NM_000152.5(GAA):c.1551+1G>T AND Glycogen storage disease, type II

Germline classification:: Pathogenic/Likely pathogenic (7 submissions)
Last evaluated:: Jun 22, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000671915.12

Allele description [Variation Report for NM_000152.5(GAA):c.1551+1G>T]

NM_000152.5(GAA):c.1551+1G>T

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.1551+1G>T

HGVS:

NC_000017.11:g.80110841G>T
NG_009822.1:g.14286G>T
NG_137935.1:g.1131G>T
NM_000152.5:c.1551+1G>TMANE SELECT
NM_001079803.3:c.1551+1G>T
NM_001079804.3:c.1551+1G>T
NM_001406741.1:c.1551+1G>T
NM_001406742.1:c.1551+1G>T
LRG_673t1:c.1551+1G>T
LRG_673:g.14286G>T
NC_000017.10:g.78084640G>T
NC_000017.10:g.78084640G>T
NM_000152.3:c.1551+1G>T
NM_000152.4(GAA):c.1551+1G>T
NM_000152.4:c.1551+1G>T

Links:

dbSNP: rs770780848

NCBI 1000 Genomes Browser:

rs770780848

Molecular consequence:

NM_000152.5:c.1551+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001079803.3:c.1551+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001079804.3:c.1551+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406741.1:c.1551+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406742.1:c.1551+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]

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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Homo sapiens natriuretic peptide receptor 1 (NPR1), mRNA
Homo sapiens natriuretic peptide receptor 1 (NPR1), mRNA
gi|1519246370|ref|NM_000906.4|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000796949	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Pathogenic (Jan 5, 2018)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 22252923, 25243733 Citation Link,
SCV001422696	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 (3) [See all records that cite these PMIDs] 25243733, 25703594, 25741868 Citation Link,
SCV001572465	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Apr 8, 2021)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 22252923, 25243733, 31086307, 30155607, 31606152, 33301762 Citation Link,
SCV002810428	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 23, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003442563	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Apr 1, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 31086307, 25243733, 28492532
SCV003934920	Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 22, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 31342611, 25741868
SCV004848816	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 3, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

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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
South East Asian	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Fibromyalgia-like symptoms associated with irritable bowel syndrome: A challenging diagnosis of late-onset Pompe disease.

Gesquière-Dando A, Attarian S, Maues De Paula A, Pouget J, Salort-Campana E.

Muscle Nerve. 2015 Aug;52(2):300-4. doi: 10.1002/mus.24618. Epub 2015 Jun 18.

PubMed [citation]

PMID:: 25703594

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 Counsyl, SCV000796949.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

#	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 Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001422696.2

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

Description

The c.1551+1G>T variant in GAA has been reported in five individuals with glycogen storage disease II, segregated with disease in two affected relatives from one family (PMID: 25703594) and has been identified in 0.003% (1/34580) of Latino chromosomes and 0.001% (1/113512) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs770780848). 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 Counsyl (VariationID: 555986). This variant occurs in the invariant region (+/- 1/2) of the splice consensus sequence and is predicted to cause in-frame exon skipping and a leaky splice site leading to an abnormal or absent protein. There is an in-frame cryptic splice site 6 bases from the intron-exon boundary, providing evidence that this variant may add 2 amino acids instead of causing loss of function. However, this information is not predictive enough to determine pathogenicity. Loss of function of the GAA gene is an established disease mechanism in autosomal recessive glycogen storage disease II. The phenotype of individuals that are compound heterozygous for this variant is highly specific for glycogen storage disease II based on GAA enzyme activity in fibroblasts being <10% of wild type, consistent with disease (PMID: 25703594, 25243733). Additionally, the presence of this variation in combination with reported pathogenic variant c.-32-13T>G (VariationID: 4027, PMID: 30155607, 25703594) and likely pathogenic variant p.Asp419Val (PMID: 25243733) and in individuals with glycogen storage disease II increases the likelihood that the c.1551+1G>T 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: PVS1_moderate, PM3, PM2, 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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001572465.1

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

Description

Variant summary: GAA c.1551+1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5 splicing donor site. Bergsma et al, 2014 report that the variant causes in-frame exon 10 skipping and a leaky wild-type splicing (Bergsma_2014). The variant allele was found at a frequency of 8e-06 in 251156 control chromosomes (gnomAD). c.1551+1G>T has been reported in the literature in multiple individuals (both homozygous and compound heterozygous patients) affected with Glycogen Storage Disease, Type 2 (Pompe Disease) (Bergsma_2014, Gupta_2020, Kishnani_2019, Semplicini_2018, Thomas_2021). Several of these patients had juvenile and infantile onset of the disease. These data indicate that the variant is very likely to be associated with disease. Patient homozygous for the variant show reduced alpha-glucosidase activity (Thomas_2021). Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely 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 Fulgent Genetics, Fulgent Genetics, SCV002810428.1

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV003442563.2

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

Description

This sequence change affects a donor splice site in intron 10 of the GAA gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs770780848, gnomAD 0.003%). Disruption of this splice site has been observed in individual(s) with Pompe disease (PMID: 25243733, 31086307). ClinVar contains an entry for this variant (Variation ID: 555986). Studies have shown that disruption of this splice site results in skipping of exon 10, but is expected to preserve the integrity of the reading-frame (PMID: 25243733). 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 Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, SCV003934920.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	South East Asian	1	not provided	not provided	clinical testing	PubMed (2)

Description

The homozygous splice site variant c.1551+1G>T has been identified in the proband with phenotypes: respiratory distress, muscle weakness, proximal and distal muscles weakness in lower and upper extremities. This variant has been identified in a proband in a compound heterozygous state with c.1861T>C (p.Trp621Arg) presented with symptoms at 7 months with cardiomegaly, respiratory distress, muscle weakness.

#	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 Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004848816.1

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

Description

The c.1551+1G>T variant in GAA has been reported in at least five individuals with glycogen storage disease II (3 in the compound heterozygous state) and segregated with disease in 1 family member (Gesquière-Dando 2015 PMID: 25703594, Bali 2012 PMID: 22252923, Bergsma 2015 PMID: 25243733, Kishnani 2019 PMID: 31086307). It has been reported in ClinVar (Variation ID 555986) and was absent from large population databases. This variant occurs in the invariant region (+/- 1/2) of the splice consensus sequence, and in vitro functional studies suggest it causes in-frame exon 10 skipping and a leaky wild-type splice site leading to an abnormal or absent protein (Gesquière-Dando 2015 PMID: 25703594, Bergsma 2015 PMID: 25243733). Loss of function of the GAA gene is an established disease mechanism in autosomal recessive glycogen storage disease II. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive glycogen storage disease II. ACMG/AMP Criteria applied: PM3_Strong, PM2_Supporting, PS3_Moderate, PM4.

#	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: Sep 29, 2024

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