NM_000152.5(GAA):c.1843G>A (p.Gly615Arg) AND Glycogen storage disease, type II

Germline classification:: Likely pathogenic (8 submissions)
Last evaluated:: Sep 6, 2022
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:: RCV000169115.18

Allele description [Variation Report for NM_000152.5(GAA):c.1843G>A (p.Gly615Arg)]

NM_000152.5(GAA):c.1843G>A (p.Gly615Arg)

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.1843G>A (p.Gly615Arg)

Other names:

NM_000152.5(GAA):c.1843G>A

HGVS:

NC_000017.11:g.80112666G>A
NG_009822.1:g.16111G>A
NM_000152.5:c.1843G>AMANE SELECT
NM_001079803.3:c.1843G>A
NM_001079804.3:c.1843G>A
NP_000143.2:p.Gly615Arg
NP_001073271.1:p.Gly615Arg
NP_001073272.1:p.Gly615Arg
LRG_673t1:c.1843G>A
LRG_673:g.16111G>A
NC_000017.10:g.78086465G>A
NM_000152.3:c.1843G>A
NM_000152.4(GAA):c.1843G>A
P10253:p.Gly615Arg

Protein change:

G615R

Links:

UniProtKB: P10253#VAR_008690; dbSNP: rs549029029

NCBI 1000 Genomes Browser:

rs549029029

Molecular consequence:

NM_000152.5:c.1843G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001079803.3:c.1843G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001079804.3:c.1843G>A - missense variant - [Sequence Ontology: SO:0001583]

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

Recent activity

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Homo sapiens polypyrimidine tract binding protein 2 (PTBP2), transcript variant ...
Homo sapiens polypyrimidine tract binding protein 2 (PTBP2), transcript variant 3, mRNA
gi|1677499936|ref|NM_001300987.2|

Nucleotide
sulfoquinovosyl transferase SQD2 isoform X2 [Glycine max]
sulfoquinovosyl transferase SQD2 isoform X2 [Glycine max]
gi|955331144|ref|XP_014633489.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000220317	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Likely pathogenic (May 14, 2014)	unknown	literature only	PubMed (9) [See all records that cite these PMIDs] 24269976, 14695532, 15366815, 18607768, 18458862, 21232767, 16860134, 10338092, 20080426 Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015), Citation Link,
SCV000824487	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 6, 2023)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 19862843, 10338092, 15366815, 16860134, 18458862, 18607768, 21757382, 24269976, 25037089, 28492532
SCV000919384	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jul 5, 2018)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 15366815, 18458862, 21757382 Citation Link,
SCV001422905	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 (10) [See all records that cite these PMIDs] 24269976, 18607768, 10338092, 18458862, 21757382, 16860134, 21232767, 15366815, 20080426, 25741868 Citation Link,
SCV001459739	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 16, 2020)	germline	clinical testing
SCV002583372	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	reviewed by expert panel (clingen_lsd_acmg_specifications_v2-1)	Likely pathogenic (Sep 6, 2022)	germline	curation	Citation Link,
SCV002787554	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 14, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004197792	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 24, 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	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, literature only

Citations

PubMed

Twenty-two novel mutations in the lysosomal alpha-glucosidase gene (GAA) underscore the genotype-phenotype correlation in glycogen storage disease type II.

Hermans MM, van Leenen D, Kroos MA, Beesley CE, Van Der Ploeg AT, Sakuraba H, Wevers R, Kleijer W, Michelakakis H, Kirk EP, Fletcher J, Bosshard N, Basel-Vanagaite L, Besley G, Reuser AJ.

Hum Mutat. 2004 Jan;23(1):47-56.

PubMed [citation]

PMID:: 14695532

The pharmacological chaperone 1-deoxynojirimycin increases the activity and lysosomal trafficking of multiple mutant forms of acid alpha-glucosidase.

Flanagan JJ, Rossi B, Tang K, Wu X, Mascioli K, Donaudy F, Tuzzi MR, Fontana F, Cubellis MV, Porto C, Benjamin E, Lockhart DJ, Valenzano KJ, Andria G, Parenti G, Do HV.

Hum Mutat. 2009 Dec;30(12):1683-92. doi: 10.1002/humu.21121.

