NM_000152.5(GAA):c.2237G>C (p.Trp746Ser) AND Glycogen storage disease, type II

Germline classification:: Pathogenic/Likely pathogenic (9 submissions)
Last evaluated:: Mar 12, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000626060.28

Allele description [Variation Report for NM_000152.5(GAA):c.2237G>C (p.Trp746Ser)]

NM_000152.5(GAA):c.2237G>C (p.Trp746Ser)

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>C (p.Trp746Ser)

HGVS:

NC_000017.11:g.80117015G>C
NG_009822.1:g.20460G>C
NM_000152.5:c.2237G>CMANE SELECT
NM_001079803.2(GAA):c.2237G>C
NM_001079803.3:c.2237G>C
NM_001079804.3:c.2237G>C
NP_000143.2:p.Trp746Ser
NP_001073271.1:p.Trp746Ser
NP_001073272.1:p.Trp746Ser
LRG_673t1:c.2237G>C
LRG_673:g.20460G>C
NC_000017.10:g.78090814G>C
NM_000152.3:c.2237G>C
NM_000152.4:c.2237G>C
NM_001079803.2(GAA):c.2237G>C
NM_001079803.2:c.2237G>C
P10253:p.Trp746Ser

Protein change:

W746S

Links:

UniProtKB: P10253#VAR_068632; dbSNP: rs752921215

NCBI 1000 Genomes Browser:

rs752921215

Molecular consequence:

NM_000152.5:c.2237G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001079803.3:c.2237G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001079804.3:c.2237G>C - missense variant - [Sequence Ontology: SO:0001583]

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

Recent activity

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protein unc-80 homolog isoform X12 [Rattus norvegicus]
protein unc-80 homolog isoform X12 [Rattus norvegicus]
gi|1958805107|ref|XP_038940529.1|

Protein
NADH dehydrogenase subunit 6 (mitochondrion) [Apterichtus klazingai]
NADH dehydrogenase subunit 6 (mitochondrion) [Apterichtus klazingai]
gi|2580280160|gb|WNH21308.1|

Protein
Chromosome neighbors for GEO Profiles (Select 77148430) (20)
GEO Profiles
BioAssays, Active for PubChem Compound (Select 91623361) (0)
PubChem BioAssay
Protein Links for Conserved Domains (Select 236686) (4300)
Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000746682	Genomic Research Center, Shahid Beheshti University of Medical Sciences	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Dec 18, 2017)	inherited	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000795205	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Likely pathogenic (Nov 8, 2017)	unknown	clinical testing	PubMed (6) [See all records that cite these PMIDs] 22644586, 18425781, 23430493, 22081099, 24169249, 28490439 Citation Link,
SCV000950050	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 19, 2024)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 18425781, 22081099, 18458862, 21232767, 21757382, 23430493, 25093132, 25526786, 27099502, 28492532
SCV001422665	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 (6) [See all records that cite these PMIDs] 22644586, 18425781, 22081099, 28490439, 24169249, 25741868 Citation Link,
SCV001459753	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 16, 2020)	germline	clinical testing
SCV003800659	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jan 18, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV003927051	Biochemical Genetics Department, Cyprus Institute of Neurology and Genetics	criteria provided, single submitter (ClinGen LSD ACMG Specifications V2)	Pathogenic (May 5, 2023)	germline	clinical testing	Citation Link,
SCV004195498	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 12, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004848904	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (Feb 2, 2023)	germline	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	inherited	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	5	1	not provided	6	yes	clinical testing, curation
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Identification of eight novel mutations of the acid alpha-glucosidase gene causing the infantile or juvenile form of glycogen storage disease type II.

Wan L, Lee CC, Hsu CM, Hwu WL, Yang CC, Tsai CH, Tsai FJ.

J Neurol. 2008 Jun;255(6):831-8. doi: 10.1007/s00415-008-0714-0. Epub 2008 May 6.

PubMed [citation]

PMID:: 18458862

Later-onset Pompe disease: early detection and early treatment initiation enabled by newborn screening.

Chien YH, Lee NC, Huang HJ, Thurberg BL, Tsai FJ, Hwu WL.

J Pediatr. 2011 Jun;158(6):1023-1027.e1. doi: 10.1016/j.jpeds.2010.11.053. Epub 2011 Jan 13.

PubMed [citation]

PMID:: 21232767

See all PubMed Citations (14)

Details of each submission

From Genomic Research Center, Shahid Beheshti University of Medical Sciences, SCV000746682.2

#	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	inherited	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Counsyl, SCV000795205.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

#	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, SCV000950050.4

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

Description

This sequence change replaces tryptophan, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 746 of the GAA protein (p.Trp746Ser). This variant is present in population databases (rs752921215, gnomAD 0.03%). This missense change has been observed in individuals with Pompe disease (PMID: 18425781, 22081099). ClinVar contains an entry for this variant (Variation ID: 188484). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GAA function (PMID: 23430493). This variant disrupts the p.Trp746 amino acid residue in GAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18458862, 21232767, 21757382, 23430493, 25093132, 25526786, 27099502). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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, SCV001422665.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (6)

