NM_000152.5(GAA):c.2297A>C (p.Tyr766Ser) AND Glycogen storage disease, type II

Germline classification:: Pathogenic (7 submissions)
Last evaluated:: Jun 3, 2022
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001065031.21

Allele description [Variation Report for NM_000152.5(GAA):c.2297A>C (p.Tyr766Ser)]

NM_000152.5(GAA):c.2297A>C (p.Tyr766Ser)

Gene:

GAA:alpha glucosidase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

17q25.3

Genomic location:

Preferred name:

NM_000152.5(GAA):c.2297A>C (p.Tyr766Ser)

Other names:

NM_000152.5(GAA):c.2297A>C

HGVS:

NC_000017.11:g.80117075A>C
NG_009822.1:g.20520A>C
NM_000152.4(GAA):c.2297A>C
NM_000152.5:c.2297A>CMANE SELECT
NM_001079803.3:c.2297A>C
NM_001079804.3:c.2297A>C
NP_000143.2:p.Tyr766Ser
NP_001073271.1:p.Tyr766Ser
NP_001073272.1:p.Tyr766Ser
LRG_673t1:c.2297A>C
LRG_673:g.20520A>C
NC_000017.10:g.78090874A>C
NM_000152.3:c.2297A>C
NM_000152.4(GAA):c.2297A>C
NM_000152.4:c.2297A>C
NM_000152.5:c.2297A>C
NM_001079803.2:c.2297A>C
p.Tyr766Ser

Protein change:

Y766S

Links:

dbSNP: rs144016984

NCBI 1000 Genomes Browser:

rs144016984

Molecular consequence:

NM_000152.5:c.2297A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001079803.3:c.2297A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001079804.3:c.2297A>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Glycogen storage disease, type II (GSD2)
Synonyms:: ACID ALPHA-GLUCOSIDASE DEFICIENCY; ALPHA-1,4-GLUCOSIDASE DEFICIENCY; CARDIOMEGALIA GLYCOGENICA DIFFUSA; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009290; MedGen: C0017921; Orphanet: 365; OMIM: 232300

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001229969	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 19, 2025)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 22521436, 22538254, 28394184, 21605996, 29124014, 28492532
SCV001339198	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Sep 10, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 28394184, 26693141, 22521436 Citation Link,
SCV001423071	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 22, 2020)	germline	curation	PubMed (5) [See all records that cite these PMIDs] 21637107, 26693141, 22521436, 28394184, 25741868 Citation Link,
SCV002092123	Natera, Inc.	no assertion criteria provided	Pathogenic (Jun 15, 2020)	germline	clinical testing
SCV002540647	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	reviewed by expert panel (clingen_lsd_acmg_specifications_v2-1)	Pathogenic (Jun 3, 2022)	germline	curation	Citation Link,
SCV002779808	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 13, 2022)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004195427	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 9, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation

Citations

PubMed

The emerging phenotype of long-term survivors with infantile Pompe disease.

Prater SN, Banugaria SG, DeArmey SM, Botha EG, Stege EM, Case LE, Jones HN, Phornphutkul C, Wang RY, Young SP, Kishnani PS.

Genet Med. 2012 Sep;14(9):800-10. doi: 10.1038/gim.2012.44. Epub 2012 Apr 26.

PubMed [citation]

PMID:: 22538254
PMCID:: PMC3947503

Expanding the clinical spectrum of late-onset Pompe disease: dilated arteriopathy involving the thoracic aorta, a novel vascular phenotype uncovered.

El-Gharbawy AH, Bhat G, Murillo JE, Thurberg BL, Kampmann C, Mengel KE, Kishnani PS.

Mol Genet Metab. 2011 Aug;103(4):362-6. doi: 10.1016/j.ymgme.2011.04.009. Epub 2011 May 5.

