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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

Pathogenic

Met criteria codes 4
PP4 PM3_Supporting PM2_Supporting PVS1

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
PP4
One patient with infantile onset Pompe disease, identified by newborn screen and treated with enzyme replacement therapy, has been reported (PMID: 32373469) (PP4).
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)
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).
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