NM_000152.5(GAA):c.2237G>A (p.Trp746Ter) 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:: RCV000501120.23

Allele description [Variation Report for NM_000152.5(GAA):c.2237G>A (p.Trp746Ter)]

NM_000152.5(GAA):c.2237G>A (p.Trp746Ter)

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.2237G>A (p.Trp746Ter)

HGVS:

NC_000017.11:g.80117015G>A
NG_009822.1:g.20460G>A
NM_000152.5:c.2237G>AMANE SELECT
NM_001079803.3:c.2237G>A
NM_001079804.3:c.2237G>A
NP_000143.2:p.Trp746Ter
NP_001073271.1:p.Trp746Ter
NP_001073272.1:p.Trp746Ter
LRG_673t1:c.2237G>A
LRG_673:g.20460G>A
NC_000017.10:g.78090814G>A
NC_000017.10:g.78090814G>A
NM_000152.3:c.2237G>A
NM_000152.4(GAA):c.2237G>A
p.Trp746Ter

Protein change:

W746*

Links:

dbSNP: rs752921215

NCBI 1000 Genomes Browser:

rs752921215

Molecular consequence:

NM_000152.5:c.2237G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001079803.3:c.2237G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001079804.3:c.2237G>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
SCV000594901	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 23, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000752063	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 6, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 18425781, 22252923, 10206684, 24158270, 25488666, 28492532
SCV000917394	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Aug 13, 2018)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 16917947, 29451150 Citation Link,
SCV001371720	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	reviewed by expert panel (ClinGen LSD ACMG Specifications v1)	Pathogenic (May 5, 2020)	germline	curation	PubMed (9) [See all records that cite these PMIDs] 17056254, 18429042, 26497565, 24269976, 12923862, 24158270, 21484825, 22237443, 16917947 Citation Link,
SCV001422772	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 (14) [See all records that cite these PMIDs] 18285536, 25526786, 18429042, 26497565, 10206684, 12923862, 25488666, 24158270, 21484825, 24169249, 22237443, 16917947, 22980766, 25741868 Citation Link,
SCV002092116	Natera, Inc.	no assertion criteria provided	Pathogenic (Aug 31, 2020)	germline	clinical testing
SCV002789737	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 13, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004195420	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 26, 2024)	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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation

Citations

PubMed

Update of the Pompe disease mutation database with 107 sequence variants and a format for severity rating.

Kroos M, Pomponio RJ, van Vliet L, Palmer RE, Phipps M, Van der Helm R, Halley D, Reuser A; GAA Database Consortium..

Hum Mutat. 2008 Jun;29(6):E13-26. doi: 10.1002/humu.20745.

PubMed [citation]

PMID:: 18425781

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 (20)

Details of each submission

From Genetic Services Laboratory, University of Chicago, SCV000594901.1

#	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	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000752063.6

#	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 creates a premature translational stop signal (p.Trp746*) 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 (rs752921215, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with Pompe disease (PMID: 10206684, 24158270, 25488666). ClinVar contains an entry for this variant (Variation ID: 280063). 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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000917394.1

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

Description

Variant summary: GAA c.2237G>A (p.Trp746X) 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.2560C>T, p.Arg854*). The variant allele was found at a frequency of 8.1e-06 in 245810 control chromosomes (gnomAD). c.2237G>A has been reported in the literature in multiple individuals affected with Late Onset Pompe Disease (Montalvo_2006, Liu_2018). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite 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 ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel, SCV001371720.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (9)

Description

This variant, c.2237G>A (p.Trp746Ter), which results in a premature termination codon, is expected to result in nonsense mediated decay and absence of gene product, meeting PVS1. This is supported by the finding that patients with this variant have no GAA cross-reactive immunological material in protein isolated from skin fibroblast cultures i.e. CRIM-negative (PMID 22252923). The highest population minor allele frequency in gnomAD for this variant is 0.000008834 in the European non-Finnish population, meeting PM2 (<0.001). This variant has been reported in at least 15 patients who also meet the LSD VCEP's PP4 criterion (PMIDs 12923862, 16917947, 17056254, 18285536, 21484825, 22237443, 24158270, 26497565). The c.2237G>A variant was found in compound heterozygosity with c.-32-13T>G in 9 of 40 Italian patients studied; six of these patients meet PP4 and in 4 of those patients the phase was confirmed in trans (PMID 16917947) (4.5 points). Additional patients meeting PP4 have been reported to be compound heterozygous for the variant and c.-32-13T>G, c.2481+110_2646+39del, c.1128_1129delinsC, c.670C>T (p.Arg224Trp), c.853C>T (p.Pro285Ser) (PMIDs 12923862, 17056254, 18285536, 21484825, 22237443); the phase was not confirmed in any of these cases. Four patients meeting PP4 criteria are reported to be homozygous for the variant (PMID 26497565). Four additional patients have been reported with this variant but residual GAA activity was not reported, and therefore PP4 cannot be assessed (PMID 18429042, 24269976). Based on this data, PP4 and PM3_Very Strong are met. There is a ClinVar entry for this variant (Variation ID: 280063; 2 star review status) with 5 submitters all classifying the variant as 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_Very strong, 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 Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001422772.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (14)

Description

The p.Trp746Ter variant in GAA has been reported in at least 33 individuals (including 15 Italians, 5 from the UK, and 4 Chinese individuals) with Glycogen Storage Disease II (PMID: 26497565, 10206684, 12923862, 16917947, 18429042, 18285536, 21484825, 22980766, 24158270, 22237443, 24169249, 25488666, 25526786, 24269976, 17056254), and has also been reported pathogenic by GeneDx, UChicago, EGL Genetic Diagnostics, Integrated Genetics, and Invitae in ClinVar (Variation ID: 280063). This variant has been identified in 0.001% (1/113202) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs752921215). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This nonsense variant leads to a premature termination codon at position 746, 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 II. The presence of this variant in the homozygous state and in trans with pathogenic variants, and in individuals with Glycogen Storage Disease II increases the likelihood that the p.Trp746Ter variant is pathogenic (PMID: 26497565, 16917947). The phenotype of individuals heterozygous for this variant is highly specific for Glycogen Storage Disease II with reduced GAA activity detected in relevant tissues, consistent with disease (PMID: 26497565, 24158270, 22237443, 21484825, 17056254, 12923862, 18285536, 16917947). Another variant at the same position with the same amino acid change, c.2238G>A (p.Trp746Ter), has been reported as a pathogenic and likely pathogenic variant in association with Glycogen Storage Disease II in ClinVar (Variation ID: 370904). 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, PM3_VeryStrong, PM2, 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., SCV002092116.1

#	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, SCV002789737.1

#	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 Baylor Genetics, SCV004195420.2

#	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

Last Updated: Sep 29, 2024

Relating variation to medicine