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NM_000152.5(GAA):c.971dup (p.Ser325fs) AND Glycogen storage disease, type II

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Mar 6, 2024
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:
RCV001789729.4

Allele description [Variation Report for NM_000152.5(GAA):c.971dup (p.Ser325fs)]

NM_000152.5(GAA):c.971dup (p.Ser325fs)

Gene:
GAA:alpha glucosidase [Gene - OMIM - HGNC]
Variant type:
Duplication
Cytogenetic location:
17q25.3
Genomic location:
Preferred name:
NM_000152.5(GAA):c.971dup (p.Ser325fs)
Other names:
NM_001079804.3:c.971dup; NM_000152.5(GAA):c.971dup; p.Ser325fs
HGVS:
  • NC_000017.11:g.80108305dup
  • NG_009822.1:g.11750dup
  • NM_000152.5:c.971dupMANE SELECT
  • NM_001079803.3:c.971dup
  • NM_001079804.3:c.971dup
  • NP_000143.2:p.Ser325fs
  • NP_001073271.1:p.Ser325fs
  • NP_001073272.1:p.Ser325fs
  • LRG_673:g.11750dup
  • NC_000017.10:g.78082104dup
Protein change:
S325fs
Links:
dbSNP: rs2143852733
NCBI 1000 Genomes Browser:
rs2143852733
Molecular consequence:
  • NM_000152.5:c.971dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001079803.3:c.971dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001079804.3:c.971dup - 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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Assertion and evidence details

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Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002032132ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel
reviewed by expert panel

(clingen_lsd_acmg_specifications_v2-1)		Pathogenic
(Mar 6, 2024) 		germlinecuration

Citation Link

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Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedcuration

Details of each submission

From ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel, SCV002032132.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The NM_000152.5:c.971dupC (p.Ser325GlufsTer5) variant in GAA is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 6 out of 20, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). One patient reported to have infantile-onset Pompe disease is compound heterozygous for the variant and a variant that has been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP, c.1802C>T (p.Ser601Leu) (ClinVar Variation ID: 194154; SCV002032130.1); the phase is unconfirmed (PMID: 28394184) (PM3_Supporting). There is insufficient data to apply PP4. The variant is absent in gnomAD v2.1.1. (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. Initially, the variant was classified a likely pathogenic by the ClinGen Lysosomal Diseases VCEP on August 17, 2021, but it was reclassified as pathogenic on Jan 15, 2024, due to the application of PM3_Supporting. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PVS1, PM2_Supporting, PM3_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on Feb 6, 2024).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Apr 6, 2024