NM_000152.5(GAA):c.1076-22T>G AND Glycogen storage disease, type II

Germline classification:: Pathogenic (6 submissions)
Last evaluated:: Feb 6, 2024
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:: RCV000409600.16

Allele description [Variation Report for NM_000152.5(GAA):c.1076-22T>G]

NM_000152.5(GAA):c.1076-22T>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.1076-22T>G

HGVS:

NC_000017.11:g.80108467T>G
NG_009822.1:g.11912T>G
NM_000152.5:c.1076-22T>GMANE SELECT
NM_001079803.3:c.1076-22T>G
NM_001079804.3:c.1076-22T>G
LRG_673t1:c.1076-22T>G
LRG_673:g.11912T>G
NC_000017.10:g.78082266T>G
NM_000152.3:c.1076-22T>G
NM_000152.4(GAA):c.1076-22T>G

Links:

dbSNP: rs762260678

NCBI 1000 Genomes Browser:

rs762260678

Molecular consequence:

NM_000152.5:c.1076-22T>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001079803.3:c.1076-22T>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001079804.3:c.1076-22T>G - intron variant - [Sequence Ontology: SO:0001627]

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
SCV000485540	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Likely pathogenic (Jan 5, 2016)	unknown	clinical testing	PubMed (6) [See all records that cite these PMIDs] 10737124, 9259196, 22613277, 25455803, 22676651, 23013746 mdi-5618_320494_Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015).pdf, Citation Link,
SCV001205933	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jul 7, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 9259196, 10737124, 22613277, 28492532
SCV001422619	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 22, 2020)	germline	curation	PubMed (8) [See all records that cite these PMIDs] 10737124, 9259196, 25455803, 21484825, 22613277, 22676651, 23013746, 25741868 Citation Link,
SCV001455603	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 16, 2020)	germline	clinical testing
SCV004197914	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 17, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004809072	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	reviewed by expert panel (clingen_lsd_acmg_specifications_v2-1)	Pathogenic (Feb 6, 2024)	germline	curation	Citation Link

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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

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Adult-onset glycogen storage disease type II: phenotypic and allelic heterogeneity in German patients.

Vorgerd M, Burwinkel B, Reichmann H, Malin JP, Kilimann MW.

Neurogenetics. 1998 Mar;1(3):205-11.

PubMed [citation]

PMID:: 10737124

See all PubMed Citations (9)

Details of each submission

From Counsyl, SCV000485540.2

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

#	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, SCV001205933.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

Studies have shown that this variant results in skipping of exon 6, but is expected to preserve the integrity of the reading-frame (PMID: 9259196). ClinVar contains an entry for this variant (Variation ID: 370278). This variant is also known as IVS6-22T>G. This variant has been observed in individual(s) with glycogen storage disease type II (GSD II) (PMID: 9259196, 10737124, 22613277). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs762260678, gnomAD 0.003%). This sequence change falls in intron 6 of the GAA gene. It does not directly change the encoded amino acid sequence of the GAA protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. 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 Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001422619.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (8)

Description

The c.1076-22T>G variant in GAA has been reported in 8 individuals (including 3 Germans, 2 Dutch, and 1 African American/Caucasian individuals) with Glycogen Storage Disorder II (PMID: 10737124, 9259196, 25455803, 22613277, 21484825, 22676651, 23013746), and has also been reported likely pathogenic by Counsyl in ClinVar (Variation ID: 370278). This variant has been identified in 0.003% (3/112848) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs762260678). 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 with RNA extracted from individuals homozygous for this variant provide some evidence that the c.1076-22T>G variant may cause abnormal splicing (PMID: 10737124). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact splicing, though this information is not predictive enough to determine pathogenicity. The presence of this variant in the homozygous state and in combination with pathogenic variants, and in individuals with Glycogen Storage Disorder II increases the likelihood that the c.1076-22T>G variant is pathogenic (PMID: 10737124, 22676651, 22613277, 9259196, 21484825). The phenotype of homozygous and heterozygous individuals with this variant is highly specific for Glycogen Storage Disease II based on reduced GAA activity detected in relevant tissues (PMID: 10737124, 22676651, 22613277, 9259196, 21484825). In summary, this variant meets criteria to be classified as pathogenic for Glycogen Storage Disorder II in an autosomal recessive manner based on in vitro functional studies and multiple occurrences with pathogenic variants. ACMG/AMP Criteria applied: PM3_Strong, PS3, PM2, PP3, 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 Natera, Inc., SCV001455603.1

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

#	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, SCV004197914.2

#	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, SCV004809072.1

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

Description

The NM_000152.5:c.1076-22T>G variant in GAA occurs within intron 6. Experimental studies show that the variant causes skipping of biologically-relevant-exon 6 resulting in an in-frame deletion of amino acids 319-358 (PMIDs 9259196, 10737124). This includes part of the GAA catalytic barrel (amino acids 347-727) (Kroos et al, 2012, PMID 22253258; Deming et al, 2017; DOI 10.1101/212837) (PVS1_Strong). At least 7 probands have been reported with this variant, at least 5 of them with reported GAA activity <10% normal in lymphocytes, leukocytes or muscle samples, or <30% normal in cultured fibroblasts, or in the affected range in a clinically validated dried blood spot assay (PP4_Moderate). Of these individuals, 6 are compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic or likely pathogenic by the ClinGen Lysosomal Diseases VCEP, including 2 confirmed in trans - c.2560C>T (p.Arg854Ter) (ClinVar Variation ID: 4034, SCV001371731.1) (PMID: 9259196), c.1437+1G>A (ClinVar Variation ID: 555864, SCV004227900.1), and 4 with phase unknown - c.1942G>A (p.Gly648Ser) (ClinVar Variation ID: 188902, SCV001371752.2) (PMID: 25455803), c.-32-13T>G (ClinVar Variation ID: 4027) (PMID: 22613277), c.1841C>A (p.Thr614Lys) (ClinVar Variation ID: 167113, SCV001371751.1) (PMID: 21484825), and c.525delT (ClinVar Variation ID: 4033, SCV001443331.1) (PMID: 29181627). In addition, two siblings are homozygous for the variant (PMID: 10737124) (PM3_VeryStrong). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00002658 (3/112848 alleles) in the European non-Finnish population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 370278). In summary, this variant meets the criteria to be classified as Pathogenic for Pompe disease based on the GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PVS1_Strong, PM3_Strong, PP4_Moderate, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on February 6, 2024).

#	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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