PubMed [citation]

PMID:: 21605996

See all PubMed Citations (9)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001229969.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change replaces tyrosine, which is neutral and polar, with serine, which is neutral and polar, at codon 766 of the GAA protein (p.Tyr766Ser). This variant is present in population databases (rs144016984, gnomAD 0.006%). This missense change has been observed in individual(s) with Pompe disease (PMID: 22521436, 22538254, 28394184; externalcommunication). ClinVar contains an entry for this variant (Variation ID: 420102). 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%. This variant disrupts the p.Tyr766 amino acid residue in GAA. Other variant(s) that disrupt this residue have been observed in individuals with GAA-related conditions (PMID: 21605996, 29124014), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001339198.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Variant summary: GAA c.2297A>C (p.Tyr766Ser) results in a non-conservative amino acid change located in the glycosyl hydrolase family 31, C-terminal domain (IPR048395) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250124 control chromosomes (gnomAD). c.2297A>C has been reported in the literature in multiple individuals affected with glycogen storage disease, type 2 (Pompe Disease) (examples: Yonee_2012, Bali_2015, Chen_2017). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 28394184, 26693141, 22521436). ClinVar contains an entry for this variant (Variation ID: 420102). Based on the evidence outlined above, the variant was classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001423071.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (5)

Description

The p.Tyr766Ser variant in GAA has been reported in 6 individuals (including 1 Japanese individual and 1 Chinese individual) with Glycogen Storage Disease II (PMID: 26693141, 21637107, 22521436), and has also been reported pathogenic by GeneDx in ClinVar (Variation ID: 420102). This variant has been identified in 0.005% (1/18378) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs144016984). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The presence of this variant in the homozygous state and in combination with a pathogenic variant, and in individuals with Glycogen Storage Disease II increases the likelihood that the p.Tyr766Ser variant is pathogenic (PMID: 22521436, 21637107). The phenotype of an individual heterozygous for this variant is highly specific for Glycogen Storage Disease II based on GAA activity consistent with disease (PMID: 21637107, 22521436). One additional variant at the same position, p.Tyr766Cys, has been reported as a VUS in ClinVar (Variation ID: 285197). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM3, PM2, PP3, PP4 (Richards 2015).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Natera, Inc., SCV002092123.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel, SCV002540647.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	not provided

Description

The NM_000152.5: c.2297A>C variant in GAA is a missense variant predicted to cause substitution of tyrosine by serine at amino acid 766 (p.Tyr766Ser). At least 12 patients with this variant have been reported including 7 with documented GAA deficiency with <1% of normal mean control level of GAA activity in cultured fibroblasts or GAA activity in the affected leukocytes or dried blood spot (PMID: 22538254, 22521436, 31875618, Clinical Laboratory data), one noted to have deficient GAA activity but results were not provided (PMID: 28394184), and two reported to have Pompe disease with no further details (PMID: 26693141). At least three of these patients are receiving enzyme replacement therapy (PMID: 22521436, 22538254, 26693141 29289479, 30214072, 31899940) (PP4_Moderate). Of the reported patients, at least three are homozygous (PMID: 22521436, 22538254, 26693141 29289479, 31899940, Clinical Laboratory data, and seven were compound heterozygous for the variant and a variant classified as pathogenic by the ClinGen LSD VCEP including c.1309C>T (p.Arg437Cys) (PMID: 22521436), c.-32-13T>G (Clinical Laboratory Data), c.2608C>T (p.Arg870Ter) (Clinical Laboratory Data), c.525delT (PMID: 30214072), all phase unknown, and c.1822C>T (p.Arg608Ter), confirmed in trans by parental testing (PMID: 31875618) (PM3_Very Strong). Two other individuals are compound heterozygous for the variant and either c.1118T>G (p.Leu373Arg) (Clinical Laboratory data) or c.2105G>A (p.Arg702His) (PMID: 28394184) but the allelic data from these patients will be used in the classification of the second variant and is not included here to avoid circular logic. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00005441 (1/18378 alleles) in the East Asian population, which is lower than the ClinGen LSD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion. The computational predictor REVEL gives a score of 0.98 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). To our knowledge, the results of functional studies for this variant have not been published. Two other missense variants, c.2297A>G (p.Tyr766Cys) and 2296T>A (p.Tyr766Asn), in the same codon have been reported in patients with Pompe disease. The classification of c.2297A>C (p.Tyr766Ser) will be used to apply PM5 for those other variants and is not included here to avoid circular logic. There is a ClinVar entry for this variant (Variation ID: 420102; 2 star review status) with five submitters classifying the variant as pathogenic and one as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Storage Disorders Expert Panel: PM3_VeryStrong, PP4_Moderate, PP3, PM2_Supporting. Classification approved by the ClinGen LSD VCEP on May 16, 2022.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Fulgent Genetics, Fulgent Genetics, SCV002779808.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV004195427.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Apr 28, 2025

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