U.S. flag

An official website of the United States government

NM_000152.5(GAA):c.1326+1G>A AND Glycogen storage disease, type II

Germline classification:
Pathogenic (3 submissions)
Last evaluated:
Oct 17, 2022
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:
RCV001249034.7

Allele description [Variation Report for NM_000152.5(GAA):c.1326+1G>A]

NM_000152.5(GAA):c.1326+1G>A

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.1326+1G>A
HGVS:
  • NC_000017.11:g.80108829G>A
  • NG_009822.1:g.12274G>A
  • NM_000152.5:c.1326+1G>AMANE SELECT
  • NM_001079803.3:c.1326+1G>A
  • NM_001079804.3:c.1326+1G>A
  • NM_001406741.1:c.1326+1G>A
  • NM_001406742.1:c.1326+1G>A
  • LRG_673:g.12274G>A
  • NC_000017.10:g.78082628G>A
  • NC_000017.10:g.78082628G>A
  • NM_000152.5(GAA):c.1326+1G>AMANE SELECT
Links:
dbSNP: rs1205507761
NCBI 1000 Genomes Browser:
rs1205507761
Molecular consequence:
  • NM_000152.5:c.1326+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001079803.3:c.1326+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001079804.3:c.1326+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001406741.1:c.1326+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001406742.1:c.1326+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]

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

Recent activity

Clear Turn Off Turn On

    Your browsing activity is empty.

    Activity recording is turned off.

    Turn recording back on

    See more...

    Assertion and evidence details

    Help
    Submission AccessionSubmitterReview Status
    (Assertion method)    		Clinical Significance
    (Last evaluated)    		OriginMethodCitations
    SCV001422969Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
    criteria provided, single submitter

    (ACMG Guidelines, 2015)    		Uncertain significance
    (Jan 22, 2020)     		germlinecuration

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

    Citation Link,

    SCV002817440ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel
    reviewed by expert panel

    (clingen_lsd_acmg_specifications_v2-1)    		Pathogenic
    (Oct 17, 2022)     		germlinecuration

    Citation Link,

    SCV004296867Labcorp Genetics (formerly Invitae), Labcorp
    criteria provided, single submitter

    (Invitae Variant Classification Sherloc (09022015))    		Pathogenic
    (Dec 27, 2023)     		germlineclinical testing

    PubMed (5)
    [See all records that cite these PMIDs]

    Help

    Summary from all submissions

    EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
    not providedgermlineunknownnot providednot providednot providednot providednot providedclinical 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

    Splicing in action: assessing disease causing sequence changes.

    Baralle D, Baralle M.

    J Med Genet. 2005 Oct;42(10):737-48. Review.

    PubMed [citation]
    PMID:
    16199547
    PMCID:
    PMC1735933
    See all PubMed Citations (6)

    Details of each submission

    From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001422969.2

    #EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
    1not providednot providednot providednot providedcuration PubMed (1)

    Description

    The c.1326+1G>A variant in GAA has been reported in three individuals with glycogen storage disease II (PMID: 22644586, 10189220) and has been identified in 0.01% (1/8708) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1205507761). 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 EGL Genetic Diagnostics (VariationID: 597944). 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. There is an in-frame cryptic splice site 6 bases from the intron-exon boundary, providing evidence that this variant may delete 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 an individual that is compound heterozygous for this variant is highly specific for glycogen storage disease II based on GAA enzyme activity in fibroblasts being <1% of wild type consistent with disease (PMID: 25256446). This variant has been seen in combination with the reported pathogenic variant p.Met519Val (PMID: 25256446) in individuals with glycogen storage disease II. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PVS1_moderate, PM2, PP4 (Richards 2015).

    #SampleMethodObservation
    OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
    1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

    From ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel, SCV002817440.1

    #EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
    1not providednot providednot providednot providedcurationnot provided

    Description

    The NM_000152.5:c.1326+1G>A variant in GAA is a canonical splice site variant in the donor splice site of intron 8. RT-PCR evidence suggests that the variant results in nonsense-mediated decay (PMID: 10189220) (PVS1). Two African-American patients with infantile-onset Pompe disease have been reported with this variant. GAA activity is available for one of these patients and was 0.35% in fibroblasts (PMID: 10189220) (PP4_Moderate). These patients are compound heterozygous for the variant and either c.1441T>C (p.Trp481Arg) or c.1555A>G (p.Met519Val) (PMID: 10189220, 25256446). The allelic data from these patients will be used in the classification of the second variant and is not included here to avoid circular logic. Therefore, PM3 is not met at the current time. The highest population minor allele frequency in gnomAD v2.1.1 is 0.000114 (1/8708 alleles) in the African/ African American population, which is lower than the ClinGen LSD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). There is ClinVar entry to this variant (Variant ID: 597944). In summary, this variant meets the criteria to be classified as Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by ClinGen Lysosomal Storage Disorders Variant Curation Expert Panel (Specifications Version 2.0): PVS1, PP4_moderate, PM2_supporting. (Classification approved by the ClinGen LSD VCEP on October 17, 2022).

    #SampleMethodObservation
    OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
    1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

    From Labcorp Genetics (formerly Invitae), Labcorp, SCV004296867.1

    #EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
    1not providednot providednot providednot providedclinical testing PubMed (5)

    Description

    This sequence change affects a donor splice site in intron 8 of the GAA gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in GAA are known to be pathogenic (PMID: 18425781, 22252923). This variant is present in population databases (no rsID available, gnomAD 0.01%). Disruption of this splice site has been observed in individuals with glycogen storage disease type II (PMID: 10189220). This variant is also known as IVS8 g+1a. ClinVar contains an entry for this variant (Variation ID: 597944). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

    #SampleMethodObservation
    OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
    1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

    Last Updated: Sep 29, 2024