PubMed [citation]

PMID:: 19862843

See all PubMed Citations (14)

Details of each submission

From Counsyl, SCV000220317.2

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

#	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, SCV000824487.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GAA function (PMID: 19862843). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GAA protein function. ClinVar contains an entry for this variant (Variation ID: 188786). This missense change has been observed in individual(s) with Pompe disease (PMID: 10338092, 15366815, 16860134, 18458862, 18607768, 21757382, 24269976, 25037089). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs549029029, gnomAD 0.02%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 615 of the GAA protein (p.Gly615Arg).

#	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, SCV000919384.1

#	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.1843G>A (p.Gly615Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.1e-05 in 97298 control chromosomes (gnomAD and publication). The variant, c.1843G>A, has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease), whom presented with significantly decreased enzyme activity (<10%). These data indicate that the variant is likely to be associated with disease. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. 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 Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001422905.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (10)

Description

The p.Gly615Arg variant in GAA has been reported in 13 individuals (including 4 Taiwanese, 1 Chinese, and 1 German individuals) with Glycogen Storage Disease II, segregated with disease in 2 affected relatives from 1 family (PMID: 16860134, 18458862, 10338092, 24269976, 21232767, 20080426, 15366815, 18607768, 21757382, 25037089), and has also been reported likely pathogenic by Counsyl and pathogenic by Invitae and Integrated Genetics in ClinVar (Variation ID: 188786). This variant has been identified in 0.022% (4/17994) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs549029029). 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 provide some evidence that the p.Gly615Arg variant may impact protein function (PMID: 19862843). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The presence of this variant in combination with reported pathogenic variants in individuals with Glycogen Storage Disease II increases the likelihood that the p.Gly615Arg variant is pathogenic (PMID: 16860134, 18458862). The phenotype of individuals heterozygous for this variant is highly specific for Glycogen Storage Disease II based on reduced GAA activity in relevant tissues, consistent with disease (PMID: 21757382, 16860134, 18458862). In summary, this variant meets criteria to be classified as pathogenic for Glycogen Storage Disease II in an autosomal recessive manner based on in vitro functional studies, low frequency in the general population, and multiple occurrences in combination with pathogenic variants in affected individuals. ACMG/AMP Criteria applied: PS3, PM2, PM3, 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., SCV001459739.1

#	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 ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel, SCV002583372.1

#	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.1843G>A variant in GAA is a missense variant predicted to cause substitution of glycine by arginine at amino acid 615 (p.Gly615Arg). At least 7 patients with a diagnosis of Pompe disease have been reported with this variant. Five of these patients are reported to have infantile onset Pompe disease (IOPD) and meet the criteria for PP4_Moderate with <10% GAA activity in cultured fibroblasts and/or GAA activity in the affected range in leukocytes (PMIDs: 15366815, 16860134, 18458862, 25037089), documented symptoms consistent with IOPD, and on enzyme replacement therapy (PMIDs: 16860134, 25037089) (PP4_Moderate). Of the reported patients, three are compound heterozygous, phase unknown, for another variant in GAA that has been classified as pathogenic by the ClinGen LSD VCEP, either c.2238G>A (p.Trp746Ter) (PMID: 16860134) or c.1935C>A (p.Asp645Glu) (PMID: 18458862) (2 patients). Two patients are homozygous for the variant (PMID: 15366815, 25037089) (PM3_Strong). A further two patients are compound heterozygous for the variant and either c.1832G>A (p.Gly611Asp) (PMID: 24269976) or c.1933G>C (p.Asp645His (clinical laboratory data) . The allelic data from these patients will be used in the classification of the other variant and is not included here to avoid circular. Finally, An 4 patients have been reported in the literature but the data was not included because the cDNA change for the variant was not provided, or does not match amino acid change (PMIDs: 10338092, 18607768, 21757382). The highest population minor allele frequency in gnomAD is 0.00022 in the East Asian population which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). When expressed in COS cells, the variant resulted in <2% GAA activity (PMID 19862843) (PS3_Supporting). The computational predictor REVEL gives a score of 0.989 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). There is a ClinVar entry for this variant (Variation ID: 188746, 2 star review status), with 5 submitters classifying the variant as pathogenic and one as likely pathogenic. In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP (Specifications Verions 2.0): PM3_Strong, PP4_Moderate, PS3_Supporting, PM2_Supporting, PP3.

#	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, SCV002787554.1

#	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, SCV004197792.2

#	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

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