NM_000152.5(GAA):c.1496G>A (p.Trp499Ter) AND Glycogen storage disease, type II

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Oct 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:: RCV000673032.21

Allele description [Variation Report for NM_000152.5(GAA):c.1496G>A (p.Trp499Ter)]

NM_000152.5(GAA):c.1496G>A (p.Trp499Ter)

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.1496G>A (p.Trp499Ter)

HGVS:

NC_000017.11:g.80110785G>A
NG_009822.1:g.14230G>A
NM_000152.5:c.1496G>AMANE SELECT
NM_001079803.3:c.1496G>A
NM_001079804.3:c.1496G>A
NP_000143.2:p.Trp499Ter
NP_001073271.1:p.Trp499Ter
NP_001073272.1:p.Trp499Ter
LRG_673t1:c.1496G>A
LRG_673:g.14230G>A
NC_000017.10:g.78084584G>A
NC_000017.10:g.78084584G>A
NM_000152.3:c.1496G>A
NM_000152.4(GAA):c.1496G>A
NM_000152.5(GAA):c.1496G>AMANE SELECT
p.Trp499Ter

Protein change:

W499*

Links:

dbSNP: rs766680292

NCBI 1000 Genomes Browser:

rs766680292

Molecular consequence:

NM_000152.5:c.1496G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001079803.3:c.1496G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001079804.3:c.1496G>A - nonsense - [Sequence Ontology: SO:0001587]

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
SCV000798197	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Likely pathogenic (Mar 1, 2018)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25741864, 11071489 Citation Link,
SCV001422697	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 23, 2020)	germline	curation	PubMed (3) [See all records that cite these PMIDs] 19775921, 22252923, 25741868 Citation Link,
SCV001443321	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	reviewed by expert panel (ClinGen LSD ACMG Specifications v1)	Pathogenic (Oct 5, 2020)	germline	curation	Citation Link,
SCV002184849	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 31, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 22252923, 18425781, 28492532
SCV005058767	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 22, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

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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

CRIM-negative infantile Pompe disease: characterization of immune responses in patients treated with ERT monotherapy.

Berrier KL, Kazi ZB, Prater SN, Bali DS, Goldstein J, Stefanescu MC, Rehder CW, Botha EG, Ellaway C, Bhattacharya K, Tylki-Szymanska A, Karabul N, Rosenberg AS, Kishnani PS.

Genet Med. 2015 Nov;17(11):912-8. doi: 10.1038/gim.2015.6. Epub 2015 Mar 5. Erratum in: Genet Med. 2015 Jul;17(7):596. doi: 10.1038/gim.2015.57. Rosenburg, Amy S [corrected to Rosenberg, Amy S].

PubMed [citation]

PMID:: 25741864
PMCID:: PMC4561024

Juvenile and adult-onset acid maltase deficiency in France: genotype-phenotype correlation.

Laforêt P, Nicolino M, Eymard PB, Puech JP, Caillaud C, Poenaru L, Fardeau M.

Neurology. 2000 Oct 24;55(8):1122-8.

PubMed [citation]

PMID:: 11071489

See all PubMed Citations (7)

Details of each submission

From Counsyl, SCV000798197.1

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

#	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, SCV001422697.2

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

Description

The p.Trp499Ter variant in GAA has been reported in at least 3 individuals with glycogen storage disease (PMID: 19775921, 18425781, 22252923) and has been identified in 0.003% (1/34586) Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs766680292). 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 likely pathogenic by Counsyl (Variation ID: 556959). This nonsense variant leads to a premature termination codon at position 499, which is 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. The phenotype of an individual homozygous for this variant is highly specific for glycogen storage disease based on GAA enzyme activity in fibroblasts being <1% of wild type, consistent with disease (PMID: 19775921). Additionally, the homozygous occurrence of this variant and in an individual with glycogen storage disease (PMID: 19775921) slightly increases the likelihood that the p.Trp499Ter variant is pathogenic. In summary, this variant meets criteria to be classified as pathogenic for GAA in an autosomal recessive manner based on the prediction that it causes loss of function of the GAA gene, its low frequency in the general population, and the homozygous occurrence of the variant in an affected individual. ACMG/AMP Criteria applied: PVS1, PM2, PP4, PM3_supporting (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 ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel, SCV001443321.1

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

Description

This variant, c.1496G>A (p.Trp499Ter) is a nonsense variant which is predicted to cause nonsense mediated decay resulting in lack of gene product. This is supported by the absence of cross reactive immunological material in cultured skin fibroblasts from a patient with this variant (PMIDs 19775921, 22252923, and 25741864). Therefore, PVS1 can be applied. This patient, who has infantile onset Pompe disease, meets the ClinGen LSD VCEP's specifications for PP4, and is homozygous for the variant, meeting PM3_Supporting. Additional patients have been reported, including 2 homozygous Tunisian patients (PMID 32125626), but the residual GAA activity was not provided, and this data was not included. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003 in the Latino population, which meets PM2. There is a ClinVar entry for this variant (Variation ID 556959, 1 star review status), with one submitter 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. ACMG/AMP criteria met, based on the specifications of 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, SCV002184849.3

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

Description

This sequence change creates a premature translational stop signal (p.Trp499*) 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). This variant is present in population databases (rs766680292, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with Pompe disease (PMID: 18425781). ClinVar contains an entry for this variant (Variation ID: 556959). 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, SCV005058767.1

#	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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