NM_000152.5(GAA):c.1645G>A (p.Gly549Arg) AND Glycogen storage disease, type II

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Aug 25, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV002629939.2

Allele description [Variation Report for NM_000152.5(GAA):c.1645G>A (p.Gly549Arg)]

NM_000152.5(GAA):c.1645G>A (p.Gly549Arg)

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.1645G>A (p.Gly549Arg)

HGVS:

NC_000017.11:g.80111991G>A
NG_009822.1:g.15436G>A
NM_000152.5:c.1645G>AMANE SELECT
NM_001079803.3:c.1645G>A
NM_001079804.3:c.1645G>A
NM_001406741.1:c.1645G>A
NM_001406742.1:c.1645G>A
NP_000143.2:p.Gly549Arg
NP_000143.2:p.Gly549Arg
NP_001073271.1:p.Gly549Arg
NP_001073272.1:p.Gly549Arg
NP_001393670.1:p.Gly549Arg
NP_001393671.1:p.Gly549Arg
LRG_673t1:c.1645G>A
LRG_673:g.15436G>A
LRG_673p1:p.Gly549Arg
NC_000017.10:g.78085790G>A
NM_000152.3:c.1645G>A

Protein change:

G549R

Molecular consequence:

NM_000152.5:c.1645G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001079803.3:c.1645G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001079804.3:c.1645G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406741.1:c.1645G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406742.1:c.1645G>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
SCV003524347	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 25, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 17213836, 19862843, 22990675, 25036864, 14695532, 16917947, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003524347

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Aug 25, 2023)

germline

clinical testing

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

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

Citations

PubMed

Pharmacological enhancement of mutated alpha-glucosidase activity in fibroblasts from patients with Pompe disease.

Parenti G, Zuppaldi A, Gabriela Pittis M, Rosaria Tuzzi M, Annunziata I, Meroni G, Porto C, Donaudy F, Rossi B, Rossi M, Filocamo M, Donati A, Bembi B, Ballabio A, Andria G.

Mol Ther. 2007 Mar;15(3):508-14. Epub 2007 Jan 9.

PubMed [citation]

PMID:: 17213836

The pharmacological chaperone 1-deoxynojirimycin increases the activity and lysosomal trafficking of multiple mutant forms of acid alpha-glucosidase.

Flanagan JJ, Rossi B, Tang K, Wu X, Mascioli K, Donaudy F, Tuzzi MR, Fontana F, Cubellis MV, Porto C, Benjamin E, Lockhart DJ, Valenzano KJ, Andria G, Parenti G, Do HV.

Hum Mutat. 2009 Dec;30(12):1683-92. doi: 10.1002/humu.21121.

PubMed [citation]

PMID:: 19862843

See all PubMed Citations (7)

Details of each submission

From Invitae, SCV003524347.2

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

Description

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Experimental studies have shown that this missense change affects GAA function (PMID: 14695532, 16917947, 17213836, 19862843, 22990675, 25036864). 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 expected to disrupt GAA protein function. ClinVar contains an entry for this variant (Variation ID: 2202283). This missense change has been observed in individual(s) with Pompe disease (PMID: 14695532, 16917947). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 549 of the GAA protein (p.Gly549Arg).

#	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: Feb 20, 2024

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