NM_000152.5(GAA):c.1082C>G (p.Pro361Arg) AND Glycogen storage disease, type II

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Nov 21, 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:: RCV001078141.5

Allele description [Variation Report for NM_000152.5(GAA):c.1082C>G (p.Pro361Arg)]

NM_000152.5(GAA):c.1082C>G (p.Pro361Arg)

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.1082C>G (p.Pro361Arg)

Other names:

NM_000152.5(GAA):c.1082C>G; p.Pro361Arg

HGVS:

NC_000017.11:g.80108495C>G
NG_009822.1:g.11940C>G
NM_000152.5:c.1082C>GMANE SELECT
NM_001079803.3:c.1082C>G
NM_001079804.3:c.1082C>G
NP_000143.2:p.Pro361Arg
NP_001073271.1:p.Pro361Arg
NP_001073272.1:p.Pro361Arg
LRG_673:g.11940C>G
NC_000017.10:g.78082294C>G

Protein change:

P361R

Links:

dbSNP: rs755253527

NCBI 1000 Genomes Browser:

rs755253527

Molecular consequence:

NM_000152.5:c.1082C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001079803.3:c.1082C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001079804.3:c.1082C>G - missense variant - [Sequence Ontology: SO:0001583]

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
SCV001156139	Molecular Therapies Laboratory, Murdoch University	no assertion criteria provided	Pathogenic	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 26497565, 25526786, 22644586, 32317649, 32012848
SCV004227902	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	reviewed by expert panel (clingen_lsd_acmg_specifications_v2-1)	Likely pathogenic (Nov 21, 2023)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001156139

Molecular Therapies Laboratory, Murdoch University

no assertion criteria provided

Pathogenic

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV004227902

ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel

reviewed by expert panel

(clingen_lsd_acmg_specifications_v2-1)

Likely pathogenic
(Nov 21, 2023)

germline

curation

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	curation
Causasians	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Response of 33 UK patients with infantile-onset Pompe disease to enzyme replacement therapy.

Broomfield A, Fletcher J, Davison J, Finnegan N, Fenton M, Chikermane A, Beesley C, Harvey K, Cullen E, Stewart C, Santra S, Vijay S, Champion M, Abulhoul L, Grunewald S, Chakrapani A, Cleary MA, Jones SA, Vellodi A.

J Inherit Metab Dis. 2016 Mar;39(2):261-71. doi: 10.1007/s10545-015-9898-5. Epub 2015 Oct 26.

PubMed [citation]

PMID:: 26497565

Clinical and GAA gene mutation analysis in mainland Chinese patients with late-onset Pompe disease: identifying c.2238G > C as the most common mutation.

Liu X, Wang Z, Jin W, Lv H, Zhang W, Que C, Huang Y, Yuan Y.

BMC Med Genet. 2014 Dec 20;15:141. doi: 10.1186/s12881-014-0141-2.

PubMed [citation]

PMID:: 25526786
PMCID:: PMC4411720

See all PubMed Citations (5)

Details of each submission

From Molecular Therapies Laboratory, Murdoch University, SCV001156139.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Causasians	1	not provided	not provided	clinical testing	PubMed (5)

Description

Elevated CK (950 units); low GAA enzyme activity (0.8 units); urine tetrasaccharides elevated (40 units); respiratory functions normal

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel, SCV004227902.1

#	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.1082C>G variant in GAA is a missense variant predicted to cause substitution of proline by arginine at amino acid 361 (p.Pro361Arg). This variant has been observed in the literature in two cases consistent with late-onset Pompe disease (PMID: 30312517, 32012848) with documented GAA deficiency. Both met PP4 specifications (PP4_Moderate), in compound heterozygosity with the known pathogenic variant c.-32-13T>G, phase not confirmed (PM3). The highest population minor allele frequency in gnomAD v4.0.0 is 0.0000008993 (1/1111956 alleles) in the European (non-Finnish) population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.945 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Another missense variant (c.1082C>T, p.Pro361Leu) (ClinVar Variation ID: 403712) in the same codon has been classified as pathogenic for Pompe disease by the ClinGen Lysosomal Diseases VCEP (PM5). There is a ClinVar entry for this variant (Variation ID: 289367, 1-star review status) with 2 submitter, classifying this variant as a VUS. In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (Specifications Version 2.0): PP4_Moderate, PM3, PM2_Supporting, PP3, PM5. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on November 21, 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: Jun 23, 2024

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