NM_000152.5(GAA):c.258dup (p.Asn87fs) AND Glycogen storage disease, type II

Germline classification:: Pathogenic (7 submissions)
Last evaluated:: Sep 28, 2021
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:: RCV000291526.18

Allele description [Variation Report for NM_000152.5(GAA):c.258dup (p.Asn87fs)]

NM_000152.5(GAA):c.258dup (p.Asn87fs)

Gene:

GAA:alpha glucosidase [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

17q25.3

Genomic location:

Preferred name:

NM_000152.5(GAA):c.258dup (p.Asn87fs)

Other names:

NM_000152.5(GAA):c.258dup; p.Asn87fs

HGVS:

NC_000017.11:g.80104844dup
NG_009822.1:g.8289dup
NM_000152.4(GAA):c.258dupC
NM_000152.5:c.258dupMANE SELECT
NM_001079803.3:c.258dup
NM_001079804.3:c.258dup
NP_000143.2:p.Asn87fs
NP_001073271.1:p.Asn87fs
NP_001073272.1:p.Asn87fs
LRG_673:g.8289dup
NC_000017.10:g.78078636_78078637insC
NC_000017.10:g.78078643dup
NC_000017.11:g.80104844_80104845insC
NM_000152.3:c.258dup
NM_000152.4(GAA):c.258dupC
NM_000152.4:c.258dupC
NM_000152.5:c.258dup
NM_000152.5:c.258dupCMANE SELECT
p.Asn87Glnfs

Protein change:

N87fs

Links:

dbSNP: rs761317813

NCBI 1000 Genomes Browser:

rs761317813

Molecular consequence:

NM_000152.5:c.258dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001079803.3:c.258dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001079804.3:c.258dup - frameshift variant - [Sequence Ontology: SO:0001589]

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000816240	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 12, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 18425781, 22252923, 10206684, 16917947, 21484825, 28492532
SCV001338289	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Feb 9, 2020)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 16917947, 21484825, 30564623, 31086307, 10206684 Citation Link,
SCV001422880	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 (5) [See all records that cite these PMIDs] 26873529, 10206684, 21484825, 16917947, 25741868 Citation Link,
SCV001453579	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 16, 2020)	germline	clinical testing
SCV002032142	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	reviewed by expert panel (clingen_lsd_acmg_specifications_v2-1)	Pathogenic (Sep 28, 2021)	germline	curation	Citation Link,
SCV002807224	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 12, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004195446	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 17, 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	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 (10)

Details of each submission

From Invitae, SCV000816240.6

#	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 creates a premature translational stop signal (p.Asn87Glnfs*9) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with glycogen storage disease II (PMID: 10206684, 16917947, 21484825). ClinVar contains an entry for this variant (Variation ID: 282842). 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, SCV001338289.1

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

Description

Variant summary: GAA c.258dupC (p.Asn87GlnfsX9) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 1.2e-05 in 246016 control chromosomes. c.258dupC has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) (example, Beesley_1998, Montalvo_2006, Bali_2011, Nallamilli_2018, Kishnani_2019). These data indicate that the variant is likely to be associated with disease. 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 without evidence for independent evaluation. All laboratories 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 Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001422880.2

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

Description

The heterozygous p.Asn87GlnfsTer9 variant in GAA has been reported in 5 individuals (including 1 from the UK and 1 Italian individual) with Glycogen Storage Disease II (PMID: 16917947, 26873529, 21484825, 10206684), and has also been reported pathogenic by EGL Genetic Diagnostics and Invitae in ClinVar (Variation ID: 282842). Data from large population studies is insufficient to assess the frequency of this variant. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 87 and leads to a premature termination codon 9 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the GAA gene is a moderately established disease mechanism in autosomal recessive Glycogen Storage Disease II. The presence of this variant in combination with a pathogenic variant and in an individual with Glycogen Storage Disease II increases the likelihood that the p.Asn87GlnfsTer9 variant is pathogenic (PMID: 26873529). The phenotype of an individual heterozygous for this variant is highly specific for Glycogen Storage Disease II with less than 5% of normal GAA activity detected in their fibroblasts (PMID: 21484825, 26873529). In summary, this variant meets criteria to be classified as pathogenic for Glycogen Storage Disorder II in an autosomal recessive manner based on the predicted impact of the variant and an occurrence with a pathogenic GAA variant in an individual with Glycogen Storage Disorder II. ACMG/AMP Criteria applied: PVS1, PM3_Supporting, 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., SCV001453579.1

#	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, SCV002032142.1

#	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.258dup (p.Asn87GlnfsTer9) variant in GAA is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 2/20, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). At least 10 patients with this variant and reported to have Pompe disease have been reported. This includes two patients with documented laboratory values showing GAA deficiency meeting the ClinGen LSD VCEP’s specifications for PP4_Moderate; one of them on enzyme replacement therapy (PMID 21484825, 31467850), a further 7, at least, patients on enzyme replacement therapy, without documented values for GAA activity, meeting specifications for PP4 (PMID 26873529, 31086307, 31392188, 31676142, 32248831), and additional patients with insufficient details to meet the requirements for PP4 (PMID 10206684, 16917947, 29961517, 30564623). At least 7 patients are compound heterozygous for the variant and a pathogenic variant, c.-32-13T>G, in GAA (PM3). Another two patients are compound heterozygous for the variant and either c.1195-8G>A (PMID 21484825) or c.1115A>T (p.His372Leu) (PMID 31467850). The in trans data from both of these patients will be used in the assessment of the other variant and is, therefore, not included here in order to avoid circular logic. The variant is absent in gnomAD v2.1.1 (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 282842, 2 star review status) with five submitters classifying the variant as pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific GAA criteria met, as specified by the ClinGen LSD VCEP (Specification Version 2.0): PVS1, PM3, PP4_Moderate, PM2_Supporting.

#	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, SCV002807224.1

#	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, SCV004195446.1

#	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

Last Updated: Mar 30, 2024

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