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

Clinical significance:Pathogenic (Last evaluated: Apr 8, 2021)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000671915.3

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
  • NM_000152.5:c.1551+1G>TMANE SELECT
  • NM_001079803.3:c.1551+1G>T
  • NM_001079804.3:c.1551+1G>T
  • LRG_673t1:c.1551+1G>T
  • LRG_673:g.14286G>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]

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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000796949Counsylcriteria provided, single submitter
Pathogenic
(Jan 5, 2018)
unknownclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV001422696Broad Institute Rare Disease Group, Broad Instituteno assertion criteria providedLikely pathogenic
(Jan 22, 2020)
germlinecuration

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV001572465Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Pathogenic
(Apr 8, 2021)
germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing, curation
not providedunknownunknownnot providednot providednot providednot providednot providedclinical 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 (7)

Details of each submission

From Counsyl, SCV000796949.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Broad Institute Rare Disease Group, Broad Institute, SCV001422696.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcuration PubMed (2)

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).

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001572465.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical 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.

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

Last Updated: Jun 14, 2021

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