. The severe infantile form, or Pompe disease, presents at birth with massive accumulation of glycogen in muscle, heart and liver. Cardiomyopathy and muscular hypotonia are the cardinal features of this form whose life expectancy is less than two years. The juvenile and adult forms present as limb-girdle muscular dystrophy beginning in the lower limbs. Final outcome depends on respiratory muscle failure. Patients with the adult form can be free of clinical symptoms for most of their life but finally develop a slowly progressive myopathy. {ECO:0000269|PubMed:10189220, ECO:0000269|PubMed:10206684, ECO:0000269|PubMed:10338092, ECO:0000269|PubMed:10737124, ECO:0000269|PubMed:11071489, ECO:0000269|PubMed:11738358, ECO:0000269|PubMed:12601120, ECO:0000269|PubMed:12923862, ECO:0000269|PubMed:14643388, ECO:0000269|PubMed:14695532, ECO:0000269|PubMed:14972326, ECO:0000269|PubMed:15145338, ECO:0000269|PubMed:15668445, ECO:0000269|PubMed:16433701, ECO:0000269|PubMed:1652892, ECO:0000269|PubMed:16782080, ECO:0000269|PubMed:1684505, ECO:0000269|PubMed:16917947, ECO:0000269|PubMed:17643989, ECO:0000269|PubMed:18425781, ECO:0000269|PubMed:18429042, ECO:0000269|PubMed:1898413, ECO:0000269|PubMed:19588081, ECO:0000269|PubMed:20080426, ECO:0000269|PubMed:20350966, ECO:0000269|PubMed:21109266, ECO:0000269|PubMed:22644586, ECO:0000269|PubMed:22676651, ECO:0000269|PubMed:25681614, ECO:0000269|PubMed:7695647, ECO:0000269|PubMed:7717400, ECO:0000269|PubMed:7866409, ECO:0000269|PubMed:7881422, ECO:0000269|PubMed:7981676, ECO:0000269|PubMed:8094613, ECO:0000269|PubMed:8401535, ECO:0000269|PubMed:8834250, ECO:0000269|PubMed:9521422, ECO:0000269|PubMed:9535769, ECO:0000269|PubMed:9660056, ECO:0000269|Ref.5}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.935

Intolerance Scores

LoFtool: 0.0315
RVIS EVS: -1.16
RVIS percentile EVS: 6.1

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.524

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium