NM_000152.5(GAA):c.2662G>T (p.Glu888Ter) AND Glycogen storage disease, type II

Germline classification:: Pathogenic (7 submissions)
Last evaluated:: May 4, 2020
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:: RCV000701656.21

Allele description [Variation Report for NM_000152.5(GAA):c.2662G>T (p.Glu888Ter)]

NM_000152.5(GAA):c.2662G>T (p.Glu888Ter)

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.2662G>T (p.Glu888Ter)

HGVS:

NC_000017.11:g.80118668G>T
NG_009822.1:g.22113G>T
NM_000152.5:c.2662G>TMANE SELECT
NM_001079803.3:c.2662G>T
NM_001079804.3:c.2662G>T
NP_000143.2:p.Glu888Ter
NP_001073271.1:p.Glu888Ter
NP_001073272.1:p.Glu888Ter
LRG_673t1:c.2662G>T
LRG_673:g.22113G>T
NC_000017.10:g.78092467G>T
NM_000152.3:c.2662G>T
NM_000152.4(GAA):c.2662G>T
p.Glu888Ter

Protein change:

E888*

Links:

dbSNP: rs765718882

NCBI 1000 Genomes Browser:

rs765718882

Molecular consequence:

NM_000152.5:c.2662G>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001079803.3:c.2662G>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001079804.3:c.2662G>T - nonsense - [Sequence Ontology: SO:0001587]

Observations:

Condition(s)

Name:: Glycogen storage disease, type II (GSD2)
Synonyms:: ACID ALPHA-GLUCOSIDASE DEFICIENCY; GLYCOGENOSIS, GENERALIZED, CARDIAC FORM; GSD II; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009290; MedGen: C0017921; Orphanet: 365; OMIM: 232300

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Synpo2l synaptopodin 2-like [Mus musculus]
Synpo2l synaptopodin 2-like [Mus musculus]
Gene ID:68760

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Ddi2 DNA-damage inducible protein 2 [Mus musculus]
Ddi2 DNA-damage inducible protein 2 [Mus musculus]
Gene ID:68817

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000830468	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 4, 2023)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 18425781, 22252923, 16531044, 17723315, 18458862, 20080426, 21644219, 28032299, 28394184, 28492532
SCV000919385	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Dec 20, 2018)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 16531044, 28394184, 25526786 Citation Link,
SCV001371767	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	reviewed by expert panel (ClinGen LSD ACMG Specifications v1)	Pathogenic (May 4, 2020)	germline	curation	PubMed (11) [See all records that cite these PMIDs] 25626711, 25526786, 31743840, 24269976, 27417441, 18458862, 25455803, 16531044, 17723315, 21232767, 28394184 Citation Link,
SCV001422961	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 22, 2020)	germline	curation	PubMed (6) [See all records that cite these PMIDs] 25526786, 18458862, 16531044, 17723315, 21232767, 25741868 Citation Link,
SCV001463866	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 16, 2020)	germline	clinical testing
SCV002580921	MGZ Medical Genetics Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 24, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004195465	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 26, 2024)	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	germline	yes	1	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

Update of the Pompe disease mutation database with 107 sequence variants and a format for severity rating.

Kroos M, Pomponio RJ, van Vliet L, Palmer RE, Phipps M, Van der Helm R, Halley D, Reuser A; GAA Database Consortium..

Hum Mutat. 2008 Jun;29(6):E13-26. doi: 10.1002/humu.20745.

PubMed [citation]

PMID:: 18425781

Predicting cross-reactive immunological material (CRIM) status in Pompe disease using GAA mutations: lessons learned from 10 years of clinical laboratory testing experience.

Bali DS, Goldstein JL, Banugaria S, Dai J, Mackey J, Rehder C, Kishnani PS.

Am J Med Genet C Semin Med Genet. 2012 Feb 15;160C(1):40-9. doi: 10.1002/ajmg.c.31319. Epub 2012 Jan 17.

PubMed [citation]

PMID:: 22252923
PMCID:: PMC3278076

See all PubMed Citations (18)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000830468.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

This sequence change creates a premature translational stop signal (p.Glu888*) 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 (rs765718882, gnomAD 0.03%). This premature translational stop signal has been observed in individuals with glycogen storage disease, type II (GSDII), also known as Pompe disease (PMID: 16531044, 17723315, 18458862, 20080426, 21644219, 28032299, 28394184). ClinVar contains an entry for this variant (Variation ID: 578595). 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, SCV000919385.1

#	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.2662G>T (p.Glu888X) 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. The variant allele was found at a frequency of 2e-05 in 245054 control chromosomes (gnomAD). The variant, c.2662G>T, has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) in both compound heterozygotes and homozygotes (Kostera-Pruszczyk_2006, Liu_2014, Chen_2017), and is one of the most common disease variant in Northern Chinese. These data indicate that the variant is likely to be associated with disease. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. 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 ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel, SCV001371767.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (11)

Description

This variant, c.2662G>T (p.Glu888Ter), is a nonsense variant that is predicted to result in nonsense-mediated decay and lack of gene product, meeting PVS1. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00027 in the East Asian population, meeting PM2. At least 6 patients have been reported with this variant and deficiency of GAA activity meeting the ClinGen LSD VCEP's PP4 specifications. One of these individuals is compound heterozygous for the variant and c.-32-13T>G, phase unknown (PMID 16531044), and another is homozygous for the variant (PMID 17723315). This data meets PM3. Other individuals meeting PP4 specifications are compound heterozygous for the variant and either c.1574T>A (p.Phe525Tyr) (PMID 21232767), c.1935C>A (p.Asp645Glu) (PMID 18458862), or c.2238G>C (p.Trp746Cys) (PMID 25526786). However in each case, the in trans data from these patients will be used in the assessment of the other variant and was not used here in order to avoid a circular argument. Additional cases with the variant have been reported but were not included because the residual GAA activity was not provided, and therefore PP4 cannot be assessed (PMIDs 24269976, 25455803, 25626711, 27417441, 28394184, 31743840), or the patient carried a pseudodeficiency allele (PMID 21232767). There is a ClinVar entry for this variant (Variation ID: 578595) with two submitters classifying the variant as 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, PM3, PP4.

#	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, SCV001422961.2

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

Description

The p.Glu888Ter variant in GAA has been reported in at least 8 individuals with glycogen storage disease (PMID: 25526786, 21232767, 18458862, 17723315, 16531044) and has been identified in 0.027% (5/18392) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs765718882). 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 as pathogenic by Invitae and Integrated Genetics (VariationID: 578595). This nonsense variant leads to a premature termination codon at position 888, which is 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. The phenotype of individuals homozygous for this variant is highly specific for glycogen storage disease based on GAA enzyme activity in lymphocytes and fibroblasts being <10% of wild type, consistent with disease (PMID: 25526786, 21232767, 17723315, 18458862). In addition, the presence of this variant in individuals with glycogen storage disease has been observed in combination with reported pathogenic and likely pathogenic variants (VariationID: 265160, 4027, 4029, 4032; PMID: 25526786, 21232767, 18458862, 17723315, 16531044). In summary, this variant meets criteria to be classified as pathogenic for glycogen storage disease II in an autosomal recessive manner based on the prediction that it will cause loss of function of the GAA gene and the presence of the variant in combination with numerous other pathogenic variants in affected individuals with phenotypes highly specific for GAA. ACMG/AMP Criteria applied: PVS1, PM3_supporting, PP4_moderate, PM2 (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., SCV001463866.1

#	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 MGZ Medical Genetics Center, SCV002580921.1

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

From Baylor Genetics, SCV004195465.2

#	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: Oct 20, 2024

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