NM_000152.5(GAA):c.2501_2502del (p.Thr834fs) AND Glycogen storage disease, type II

Germline classification:: Pathogenic (8 submissions)
Last evaluated:: May 5, 2020
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:: RCV000285320.18

Allele description [Variation Report for NM_000152.5(GAA):c.2501_2502del (p.Thr834fs)]

NM_000152.5(GAA):c.2501_2502del (p.Thr834fs)

Gene:

GAA:alpha glucosidase [Gene - OMIM - HGNC]

Variant type:

Microsatellite

Cytogenetic location:

17q25.3

Genomic location:

Preferred name:

NM_000152.5(GAA):c.2501_2502del (p.Thr834fs)

HGVS:

NC_000017.11:g.80118210CA[1]
NG_009822.1:g.21655CA[1]
NM_000152.3(GAA):c.2501_2502delCA
NM_000152.5:c.2501_2502delMANE SELECT
NM_001079803.3:c.2501_2502del
NM_001079804.3:c.2501_2502del
NP_000143.2:p.Thr834fs
NP_001073271.1:p.Thr834fs
NP_001073272.1:p.Thr834fs
LRG_673t1:c.2501_2502del
LRG_673:g.21655CA[1]
NC_000017.10:g.78092009CA[1]
NC_000017.10:g.78092009_78092010del
NC_000017.11:g.80118212_80118213delCA
NM_000152.3(GAA):c.2501_2502delCA
NM_000152.3:c.2501_2502del
NM_000152.3:c.2501_2502delCA
NM_000152.5:c.2501_2502del
NM_000152.5:c.2501_2502delCAMANE SELECT
p.Thr834Argfs

Protein change:

T834fs

Links:

dbSNP: rs886043343

NCBI 1000 Genomes Browser:

rs886043343

Molecular consequence:

NM_000152.5:c.2501_2502del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001079803.3:c.2501_2502del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001079804.3:c.2501_2502del - frameshift variant - [Sequence Ontology: SO:0001589]

Functional consequence:

RNA degradation by nonsense-mediated decay [Variation Ontology: 0347]

Observations:

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
SCV000692564	Tehran Medical Genetics Laboratory	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic	inherited	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000917399	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Nov 30, 2018)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 18425781, 22958975, 22658377 Citation Link,
SCV001132394	Counsyl	no assertion criteria provided	Pathogenic (Nov 17, 2016)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001371719	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	reviewed by expert panel (ClinGen LSD ACMG Specifications v1)	Pathogenic (May 5, 2020)	germline	curation	PubMed (4) [See all records that cite these PMIDs] 29122469, 23601496, 22958975, 19588081 Citation Link,
SCV001379737	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jun 4, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 19588081, 22958975, 29122469, 30564623, 18425781, 22252923, 28492532
SCV001423058	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 (2) [See all records that cite these PMIDs] 19588081, 25741868 Citation Link,
SCV001463862	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 16, 2020)	germline	clinical testing
SCV002810768	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 30, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

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
Iranian	inherited	no	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Transcriptional response to GAA deficiency (Pompe disease) in infantile-onset patients.

Palermo AT, Palmer RE, So KS, Oba-Shinjo SM, Zhang M, Richards B, Madhiwalla ST, Finn PF, Hasegawa A, Ciociola KM, Pescatori M, McVie-Wylie AJ, Mattaliano RJ, Madden SL, Marie SK, Klinger KW, Pomponio RJ.

Mol Genet Metab. 2012 Jul;106(3):287-300. doi: 10.1016/j.ymgme.2012.05.004. Epub 2012 May 14.

PubMed [citation]

PMID:: 22658377

B-Cell depletion and immunomodulation before initiation of enzyme replacement therapy blocks the immune response to acid alpha-glucosidase in infantile-onset Pompe disease.

Elder ME, Nayak S, Collins SW, Lawson LA, Kelley JS, Herzog RW, Modica RF, Lew J, Lawrence RM, Byrne BJ.

