NM_000152.5(GAA):c.1048G>A (p.Val350Met) AND Glycogen storage disease, type II

Germline classification:: Uncertain significance (9 submissions)
Last evaluated:: Mar 19, 2024
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:: RCV000671932.26

Allele description [Variation Report for NM_000152.5(GAA):c.1048G>A (p.Val350Met)]

NM_000152.5(GAA):c.1048G>A (p.Val350Met)

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.1048G>A (p.Val350Met)

Other names:

NM_000152.5(GAA):c.1048G>A

HGVS:

NC_000017.11:g.80108382G>A
NG_009822.1:g.11827G>A
NM_000152.5:c.1048G>AMANE SELECT
NM_001079803.3:c.1048G>A
NM_001079804.3:c.1048G>A
NP_000143.2:p.Val350Met
NP_001073271.1:p.Val350Met
NP_001073272.1:p.Val350Met
LRG_673t1:c.1048G>A
LRG_673:g.11827G>A
NC_000017.10:g.78082181G>A
NM_000152.3:c.1048G>A
NM_000152.4(GAA):c.1048G>A
NM_000152.4:c.1048G>A
NM_001079803.2:c.1048G>A
p.Val350Met

Protein change:

V350M

Links:

dbSNP: rs200412003

NCBI 1000 Genomes Browser:

rs200412003

Molecular consequence:

NM_000152.5:c.1048G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001079803.3:c.1048G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001079804.3:c.1048G>A - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000814652	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 13, 2025)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 23430949, 25451853, 36246652, 28492532
SCV001422742	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jan 22, 2020)	germline	curation	PubMed (3) [See all records that cite these PMIDs] 25451853, 25786784, 25741868 Citation Link,
SCV001455600	Natera, Inc.	no assertion criteria provided	Uncertain significance (Sep 16, 2020)	germline	clinical testing
SCV002027250	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Sep 5, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002060332	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2021))	Uncertain significance (Nov 8, 2021)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 23430949, 25451853 Citation Link,
SCV002600693	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (May 30, 2024)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 23430949, 24627108, 30155607, 33073007, 25786784, 25451853, 36246652, 36310651, 34995642 Citation Link,
SCV002777400	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Sep 14, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004195428	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 22, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004809071	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	reviewed by expert panel (clingen_lsd_acmg_specifications_v2-1)	Uncertain significance (Mar 19, 2024)	germline	curation	Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	no	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

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9..

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Newborn screening for lysosomal storage disorders in hungary.

Wittmann J, Karg E, Turi S, Legnini E, Wittmann G, Giese AK, Lukas J, Gölnitz U, Klingenhäger M, Bodamer O, Mühl A, Rolfs A.

JIMD Rep. 2012;6:117-25. doi: 10.1007/8904_2012_130. Epub 2012 Mar 21.

PubMed [citation]

PMID:: 23430949
PMCID:: PMC3565645

See all PubMed Citations (11)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000814652.7

#	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 replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 350 of the GAA protein (p.Val350Met). This variant is present in population databases (rs200412003, gnomAD 0.05%). This missense change has been observed in individual(s) with Pompe disease (PMID: 23430949, 25451853, 36246652). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 555998). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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: 36246652). 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, SCV001422742.2

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

Description

The p.Val350Met variant in GAA has been reported in 2 individuals with glycogen storage disease II (PMID: 25786784, 25451853) and has been identified in 0.04% (11/25122) of European (Finnish) chromosomes, 0.013% (17/128822) of European (non-Finnish) chromosomes, and 0.004% (1/24900) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs200412003). 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 a VUS by Counsyl and Invitae (VariationID: 555998). 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 phenotype of individuals heterozygous for this variant is highly specific for glycogen storage disease II based on GAA enzyme activity in muscle and lymphocytes being <10% of wild type, consistent with disease (PMID: 25786784, 25451853). Additionally, the presence of this variant in combination with reported pathogenic variant c.-32-13T>G and in individuals with glycogen storage disease II slightly increases the likelihood that the p.Val350Met variant is pathogenic. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: 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., SCV001455600.1

#	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 Genome-Nilou Lab, SCV002027250.1

#	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	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Myriad Genetics, Inc., SCV002060332.2

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

Description

NM_000152.3(GAA):c.1048G>A(V350M) is a missense variant classified as a variant of uncertain significance in the context of Pompe disease. V350M has been observed in cases with relevant disease (PMID 25451853, 23430949). Functional assessments of this variant are not available in the literature. V350M has been observed in population frequency databases (gnomAD: FIN 0.05%). In summary, there is insufficient evidence to classify NM_000152.3(GAA):c.1048G>A(V350M) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002600693.2

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

Description

Variant summary: GAA c.1048G>A (p.Val350Met) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.6e-05 in 251022 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in GAA causing Late Onset Pompe Disease (9.6e-05 vs 0.0042), allowing no conclusion about variant significance. c.1048G>A has been reported in the literature in infants with indications of Late Onset Pompe Disease via newborn screening who were compound heterozygous with pathogenic variants (e.g. Lee_2022, Goomber_2022). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant results in 1.5% of wild type GAA enzyme activity (Goomber_2022). The following publications have been ascertained in the context of this evaluation (PMID: 23430949, 24627108, 30155607, 33073007, 25786784, 25451853, 34995642, 36246652, 36310651). ClinVar contains an entry for this variant (Variation ID: 555998). Based on the evidence outlined above, the variant was classified as likely 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 Fulgent Genetics, Fulgent Genetics, SCV002777400.1

#	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, SCV004195428.2

#	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 ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel, SCV004809071.1

#	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(GAA):c.1048G>A variant in GAA is a missense variant predicted to cause substitution of valine by methionine at amino acid 350 (p.Val350Met). This variant has been detected in at least 12 individuals, and at least 11 patients with this variant had documented GAA deficiency with activity in the affected range in dried blood spot (Clinical Laboratory data, PMIDs: 25451853, 36310651, 36246652). However, in the absence of clinical symptoms to support that the variant causes Pompe disease, PP4 was not applied. Of those individuals, 1 was homozygous for the variant, and 11 were compound heterozygous for the variant and a pathogenic or likely pathogenic variant in GAA; 2 of those were confirmed in trans by parental testing, including c.-32-13T>G (9 patients, Clinical laboratory data, PMID:25451853, 1 patient confirmed in trans), c.2051C>T (p.Pro684Leu) (1 patient, PMID:36310651, phase unknown), c.1589del (p.Glu530GlyfsTer48) (1 patient, PMID: 36246652, phase unknown), and c.2238G>C (p.Trp746Cys) (2 patients, one confirmed in trans and one with a pseudodeficiency allele, Clinical Laboratory data). Due to lack of clinical symptoms in these patients, PM3 is not met at the current time. When expressed in HEK293 cells, GAA enzyme activity was 1.5% of the positive control (Table 3). Western blot revealed faint precursor (110 k Da) and mature (76 kDa) protein bands with lower intensity compared to the positive control, indicating this variant may be impacting GAA protein stability and processing (PS3_Supporting). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00013 (17/1128822 alleles) in the European non-Finnish population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.878 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: 555998). In summary, while patients with this variant have been reported with deficiency GAA activity, and the variant has been found in compound heterozygosity with pathogenic and likely pathogenic variants in GAA, the Lysosomal Diseases VCEP concluded that there is insufficient phenotypic evidence to indicate that this variant cuases Pompe disease at this time. Therefore, this variant will be classified as a variant of uncertain significance until further evidence is available. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PS3_Supporting, PP3, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on March 19, 2024).

#	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: May 25, 2025

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