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.1062C>A (p.Tyr354Ter)

CA16620645

423925 (ClinVar)

Gene: GAA
Condition: glycogen storage disease II
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: f8d529ac-28e8-4127-8ae9-e386d62c4cf0
Approved on: 2023-04-19
Published on: 2023-04-19

HGVS expressions

NM_000152.5:c.1062C>A
NM_000152.5(GAA):c.1062C>A (p.Tyr354Ter)
NC_000017.11:g.80108396C>A
CM000679.2:g.80108396C>A
NC_000017.10:g.78082195C>A
CM000679.1:g.78082195C>A
NC_000017.9:g.75696790C>A
NG_009822.1:g.11841C>A
ENST00000302262.8:c.1062C>A
ENST00000302262.7:c.1062C>A
ENST00000390015.7:c.1062C>A
NM_000152.3:c.1062C>A
NM_001079803.1:c.1062C>A
NM_001079804.1:c.1062C>A
NM_000152.4:c.1062C>A
NM_001079803.2:c.1062C>A
NM_001079804.2:c.1062C>A
NM_001079803.3:c.1062C>A
NM_001079804.3:c.1062C>A
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Pathogenic

Met criteria codes 4
PM2_Supporting PVS1 PM3_Supporting 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.1062C>A (p.Tyr354Ter) variant in GAA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 6/20, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). One patient with infantile onset Pompe disease, identified by newborn screen and treated with enzyme replacement therapy, has been reported (PMID: 32373469) (PP4). This patient is compound heterozygous for the variant and a variant in GAA that has been classified as pathogenic by the ClinGen LD VCEP, c.1935C>A (p.Asp645Glu) (PMID: 32373469) (PM3_Supporting). There is a ClinVar entry for this variant (Variation ID: 423925). 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. (PM2_Supporting).
PVS1
The NM_000152.5:c.1062C>A (p.Tyr354Ter) variant in GAA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 6/20, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1).
PM3_Supporting
One patient has been identified who is compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic by the ClinGen LD VCEP, c.1935C>A (p.Asp645Glu) (PMID: 32373469), (PM3_Supporting)
PP4
One patient with infantile onset Pompe disease, identified by newborn screen and treated with enzyme replacement therapy, has been reported (PMID: 32373469) (PP4).
Curation History
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