J Pediatr. 2013 Sep;163(3):847-54.e1. doi: 10.1016/j.jpeds.2013.03.002. Epub 2013 Apr 16.

PubMed [citation]

PMID:: 23601496
PMCID:: PMC3981605

See all PubMed Citations (10)

Details of each submission

From Tehran Medical Genetics Laboratory, SCV000692564.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Iranian	1	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	inherited	no	not provided	not provided	not provided		1	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000917399.1

#	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.2501_2502delCA (p.Thr834ArgfsX49) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. c.2544delC, p.Lys849fsX38 and c.2560C>T, p.Arg854X). The variant allele was found at a frequency of 8.1e-06 in 245500 control chromosomes (gnomAD). The variant, c.2501_2502delCA, has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease)(Kroos_2008, Palermo_2012, Musumeci_2012). 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 without evidence for independent evaluation and classified the variant as 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 Counsyl, SCV001132394.1

#	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, SCV001371719.1

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

Description

This variant, c.2501_2502delCA (p.Thr834Argfs) is predicted to result in a frameshift causing a premature termination codon, nonsense medicated decay, and lack of GAA gene product, meeting PVS1. The variant has a highest population minor allele frequency of 0.00005794 in the Latino population, meeting PM2. This variant was found in compound heterozygosity with a known pathogenic variant, c.-32-13T>G, in three patients, who all meet the ClinGen LSD VCEP's PP4 criterion (PMID 22958975). The phase not confirmed in any of these patients. Additional patients with this variant have been reported but were not included because the residual GAA activity was not provided, and therefore PP4 cannot be assessed (PMIDs 19588081, 29122469), or the in trans data had been counted towards another variant and therefore were not included here to avoid circular logic (c.1933G>A (p.Asp645Asn), (PMID 23601496). The data meet PP4 and PM3_Supporting. There is a ClinVar entry for this variant (Variant ID: 286229; 2 star review status) with three submitters classifying the variant as pathogenic and one as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1, PM2, PM3_Supporting, PP4.

#	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, SCV001379737.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This premature translational stop signal has been observed in individuals with Pompe disease (PMID: 19588081, 22958975, 29122469, 30564623). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 286229). This variant is present in population databases (no rsID available, gnomAD 0.006%). This sequence change creates a premature translational stop signal (p.Thr834Argfs*49) in the GAA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GAA are known to be pathogenic (PMID: 18425781, 22252923).

#	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, SCV001423058.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (2)

Description

The p.Thr834ArgfsTer49 variant in GAA has been reported in 8 individuals with Glycogen Storage Disease II (PMID: 22958975, 23601496, 29122469, 19588081), and has also been reported pathogenic by EGL and likely pathogenic by Tehran Medical Genetics Laboratory and Integrated Genetics in ClinVar (Variation ID: 286229). This variant has been identified in 0.0058% (2/34516) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs886043343). 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 is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 834 and leads to a premature termination codon 49 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the GAA gene is an established disease mechanism in autosomal recessive Glycogen Storage Disease II. The presence of this variant in combination with a reported pathogenic variant and in individuals with Glycogen Storage Disease II increases the likelihood that the p.Thr834ArgfsTer49 variant is pathogenic (PMID: 19588081). The phenotype of individuals heterozygous for this variant is highly specific for Glycogen Storage Disease II based on reduced GAA activity in a dried blood spot or muscle tissue, consistent with disease (PMID: 22958975, 23601496). In summary, this variant meets criteria to be classified as pathogenic for Glycogen Storage Disease II in an autosomal recessive manner based on the predicted impact of the variant and multiple occurrences with pathogenic GAA variants in individuals with Glycogen Storage Disease II. ACMG/AMP Criteria applied: PVS1, PM2, PM3_Supporting, 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., SCV001463862.1

#	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 Fulgent Genetics, Fulgent Genetics, SCV002810768.1

#	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

Last Updated: Oct 8, 2024

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