NM_000152.5(GAA):c.1437+1G>A AND Glycogen storage disease, type II

Germline classification:: Likely pathogenic (6 submissions)
Last evaluated:: May 16, 2023
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:: RCV000671773.13

Allele description [Variation Report for NM_000152.5(GAA):c.1437+1G>A]

NM_000152.5(GAA):c.1437+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.1437+1G>A

HGVS:

NC_000017.11:g.80110056G>A
NG_009822.1:g.13501G>A
NG_137935.1:g.346G>A
NM_000152.5:c.1437+1G>AMANE SELECT
NM_001079803.3:c.1437+1G>A
NM_001079804.3:c.1437+1G>A
NM_001406741.1:c.1437+1G>A
NM_001406742.1:c.1437+1G>A
LRG_673t1:c.1437+1G>A
LRG_673:g.13501G>A
NC_000017.10:g.78083855G>A
NC_000017.10:g.78083855G>A
NM_000152.3:c.1437+1G>A
NM_000152.4:c.1437+1G>A
NM_000152.5(GAA):c.1437+1G>AMANE SELECT

Links:

dbSNP: rs1555600575

NCBI 1000 Genomes Browser:

rs1555600575

Molecular consequence:

NM_000152.5:c.1437+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001079803.3:c.1437+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001079804.3:c.1437+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406741.1:c.1437+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406742.1:c.1437+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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000796792	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Pathogenic (Dec 29, 2017)	unknown	clinical testing	PubMed (3) [See all records that cite these PMIDs] 22252923, 22676651, 22555271 Citation Link,
SCV001422700	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,
SCV001572521	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Apr 10, 2021)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 22555271, 22252923, 22676651, 31342611, 33073007 Citation Link,
SCV002175462	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 2, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 16199547, 18425781, 11343339, 18429042, 22252923, 28492532
SCV004197858	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 10, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004227900	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	reviewed by expert panel (clingen_lsd_acmg_specifications_v2-1)	Likely pathogenic (May 16, 2023)	germline	curation	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
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Pediatric cardiomyopathy: importance of genetic and metabolic evaluation.

Kindel SJ, Miller EM, Gupta R, Cripe LH, Hinton RB, Spicer RL, Towbin JA, Ware SM.

J Card Fail. 2012 May;18(5):396-403. doi: 10.1016/j.cardfail.2012.01.017. Epub 2012 Mar 10.

PubMed [citation]

PMID:: 22555271
PMCID:: PMC3345128

A cross-sectional single-centre study on the spectrum of Pompe disease, German patients: molecular analysis of the GAA gene, manifestation and genotype-phenotype correlations.

Herzog A, Hartung R, Reuser AJ, Hermanns P, Runz H, Karabul N, Gökce S, Pohlenz J, Kampmann C, Lampe C, Beck M, Mengel E.

Orphanet J Rare Dis. 2012 Jun 7;7:35. doi: 10.1186/1750-1172-7-35.

PubMed [citation]

PMID:: 22676651
PMCID:: PMC3479421

See all PubMed Citations (11)

Details of each submission

From Counsyl, SCV000796792.1

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

#	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, SCV001422700.2

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

Description

The c.1437+1G>A variang in GAA has been reported in 4 individuals with glycogen storage disease II (PMID: 22555271, 28266734, 22676651, 22252923) and has been reported in ClinVar as pathogenic by Counsyl (VariationID: 555864). This variant has been identified in 0.003% (1/34538) Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1555600575). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies using an expression vector system demonstrating abnormal splicing provide some evidence that the c.1437+1G>A variant may impact protein function (PMID: 11343339). This variant occurs in the invariant region (+/- 1/2) of the splice consensus sequence and is predicted to cause skipping of exon 9 leading to an absent protein (PMID: 22676651, 22252923, 11343339). Loss of function of the GAA gene is an established disease mechanism in autosomal recessive glycogen storage disease II. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PVS1_strong, 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, SCV001572521.1

#	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.1437+1G>A 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. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 248246 control chromosomes. c.1437+1G>A has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) (example, Reuser_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/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 Labcorp Genetics (formerly Invitae), Labcorp, SCV002175462.3

#	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 affects a donor splice site in intron 9 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 not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with Pompe disease (PMID: 11343339, 18429042, 22252923). ClinVar contains an entry for this variant (Variation ID: 555864). 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.

#	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 Baylor Genetics, SCV004197858.1

#	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 ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel, SCV004227900.1

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

Description

This variant, c.1437+1G>A, alters the donor splice site of intron 9. Based on RT-PCR results from a patient who is compound heterozygous for the variant, this results in skipping of exon 9, which leads to an in frame deletion of p.Asp443_Lys479del (PMID 22676651), including part of the GAA catalytic barrel (PMID 22253258). Western blot analysis of protein extracted from cultured skin fibroblasts from a patient who is homozygous for the variant revealed that the patient was positive from cross-reactive immunological material, supporting that the variant results in an in-frame consequence (PMID 22252923). Based on these results, PVS1_Strong was applied. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003 in the Latino population, meeting PM2_Supporting. Two patients with Pompe disease have been reported who are homozygous for the variant and meet the ClinGen LSD VCEP's PP4 specifications (PMID 22555271, 22252923; personal communication), meeting PM3 and PP4_Moderate. Another patient has been reported with the variant in trans with c.1076-22G>A (PMID 22676651). In trans data from this patient will be used in the assessment of c.1076-22G>A and is not included here in order to avoid a circular argument. There is a ClinVar entry for this variant (Variation ID: 555864; two star review status) with five submitters classifying the variant as pathogenic and one submitter classifying as likely pathogenic. In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP (Specifications Version 2.0): PVS1_Strong, PM2_Supporting, PM3, PP4_Moderate.

#	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: Oct 8, 2024

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