NM_000152.5(GAA):c.-32-2A>G AND Glycogen storage disease, type II

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Feb 28, 2022
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:: RCV001249079.4

Allele description [Variation Report for NM_000152.5(GAA):c.-32-2A>G]

NM_000152.5(GAA):c.-32-2A>G

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.-32-2A>G

HGVS:

NC_000017.11:g.80104553A>G
NG_009822.1:g.7998A>G
NM_000152.5:c.-32-2A>GMANE SELECT
NM_001079803.3:c.-32-2A>G
NM_001079804.3:c.-32-2A>G
NM_001406741.1:c.-32-2A>G
NM_001406742.1:c.-32-2A>G
LRG_673:g.7998A>G
NC_000017.10:g.78078352A>G
NM_000152.4:c.-32-2A>G
NM_001079804.2:c.-32-2A>G

Links:

dbSNP: rs1445232530

NCBI 1000 Genomes Browser:

rs1445232530

Molecular consequence:

NM_000152.5:c.-32-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001079803.3:c.-32-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001079804.3:c.-32-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406741.1:c.-32-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406742.1:c.-32-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]

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
SCV001423034	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 (1) [See all records that cite this PMID] Citation Link,
SCV002103370	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Feb 28, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 18425781, 23430493, 31301153 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001423034

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 (1)
[See all records that cite this PMID]

Citation Link,

SCV002103370

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Feb 28, 2022)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link

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

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

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

See all PubMed Citations (4)

Details of each submission

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001423034.2

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

Description

The c.-32-2A>G variant in GAA has been reported in 3 Colombian siblings with Glycogen Storage Disease II (PMID: 23430493) and has been identified in 0.001% (1/105716) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1445232530). 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 occurs in the invariant region (+/- 1/2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. Loss of function of the GAA gene is an established disease mechanism in autosomal recessive glycogen storage disease. This variant has been seen in combination with a reported pathogenic variant, p.Gly828_Asn882del (Variation ID: 4031, PMID: 23430493, 7945303, 10737124), and in three individuals with Glycogen Storage Disease II (PMID: 23430493). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PVS1, 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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002103370.1

#	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.-32-2A>G 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 canonical 3' prime acceptor site. Experimental evidence supports these predictions demonstrating the variant causes skipping of exon 2 (Goina_2019). The variant allele was found at a frequency of 4.3e-06 in 233126 control chromosomes (gnomAD). c.-32-2A>G has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) (examples: Kroos_2008 and Nino_2013). 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 and classified the variant as 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

Last Updated: Mar 30, 2024

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