NM_000152.5(GAA):c.2214G>A (p.Trp738Ter) 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:: RCV000409827.24

Allele description [Variation Report for NM_000152.5(GAA):c.2214G>A (p.Trp738Ter)]

NM_000152.5(GAA):c.2214G>A (p.Trp738Ter)

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.2214G>A (p.Trp738Ter)

HGVS:

NC_000017.11:g.80116992G>A
NG_009822.1:g.20437G>A
NM_000152.5:c.2214G>AMANE SELECT
NM_001079803.3:c.2214G>A
NM_001079804.3:c.2214G>A
NP_000143.2:p.Trp738Ter
NP_001073271.1:p.Trp738Ter
NP_001073272.1:p.Trp738Ter
LRG_673t1:c.2214G>A
LRG_673:g.20437G>A
NC_000017.10:g.78090791G>A
NM_000152.3:c.2214G>A
NM_000152.4(GAA):c.2214G>A
NM_000152.4:c.2214G>A
NM_000152.5(GAA):c.2214G>AMANE SELECT
p.Trp738Ter

Protein change:

W738*

Links:

dbSNP: rs1057516328

NCBI 1000 Genomes Browser:

rs1057516328

Molecular consequence:

NM_000152.5:c.2214G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001079803.3:c.2214G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001079804.3:c.2214G>A - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Glycogen storage disease, type II (GSD2)
Synonyms:: ACID ALPHA-GLUCOSIDASE DEFICIENCY; ALPHA-1,4-GLUCOSIDASE DEFICIENCY; CARDIOMEGALIA GLYCOGENICA DIFFUSA; 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
SCV000485477	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Likely pathogenic (Dec 15, 2015)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID] mdi-5618_320494_Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015).pdf, Citation Link,
SCV001211539	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Mar 2, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 18425781, 22252923, 22676651, 28492532
SCV001422610	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 (3) [See all records that cite these PMIDs] 21644219, 22676651, 25741868 Citation Link,
SCV001443322	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	reviewed by expert panel (ClinGen LSD ACMG Specifications v1)	Pathogenic (Oct 5, 2020)	germline	curation	PubMed (5) [See all records that cite these PMIDs] 26575883, 21644219, 22676651, 20033296, 29523196 Citation Link,
SCV002015051	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Oct 25, 2021)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 22676651, 29523196, 21644219 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

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 (9)

Details of each submission

From Counsyl, SCV000485477.2

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV001211539.5

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

Description

This sequence change creates a premature translational stop signal (p.Trp738*) 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 (no rsID available, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with glycogen storage disease (PMID: 22676651). ClinVar contains an entry for this variant (Variation ID: 370223). 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, SCV001422610.2

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

Description

The p.Trp738Ter variant in GAA has been reported in 2 Chinese and 2 German individuals with Glycogen Storage Disease II, segregated with disease in 2 affected relatives from 1 family (PMID: 21644219, 22676651), and has also been reported likely pathogenic by Counsyl in ClinVar (Variation ID: 370223). This variant has been identified in 0.005% (1/18392) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1057516328). 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 738, 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 combination with a pathogenic variant, and in individuals with Glycogen Storage Disease II slightly increases the likelihood that the p.Trp738Ter variant is pathogenic (PMID: 22676651). The phenotype of an individual compound heterozygous for this variant is highly specific for Glycogen Storage Disease II based on GAA activity less than 10% of WT, consistent with disease (PMID: 22676651). 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 low frequency in the general population. ACMG/AMP Criteria applied: PVS1, PM3_supporting, PP4, 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 ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel, SCV001443322.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (5)

Description

This variant, c.2214G>A (p.Trp738Ter), is a nonsense variant that is predicted to result in nonsense-mediated decay and lack of gene product, meeting PVS1. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00005 in the East Asian population, meeting PM2. An individual with late onset Pompe disease and meeting the ClinGen LSD VCEP's specifications for PP4 who is compound heterozygous for the variant and c.-32-13T>G has been reported (PMID 22676651). This data meets PM3_Supporting. In addition, twins meeting PP4 are compound heterozygous for the variant and c.1942G>A (p.Gly648Ser) (PMID 26575883). However, the in trans data from this family will be used in the assessment of p.Gly648Ser and is not included here in order to avoid circular logic. Other cases have been reported but were not included because the residual GAA activity was not reported and therefore PP4 cannot be assessed (PMID 29523196), cDNA nomenclature was not provided (PMID 20033296), or pseudodeficiency alleles were present (PMID 21644219). There is a ClinVar entry for this variant (Variation ID: 370223; 2 star review status) with two 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. ACMG/AMP criteria applied, as specific 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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002015051.1

#	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.2214G>A (p.Trp738X) 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. The variant allele was found at a frequency of 4e-06 in 250908 control chromosomes. c.2214G>A has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease; Herzog_2012, Zheng_2011, Plockinger_2018). Four 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

Last Updated: Jan 13, 2025

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