NM_000152.5(GAA):c.1310G>A (p.Arg437His) AND Glycogen storage disease, type II

Germline classification:: Uncertain significance (7 submissions)
Last evaluated:: Mar 9, 2023
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:: RCV000553754.19

Allele description [Variation Report for NM_000152.5(GAA):c.1310G>A (p.Arg437His)]

NM_000152.5(GAA):c.1310G>A (p.Arg437His)

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.1310G>A (p.Arg437His)

HGVS:

NC_000017.11:g.80108812G>A
NG_009822.1:g.12257G>A
NM_000152.5:c.1310G>AMANE SELECT
NM_001079803.3:c.1310G>A
NM_001079804.3:c.1310G>A
NP_000143.2:p.Arg437His
NP_001073271.1:p.Arg437His
NP_001073272.1:p.Arg437His
LRG_673t1:c.1310G>A
LRG_673:g.12257G>A
NC_000017.10:g.78082611G>A
NM_000152.3:c.1310G>A
NM_000152.4(GAA):c.1310G>A
p.Arg437His

Protein change:

R437H

Links:

dbSNP: rs150868652

NCBI 1000 Genomes Browser:

rs150868652

Molecular consequence:

NM_000152.5:c.1310G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001079803.3:c.1310G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001079804.3:c.1310G>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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000626504	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 17, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 12601120, 17805474, 28492532
SCV001281357	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Uncertain significance (Apr 27, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV001422735	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 (1) [See all records that cite this PMID] Citation Link,
SCV001455609	Natera, Inc.	no assertion criteria provided	Uncertain significance (Sep 16, 2020)	germline	clinical testing
SCV002027263	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]
SCV002792987	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Feb 2, 2022)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004565266	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	Uncertain significance (Mar 9, 2023)	germline	clinical testing	Citation Link

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	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

Citations

PubMed

Juvenile-onset glycogen storage disease type II with novel mutations in acid alpha-glucosidase gene.

Lam CW, Yuen YP, Chan KY, Tong SF, Lai CK, Chow TC, Lee KC, Chan YW, Martiniuk F.

Neurology. 2003 Feb 25;60(4):715-7.

PubMed [citation]

PMID:: 12601120

Structural and biochemical studies on Pompe disease and a "pseudodeficiency of acid alpha-glucosidase".

Tajima Y, Matsuzawa F, Aikawa SI, Okumiya T, Yoshimizu M, Tsukimura T, Ikekita M, Tsujino S, Tsuji A, Edmunds T, Sakuraba H.

J Hum Genet. 2007;52(11):898-906. doi: 10.1007/s10038-007-0191-9. Epub 2007 Sep 6.

PubMed [citation]

PMID:: 17805474

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000626504.6

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

Description

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 437 of the GAA protein (p.Arg437His). This variant is present in population databases (rs150868652, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with GAA-related conditions. ClinVar contains an entry for this variant (Variation ID: 456374). 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 not expected to disrupt GAA protein function. This variant disrupts the p.Arg437 amino acid residue in GAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12601120, 17805474). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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 Illumina Laboratory Services, Illumina, SCV001281357.1

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

Description

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

#	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, SCV001422735.2

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

Description

The p.Arg437His variant in GAA has been reported in one individual with suspected glycogen storage disease II (PMID: 25681614) and has been identified in 0.041% (9/21742) of African chromosomes, 0.007% (8/109392) of European (non-Finnish) chromosomes, and 0.007% (2/27668) of South Asian chromosomes by the the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs150868652). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier disease. This variant has also been reported in ClinVar as a VUS by Invitae (VariationID: 456374). Computational prediction tools, including splice predictors, and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. One additional variant, resulting in a different amino acid change at the same position, p.Arg437Cys, has been reported pathogenic in association with glycogen storage disease II in the literature and ClinVar (PMID: 19862843, 24190153, 21984055, 21704464, 12601120, 24169249, 22521436, 17805474, 25388776, 25526786, 23884227, 18495398; VariationID: 189082). In summary, the clinical significance of the p.Arg437His variant is uncertain. ACMG/AMP Criteria applied: PM5, PM2, BP4 (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., SCV001455609.1

#	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, SCV002027263.1

#	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 Fulgent Genetics, Fulgent Genetics, SCV002792987.1

#	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 ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV004565266.1

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

Description

The GAA c.1310G>A; p.Arg437His variant (rs150868652), is reported in the literature in one individual suspected of Pompe disease (Turaca 2015). This variant is also reported in ClinVar (Variation ID: 456374), and is found in the general population with an overall allele frequency of 0.008% (20/246812 alleles) in the Genome Aggregation Database. Additionally, other variants at this codon (c.1309C>T, p.Arg437Cys) have been reported in individuals with Pompe disease and are considered pathogenic (Fukuhara 2017, Park 2021). Computational analyses predict that this variant is neutral (REVEL: 0.289). Given the lack of clinical and functional data, the significance of this variant is uncertain at this time. References: Turaca LT et al. Novel GAA mutations in patients with Pompe disease. Gene. 2015 Apr 25;561(1):124-31. PMID: 25681614. Park KS. Two Approaches for a Genetic Analysis of Pompe Disease: A Literature Review of Patients with Pompe Disease and Analysis Based on Genomic Data from the General Population. Children (Basel). 2021 Jul 16;8(7):601. PMID: 34356580. Fukuhara Y et al. A molecular analysis of the GAA gene and clinical spectrum in 38 patients with Pompe disease in Japan. Mol Genet Metab Rep. 2017 Oct 31;14:3-9. PMID: 29124014.

#	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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