NM_000152.5(GAA):c.2297A>G (p.Tyr766Cys) AND Glycogen storage disease, type II

Germline classification:: Pathogenic (6 submissions)
Last evaluated:: Jun 6, 2024
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:: RCV001049848.21

Allele description [Variation Report for NM_000152.5(GAA):c.2297A>G (p.Tyr766Cys)]

NM_000152.5(GAA):c.2297A>G (p.Tyr766Cys)

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>G (p.Tyr766Cys)

Other names:

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

HGVS:

NC_000017.11:g.80117075A>G
NG_009822.1:g.20520A>G
NM_000152.5:c.2297A>GMANE SELECT
NM_001079803.3:c.2297A>G
NM_001079804.3:c.2297A>G
NP_000143.2:p.Tyr766Cys
NP_001073271.1:p.Tyr766Cys
NP_001073272.1:p.Tyr766Cys
LRG_673t1:c.2297A>G
LRG_673:g.20520A>G
NC_000017.10:g.78090874A>G
NM_000152.3:c.2297A>G
NM_000152.4(GAA):c.2297A>G
NM_000152.4:c.2297A>G
P10253:p.Tyr766Cys

Protein change:

Y766C

Links:

UniProtKB: P10253#VAR_070019; dbSNP: rs144016984

NCBI 1000 Genomes Browser:

rs144016984

Molecular consequence:

NM_000152.5:c.2297A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001079803.3:c.2297A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001079804.3:c.2297A>G - 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
SCV001213921	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 24, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 21605996, 30564623, 22538254, 28394184, 28492532
SCV001422964	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 (4) [See all records that cite these PMIDs] 22676651, 29124014, 21605996, 25741868 Citation Link,
SCV001442688	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Oct 13, 2020)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 22676651, 29124014, 30564623, 21605996 Citation Link,
SCV001810186	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jul 22, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004195437	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 1, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005089710	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	reviewed by expert panel (clingen_lsd_acmg_specifications_v2-1)	Pathogenic (Jun 6, 2024)	germline	curation	Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	no	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
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

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

Clinical and Molecular Characterization of Infantile-Onset Pompe Disease in Mainland Chinese Patients: Identification of Two Common Mutations.

Chen X, Liu T, Huang M, Wu J, Zhu J, Guo Y, Xu X, Li F, Wang J, Fu L.

Genet Test Mol Biomarkers. 2017 Jun;21(6):391-396. doi: 10.1089/gtmb.2016.0424. Epub 2017 Apr 10.

PubMed [citation]

PMID:: 28394184

See all PubMed Citations (8)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001213921.5

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

Description

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 766 of the GAA protein (p.Tyr766Cys). This variant is present in population databases (rs144016984, gnomAD 0.006%). This missense change has been observed in individual(s) with Pompe disease (PMID: 21605996, 22538254, 30564623). ClinVar contains an entry for this variant (Variation ID: 285197). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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: 22538254, 28394184), 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 Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001422964.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (4)

Description

The p.Tyr766Cys variant in GAA has been reported in at least two individuals with glycogen storage disease II (PMID: 22676651, 21605996, 29124014) and has been identified in 0.007% (2/30610) of South Asian chromosomes and 0.004% (5/128266) of European (non-Finnish) 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. This variant has also been reported in ClinVar (VariationID: 285197) as a VUS by EGL Genetics Diagnostics. One additional likely pathogenic variant, resulting in a different amino acid change at the same position, p.Tyr766Ser, has been reported in association with disease in ClinVar, slightly supporting that a change at this position may not be tolerated (Variation ID: 420102). The phenotype of individuals heterozygous for this variant is highly specific for glycogen storage disease II based on GAA enzyme activity being <10% of wild type, consistent with disease (PMID: 22676651, 21605996, 29124014). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Additionally, the presence of this variant in combination with reported likely pathogenic variants c.1561G>A (VariationID: 4022; PMID: 22676651, 21605996) and p.Arg437Cys (VariationID:189082, PMID: 29124014) and in individuals with glycogen storage disease II increases the likelihood that the p.Tyr766Cys variant is pathogenic. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PP3, PM5_supporting, PP4, PM3_supporting (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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001442688.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

Variant summary: GAA c.2297A>G (p.Tyr766Cys) results in a non-conservative amino acid change in 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 2.4e-05 in 250124 control chromosomes (gnomAD). c.2297A>G has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) (e.g. El-Gharbawy_2011, Herzog_2012, Fukuhara_2018, Nallamilli_2018). These data indicate that the variant may be associated with disease. Experimental evidence indicated GAA activity to be <10% in compound heterozygous patients with the variant (El-Gharbawy_2011, Herzog_2012, Fukuhara_2018). Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance and two ClinVar submitters (evaluation after 2014) cite it as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely 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 Genome-Nilou Lab, SCV001810186.1

#	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	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV004195437.2

#	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

From ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel, SCV005089710.1

#	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>G variant in GAA is predicted to result in the substitution of tyrosine by cysteine at amino acid 766 (p.Tyr766Cys. At least five patients diagnosed with Pompe disease, all late onset symptoms, have been reported with this variant. Three of these patients have documented laboratory values showing deficiency GAA activity (PMID: 29124014, 35071497, 37087815) (PP4_Moderate). Four patients are compound heterozygous for the variant and another variant that has been classified as pathogenic by the ClinGen LD VCEP, all phase unconfirmed, including c.2481+110_2646+39del (ClinVar Variation ID: 657307) (PMID: 37087815, 0.5 points), c.784G>A (p.Glu262Lys) (ClinVar Variation ID: 188806, SCV002032128.1) (PMID: 35071497, 0.5 points), c.2560C>T (p.Arg854Ter) (ClinVar Variation ID: 4034, SCV001371731.1) (PMID: 30564623, 0.5 points), and c.1309C>T (p.Arg437Cys) (ClinVar Variation ID: 189082, SCV002540662.1) (PMID: 29124014, 0.5 points). Total 2 points (PM3_Strong). Another patient is reported with variant c.2297A>G (p.Tyr765Cys), which presumably is a typo for the amino acid number but cannot be confirmed (PMIDs: 21605996, 22676651). Another individual was identified by newborn screen, compound heterozygous for c.-32-13T>G (PMID: 33073003) but is not yet symptomatic, so was not included. One patient is compound heterozygous for the variant and c.1879_1881delTCC (p.Ser627del) ((PMID: 35071497), The allelic data from this patient will be used in the assessment of p.Ser627del and is not included here to avoid circular logic. The highest population minor allele frequency (MAF) in gnomAD v2.1.1 is 0.00006534 (2/30610 alleles) in the South Asian population. In gnomAD v4.1, the highest MAF is 0.00002227 (1/44894 alleles) in the East Asian population. Both are lower than the ClinGen LD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.967 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Another amino acid change at the same position, c.2297A>C (p.Tyr766Ser)(ClinVar Variation ID: 420102), has been classified as pathogenic based on the specifications of the ClinGen LD VCEP (PM5). There is a ClinVar entry for this variant (Variation ID: 285197). 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 Lysosomal Diseases VCEP (Specifications Version 2.0): PM3_Strong, PM5, PP4_Moderate, PP3, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on June 6, 2024)

#	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

Last Updated: Jan 13, 2025

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