NM_000152.5(GAA):c.726G>A (p.Ala242=) AND Glycogen storage disease, type II

Germline classification:: Uncertain significance (7 submissions)
Last evaluated:: Sep 19, 2023
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:: RCV000315968.34

Allele description [Variation Report for NM_000152.5(GAA):c.726G>A (p.Ala242=)]

NM_000152.5(GAA):c.726G>A (p.Ala242=)

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.726G>A (p.Ala242=)

Other names:

NM_000152.5(GAA):c.726G>A

HGVS:

NC_000017.11:g.80107590G>A
NG_009822.1:g.11035G>A
NM_000152.4(GAA):c.726G>A
NM_000152.5:c.726G>AMANE SELECT
NM_001079803.3:c.726G>A
NM_001079804.3:c.726G>A
NP_000143.2:p.Ala242=
NP_001073271.1:p.Ala242=
NP_001073272.1:p.Ala242=
LRG_673t1:c.726G>A
LRG_673:g.11035G>A
NC_000017.10:g.78081389G>A
NM_000152.3:c.726G>A
NM_000152.4(GAA):c.726G>A
NM_000152.4:c.726G>A
NM_000152.5:c.726G>A
p.Ala242=

Links:

dbSNP: rs148578399

NCBI 1000 Genomes Browser:

rs148578399

Molecular consequence:

NM_000152.5:c.726G>A - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001079803.3:c.726G>A - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001079804.3:c.726G>A - synonymous variant - [Sequence Ontology: SO:0001819]

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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Mus musculus ribosomal protein L34 (Rpl34), transcript variant 1, mRNA
Mus musculus ribosomal protein L34 (Rpl34), transcript variant 1, mRNA
gi|55742884|ref|NM_026724.1|

Nucleotide
JGI_XZT36450.fwd NIH_XGC_tropTad5 Xenopus tropicalis cDNA clone IMAGE:7612388 5'...
JGI_XZT36450.fwd NIH_XGC_tropTad5 Xenopus tropicalis cDNA clone IMAGE:7612388 5', mRNA sequence
gi|74091720|gnl|dbEST|31257094|gb|C 23.2|

Nucleotide
NISC_nl19e01.y1 NICHD_XGC_Emb7 Xenopus tropicalis cDNA clone IMAGE:5379168 5', m...
NISC_nl19e01.y1 NICHD_XGC_Emb7 Xenopus tropicalis cDNA clone IMAGE:5379168 5', mRNA sequence
gi|21381818|gnl|dbEST|12634244|gb|B 49.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000407269	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Uncertain significance (Jan 13, 2018)	germline	clinical testing	Citation Link,
SCV000626634	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Benign (Jan 31, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001423083	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign (Jan 22, 2020)	germline	curation	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV001810418	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign (Jul 22, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002091959	Natera, Inc.	no assertion criteria provided	Likely benign (Oct 24, 2019)	germline	clinical testing
SCV004227918	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	reviewed by expert panel (clingen_lsd_acmg_specifications_v2-1)	Uncertain significance (Sep 19, 2023)	germline	curation	Citation Link,
SCV004565165	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	Likely benign (Sep 28, 2023)	germline	clinical testing	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	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing

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

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Illumina Laboratory Services, Illumina, SCV000407269.3

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

Description

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

#	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 Invitae, SCV000626634.8

#	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	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, SCV001423083.2

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

Description

The c.726G>A (p.Ala242=) variant in GAA has not been previously reported in individuals with Glycogen Storage Disease II but has been reported as a VUS (by EGL and Illumina), a likely benign variant (by GeneDx and Mayo Clinic Genetic Testing Laboratories), and a benign variant (by Invitae) in ClinVar (Variation ID: 285366). This variant has been identified in 0.2769% (69/24916) of African chromosomes, including 1 homozygote, and 0.04516% (16/35432) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs148578399). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. However, novel synonymous variants supported by computational evidence without raised suspicion for an impact are likely benign (Richards 2015). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely benign. ACMG/AMP Criteria applied: BP4, BP7 (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 Genome-Nilou Lab, SCV001810418.1

#	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 Natera, Inc., SCV002091959.1

#	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, SCV004227918.1

#	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.726G>A variant in GAA is a synonymous (silent) variant (p.Ala242=) that is predicted to impact splicing. This variant has been detected in at least 10 individuals with low GAA activity. Of those individuals, 8 were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and 3 of those were confirmed in trans by parental testing (c.726G>A/c.525delT; 5 patients with the genotype c.−32-13T>G; 726G>A, confirmed in trans in 3 patients, PMID: 36310651; c.726G>A / c.671G>A; c.726G>A / c.1979G>A; c.726G>A and c.2560C>T), however there is no diagnosis of Pompe disease and PM3 and PP4 are not met. The computational splicing predictor SpliceAI gives a score of 0.96 for acceptor gain, predicting that the variant creates a new cryptic splice site that is stronger than the original splice site. VarSeak also classifies this variant as having a likely splicing effect by generating a cryptic splice site 35 nucleotides downstream of the authentic splice site with a higher score, meeting PP3. This is confirmed by RNA sequencing data for an individual with the c.726G>A variant demonstrated that the variant impacts splicing by introducing an alternate splice site that results in exon shrinkage. The data suggest that this results in a frameshift and introduces a premature termination codon, however the expression is not reduced, indicating a truncated protein is produced (PMID: 35304488), meeting PS3_Supporting. There is a ClinVar entry for this variant (Variation ID: 285366, 1 star review status) with 10 submitters classifying the variant as VUS (4 submitters), likely benign (3 submitters), and benign (1 submitter). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Pompe disease. ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (specifications Version 2.0): PP3, PS3_Supporting. (Classification approved by the ClinGen Lysosomal Diseases VCEP on Sept. 19, 2023)

#	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 ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV004565165.1

#	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

Last Updated: Sep 16, 2024

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