NM_000152.5(GAA):c.2481+110_2646+39del AND Glycogen storage disease, type II

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Feb 13, 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:: RCV000813887.9

Allele description [Variation Report for NM_000152.5(GAA):c.2481+110_2646+39del]

NM_000152.5(GAA):c.2481+110_2646+39del

Gene:

GAA:alpha glucosidase [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

17q25.3

Genomic location:

Preferred name:

NM_000152.5(GAA):c.2481+110_2646+39del

HGVS:

NC_000017.11:g.80117859_80118396del
NG_009822.1:g.21304_21841del
NM_000152.3:c.2481+110_2646+39del
NM_000152.5:c.2481+110_2646+39delMANE SELECT
NM_001079803.3:c.2481+110_2646+39del
NM_001079804.3:c.2481+110_2646+39del
LRG_673t1:c.2481+104_2646+33del
LRG_673:g.21304_21841del
NC_000017.10:g.78091658_78092195del
NM_000152.3:c.2481+104_2646+33del
NM_000152.3:c.2481+110_2646+39del
NM_000152.5:c.2481+110_2646+39del

Links:

dbSNP: rs1598592604

NCBI 1000 Genomes Browser:

rs1598592604

Molecular consequence:

NM_000152.5:c.2481+110_2646+39del - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001079803.3:c.2481+110_2646+39del - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001079804.3:c.2481+110_2646+39del - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_000152.5:c.2481+110_2646+39del - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001079803.3:c.2481+110_2646+39del - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001079804.3:c.2481+110_2646+39del - splice donor variant - [Sequence Ontology: SO:0001575]

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000954269	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 3, 2018)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 18607768, 25752415, 24844452, 15121988, 17723315, 19588081, 8558570, 28492532
SCV001652951	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Pathogenic (Feb 1, 2021)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 24844452, 18607768, 8558570, 17723315, 19588081, 25752415, 24033266
SCV004195500	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 13, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000954269

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 3, 2018)

germline

clinical testing

PubMed (8)
[See all records that cite these PMIDs]

SCV001652951

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Pathogenic
(Feb 1, 2021)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

SCV004195500

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Feb 13, 2024)

unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	1	1	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

Long-term intravenous treatment of Pompe disease with recombinant human alpha-glucosidase from milk.

Van den Hout JM, Kamphoven JH, Winkel LP, Arts WF, De Klerk JB, Loonen MC, Vulto AG, Cromme-Dijkhuis A, Weisglas-Kuperus N, Hop W, Van Hirtum H, Van Diggelen OP, Boer M, Kroos MA, Van Doorn PA, Van der Voort E, Sibbles B, Van Corven EJ, Brakenhoff JP, Van Hove J, Smeitink JA, de Jong G, et al.

Pediatrics. 2004 May;113(5):e448-57.

PubMed [citation]

PMID:: 15121988

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

See all PubMed Citations (10)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000954269.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

This variant is a gross deletion of the genomic region encompassing exon 18 of the GAA gene. This leads to an in-frame deletion, preserving the integrity of the reading frame. Loss-of-function variants, including gross deletions, in GAA are known to be pathogenic. Deletion of exon 18 has been reported in the literature in multiple individuals affected with glycogen storage disease type II, also known as Pompe disease (PMID: 18607768, 8558570, 17723315, 15121988, 19588081, 25752415, 24844452). This deletion is also known as c.2481+102_2646+31del (p.Gly828_Asn882del) in the literature. 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 Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV001652951.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (7)

Description

The deletion of exon 19 of GAA has been reported in the homozygous or compound heterozygous state in >20 individuals with glycogen storage disease II (GSDII; Kroos 1995 PMID:8558570, McCready 2007 PMID: 17723315, Joshi 2008 PMID: 18607768, Oba-Shinjo 2009 PMID: 19588081, Sacconi 2014 PMID:24844452, PÃ©rez-LÃ³pez 2015 PMID:25752415). Of note, this variant is often reported as a deletion of exon 18 due to exon numbering differences. It has been identified in 0.013% (1/7624) of European chromosomes in gnomAD (http://gnomad.broadinstitute.org) and has been reported as Pathogenic in ClinVar (Variation ID 657307). This variant is predicted to result in the deletion of 55 amino acids (p.Gly828_Asn882del). Although it is not predicted to alter the protein reading-frame, the low frequency of this variant in the general population combined with its identification in multiple individuals with low or absent Î±-glucosidase activity strongly suggests that it is detrimental to protein function. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive GSDII. ACMG/AMP criteria applied: PM3_Very strong, PVS1_Moderate, PP4, PM2_Supporting.

#	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		1	not provided	1	not provided

From Baylor Genetics, SCV004195500.2

#	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

Last Updated: Sep 29, 2024

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