Description

The p.Trp746Ser variant in GAA has been reported in 1 Danish, 1 Chinese, 1 Northern European, and 6 Italian individuals with Glycogen Storage Disease II (PMID: 28490439, 24169249, 18425781, 22081099), and has been identified in 0.032% (8/24924) of African chromosomes and 0.011% (4/35424) of Latino 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 variant has also been reported as a pathogenic variant by Invitae and a likely pathogenic variant by Counsyl and Shahid Beheshti University of Medical Sciences in ClinVar (Variation ID: 188484). In vitro functional studies provide some evidence that the p.Trp746Ser variant may impact GAA activity (PMID: 22644586). 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 a reported pathogenic variant in 6 individuals with Glycogen Storage Disease II increases the likelihood that the p.Trp746Ser variant is pathogenic (PMID: 22081099). The phenotype of 2 individuals heterozygous for this variant is highly specific for Glycogen Storage Disease II based on reduced GAA activity in muscle tissue, consistent with disease (PMID: 22081099). Four additional variants (p.Trp746Cys, p.Trp746Gly, p.Trp746Arg, and p.Trp746Leu) at the the same position, including a reported pathogenic variant, have been reported in association with disease in ClinVar, supporting that a change at this position may not be tolerated (Variation ID: 265160, 556431, 499293, 284776). In summary, this variant meets criteria to be classified as pathogenic for Glycogen Storage Disease II in an autosomal recessive manner based on occurrences with a pathogenic GAA variant in individuals with Glycogen Storage Disease II and functional evidence. ACMG/AMP Criteria applied: PS3, PM5, PM3_supporting, PM2, 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., SCV001459753.1

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV003800659.2

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

Description

Variant summary: GAA c.2237G>C (p.Trp746Ser) 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 6.8e-05 in 250744 control chromosomes (gnomAD). This frequency is not higher than predicted for a pathogenic variant in GAA causing Glycogen Storage Disease, Type 2 (Pompe Disease) (6.8e-05 vs 0.0042), allowing no conclusion about variant significance. c.2237G>C has been reported in the literature in multiple individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) (example: Angelini_2012). These data indicate that the variant is very likely to be associated with disease. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all 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

From Biochemical Genetics Department, Cyprus Institute of Neurology and Genetics, SCV003927051.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	5	not provided	yes	clinical testing	not provided

Description

The c.266G>A variant (maternal origin) was observed in compound heterozygosity with the c.2237G>C variant (paternal origin). Family studies showed that the c.[266G>A];[2237G>C] genotype is co-segregates with the disease, LOPD.

Description

The classification of the variant was performed according to the recommendations of ClinGen lysosomal storage disorders variant curation expert panel (Guidelines version 2, specific for the GAA gene). The NM_000152.5:c.2237G>C p.(Trp746Ser) is a missense variant that replaces a highly conserved Trp with Ser. This variant is present at a very low frequency in gnomAD databases (ƒExomes = 0.0000678, ƒgenomes = 0.0000854), only in heterozygosity and meets the PM2_Supporting criterion (1pt). This variant is located in a mutational hot-spot sequence of 17 amino-acids length with 20 missense/in-frame variants (8 pathogenic variants, 12 uncertain variants) and without benign variation, which qualifies the c.2237G>C variant as moderate pathogenic (PM1 criterion, 2pts). Five pathogenic alternative variants [Trp746Cys (chr17:78090815G>T and chr17:78090815 G>C), Trp746Leu, Trp746Gly and Trp746Arg] affecting the same amino acid (Trp746) have been reported in association with disease in ClinVar (PM5_strong: 4pts). Multiple lines of computational evidence strongly support the pathogenicity of this variant (REVEL score: 0.919) and therefore meets the PP3 criterion (supporting, 1pt). The c.2237G>C variant confirmed to be in trans with different pathogenic or likely pathogenic variants (PMID: 25526786, PMID: 18429042, PMID: 12923862, PMID: 21484825, PMID: 16917947, PMID: 18285536) in individuals with Pompe disease, thus meets the PM3_very strong criterion (4pts). In vitro functional studies provide evidence that the p.Trp746Ser variant may impact GAA activity (PMID: 22644586). In our study, the four individuals (with c.[266G>A];[2237G>C] genotype, 2-13 years) were found to have GAA activity clearly within the patient range (1.1-4.9nmol/h/mg) in leukocytes using 4-methylumbelliferyl-α-D-glucoside as a substrate. Using glycogen as a substrate, the GAA activity was found to be within the range for LOPD patients (3-10nmol/h/mg) for one subject and slightly above the upper limit for the three subjects. The presence of the KM-mutant polymorphism c.271G>A and the pseudodeficiency variant c.[1726G>A (p.Gly576Ser); 2065G>A (p.Glu689Lys)] was excluded. Based on the ClinGen LSD VCEP's specifications, this data meets PP4_Moderate rule (2pts). In summary, this variant meets the criteria to be classified as a pathogenic variant (total 14 pts) for Pompe disease.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	6	not provided	discovery		5	not provided	1	not provided

From Baylor Genetics, SCV004195498.2

#	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 Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004848904.1

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

Description

The p.Trp746Ser variant in GAA has been reported at least 3 individuals with glycogen storage disorder type II (GSD type II), two of whom were compound heterozygous with the variant a pathogenic variant on the other allele and also carried another variant (p.Gln743Arg) in cis (on the same allele as this variant) (Kroos 2008 PMID: 18425781, Liu 2013 PMID: 24169249, Preisler 2017 PMID: 28490439). It has also been identified in 0.03% (5/15284) of Latino/Admixed American chromosomes by gnomAD, v.3 (http://gnomad.broadinstitute.org), and is reported in ClinVar (Variation ID 188484). In vitro functional studies suggest the variant impairs protein function (Kroos 2012 PMID: 22644586, Niño 2013 PMID: 23430493). Computational prediction tools and conservation analyses suggest that this variant may impact the protein. Several variants involving this codon (p.Trp746Cys, p.Trp746Gly, p.Trp746Arg, and p.Trp746Leu) have been identified in individuals with GSD type II and have been classified as pathogenic in ClinVar. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive glycogen storage disorder type II. ACMG/AMP criteria applied: PM5_Strong, 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

Last Updated: Sep 29, 2024

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