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]
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  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
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Variant: NM_001079804.3:c.827_845del

CA658795238

1327504 (ClinVar)

Gene: GAA
Condition: glycogen storage disease II
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: f05787db-c895-447e-a3d9-af897f0d6d6f
Approved on: 2024-05-21
Published on: 2024-06-17

HGVS expressions

NM_001079804.3:c.827_845del
NC_000017.11:g.80107691_80107709del
CM000679.2:g.80107691_80107709del
NC_000017.10:g.78081490_78081508del
CM000679.1:g.78081490_78081508del
NC_000017.9:g.75696085_75696103del
NG_009822.1:g.11136_11154del
ENST00000570803.6:c.827_845del
ENST00000572080.2:c.827_845del
ENST00000577106.6:c.827_845del
ENST00000302262.8:c.827_845del
ENST00000302262.7:c.827_845del
ENST00000390015.7:c.827_845del
ENST00000570803.5:c.827_845del
NM_000152.3:c.827_845del
NM_001079803.1:c.827_845del
NM_001079804.1:c.827_845del
NM_000152.4:c.827_845del
NM_001079803.2:c.827_845del
NM_001079804.2:c.827_845del
NM_000152.5:c.827_845del
NM_001079803.3:c.827_845del

Pathogenic

Met criteria codes 3
PVS1 PM3 PM2_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

PDF
Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Lysosomal Diseases VCEP
The NM_000152.5:c.827_845del (p.Ile276ThrfsTer32) variant in GAA is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 5 out of 20, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). One patient with clinical features consistent with late onset Pompe disease, elevated creatine kinase, and histological features of Pompe disease was reported to be compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic by the ClinGen Lysosomal Diseases Variant Curation Expert Panel, c.2238G>C (p.Trp746Cys) (ClinVar variation ID: 265160, SCV002032122.1). The variants were confirmed to be in trans by parental DNA analysis (PMID 27099502) (PM3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). GAA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specification Version 2.0): PVS1, PM3, PM2_Supporting (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on May 21, 2024).
Met criteria codes
PVS1
The NM_000152.5:c.827_845del (p.Ile276ThrfsTer32) variant in GAA is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 5 of 20 exons, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1).
PM3
One patient was reported to be compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic by the ClinGen Lysosomal Diseases Variant Curation Expert Panel, c.2238G>C (p.Trp746Cys) (ClinVar variation ID: 265160, SCV002032122.1). The variants were confirmed to be in trans by parental DNA analysis (PMID 27099502). 1 point, PM3.
PM2_Supporting
This variant is absent in gnomAD v2.1.1 and v4.1 (PM2_Supporting).
Not Met criteria codes
PP4
One patient has been reported with clinical symptoms consistent late onset Pompe disease, and features of Pompe disease on muscle histology. While GAA activity was reported to be deficient, this evidence was not applied because pseudodeficiency variants, often seen in cis with the second variant identified in this patient (c.2238G>C (p.Trp746Cys), were not confirmed to be absent and could result in the observed low GAA activity.
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