Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_000152.5(GAA):c.2242G>T (p.Glu748Ter)

CA16041903

370268 (ClinVar)

Gene: GAA
Condition: glycogen storage disease II
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: f329994e-9f5d-4121-8d8c-dc92a28f8082
Approved on: 2023-04-11
Published on: 2023-04-19

HGVS expressions

NM_000152.5:c.2242G>T
NM_000152.5(GAA):c.2242G>T (p.Glu748Ter)
NC_000017.11:g.80117020G>T
CM000679.2:g.80117020G>T
NC_000017.10:g.78090819G>T
CM000679.1:g.78090819G>T
NC_000017.9:g.75705414G>T
NG_009822.1:g.20465G>T
ENST00000302262.8:c.2242G>T
ENST00000302262.7:c.2242G>T
ENST00000390015.7:c.2242G>T
ENST00000572080.1:n.661G>T
ENST00000573556.1:n.195G>T
NM_000152.3:c.2242G>T
NM_001079803.1:c.2242G>T
NM_001079804.1:c.2242G>T
NM_000152.4:c.2242G>T
NM_001079803.2:c.2242G>T
NM_001079804.2:c.2242G>T
NM_001079803.3:c.2242G>T
NM_001079804.3:c.2242G>T
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Pathogenic

Met criteria codes 3
PM2_Supporting PVS1 PM3_Supporting
Not Met criteria codes 1
PP4

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Lysosomal Storage Disorders Variant Curation Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Lysosomal Diseases VCEP
The NM_000152.5:c.2242G>T (p.Glu748Ter) variant in GAA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 16/20, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). One patient with this variant, diagnosed with late onset Pompe disease, has been reported (PMID: 31545528). This individual is compound heterozygous for the variant and a pathogenic variant in GAA, c.-32-13T>G, phase unknown (PMID: 31545528) (PM3_Supporting). The data are insufficient to apply PP4 based on the specifications of the ClinGen Lysosomal Diseases VCEP. The variant is absent in gnomAD v2.1.1. (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID 370268). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PVS1, PM3_Supporting, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases VCEP, April 11, 2023).
Met criteria codes
PM2_Supporting
This variant is absent in gnomAD v2.1.1.
PVS1
The NM_000152.5:c.2242G>T (p.Glu748Ter) variant in GAA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 16/20, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1).
PM3_Supporting
One patient with late onset Pompe disease is compound heterozygous for the variant and a pathogenic variant in GAA, c.-32-13T>G, phase unknown (PMID: 31545528), 0.5 points (PM3_Supporting).
Not Met criteria codes
PP4
One patient with this variant, and a diagnosis of late onset Pompe disease, has been reported. However, the data are insufficient to apply PP4 based on the specifications of the ClinGen LD VCEP.
Curation History
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