NM_000152.5(GAA):c.281_282del (p.Pro94fs) AND Glycogen storage disease, type II

Germline classification:: Likely pathogenic (4 submissions)
Last evaluated:: Mar 10, 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:: RCV000411737.15

Allele description [Variation Report for NM_000152.5(GAA):c.281_282del (p.Pro94fs)]

NM_000152.5(GAA):c.281_282del (p.Pro94fs)

Gene:

GAA:alpha glucosidase [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

17q25.3

Genomic location:

Preferred name:

NM_000152.5(GAA):c.281_282del (p.Pro94fs)

HGVS:

NC_000017.11:g.80104867_80104868del
NG_009822.1:g.8312_8313del
NM_000152.5:c.281_282delMANE SELECT
NM_001079803.3:c.281_282del
NM_001079804.3:c.281_282del
NP_000143.2:p.Pro94fs
NP_001073271.1:p.Pro94fs
NP_001073272.1:p.Pro94fs
LRG_673t1:c.281_282del
LRG_673:g.8312_8313del
NC_000017.10:g.78078666_78078667del
NC_000017.11:g.80104867_80104868delCT
NM_000152.3:c.281_282del
NM_000152.3:c.281_282delCT
NM_000152.4(GAA):c.281_282delCT
NM_000152.5(GAA):c.281_282delMANE SELECT
p.Pro94Argfs
p.Pro94fs

Protein change:

P94fs

Links:

dbSNP: rs1057516503

NCBI 1000 Genomes Browser:

rs1057516503

Molecular consequence:

NM_000152.5:c.281_282del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001079803.3:c.281_282del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001079804.3:c.281_282del - frameshift variant - [Sequence Ontology: SO:0001589]

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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LOC110120507 [Mus musculus]
LOC110120507 [Mus musculus]
Gene ID:110120507

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000485788	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Likely pathogenic (Feb 12, 2016)	unknown	clinical testing	mdi-5618_320494_Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015).pdf, Citation Link,
SCV001413514	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jul 1, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 18425781, 22252923, 28492532
SCV001423061	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 22, 2020)	germline	curation	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV001443314	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	reviewed by expert panel (clingen_lsd_acmg_specifications_v2-1)	Likely pathogenic (Mar 10, 2023)	germline	curation	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	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Update of the Pompe disease mutation database with 107 sequence variants and a format for severity rating.

Kroos M, Pomponio RJ, van Vliet L, Palmer RE, Phipps M, Van der Helm R, Halley D, Reuser A; GAA Database Consortium..

Hum Mutat. 2008 Jun;29(6):E13-26. doi: 10.1002/humu.20745.

PubMed [citation]

PMID:: 18425781

Predicting cross-reactive immunological material (CRIM) status in Pompe disease using GAA mutations: lessons learned from 10 years of clinical laboratory testing experience.

Bali DS, Goldstein JL, Banugaria S, Dai J, Mackey J, Rehder C, Kishnani PS.

Am J Med Genet C Semin Med Genet. 2012 Feb 15;160C(1):40-9. doi: 10.1002/ajmg.c.31319. Epub 2012 Jan 17.

PubMed [citation]

PMID:: 22252923
PMCID:: PMC3278076

See all PubMed Citations (4)

Details of each submission

From Counsyl, SCV000485788.2

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001413514.5

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

Description

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 370458). This variant has not been reported in the literature in individuals affected with GAA-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.006%). This sequence change creates a premature translational stop signal (p.Pro94Argfs*51) in the GAA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GAA are known to be pathogenic (PMID: 18425781, 22252923).

#	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, SCV001423061.2

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

Description

The p.Pro94ArgfsTer51 variant in GAA has not been previously reported in individuals with Glycogen Storage Disease II but has been reported likely pathogenic by Counsyl in ClinVar (Variation ID: 370458). This variant has been identified in 0.0060% (2/33534) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1057516503). 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 is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 94 and leads to a premature termination codon 51 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the GAA gene is an established disease mechanism in autosomal recessive Glycogen Storage Disease II. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PVS1, PM2 (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 ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel, SCV001443314.2

#	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.281_282del (p.Pro94ArgfsTer51) variant in GAA is a frameshift variant predicted to cause a premature stop codon, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006 in the Latino population, which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). To our knowledge, this variant has not been reported in the literature in individuals with Pompe disease, and results of experimental studies are not available. There is a ClinVar entry for this variant (Variation ID: 370458). The classification of this variant has been upgraded from Variant of Uncertain Significance to Likely Pathogenic based on the recommendations of the ClinGen Sequence Variant Interpretation Working Group, that a variant meeting PVS1 and PM2_Supporting is classified as Likely Pathogenic (https://clinicalgenome.org/site/assets/files/5182/pm2_-_svi_recommendation_-_approved_sept2020.pdf ). In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PVS1, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases VCEP, March 10, 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

Last Updated: Sep 29, 2024

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