Variant: NM_000152.5(GAA):c.2213G>A (p.Trp738Ter)

CA16041900

370222 (ClinVar)

Gene: GAA

Condition: glycogen storage disease II

Inheritance Mode: Autosomal recessive inheritance

UUID: b0804910-c066-47f5-ac05-34fd71d73e9e

Approved on: 2024-12-19

Published on: 2025-02-28

HGVS expressions

NM_000152.5:c.2213G>A
NM_000152.5(GAA):c.2213G>A (p.Trp738Ter)
NC_000017.11:g.80116991G>A
CM000679.2:g.80116991G>A
NC_000017.10:g.78090790G>A
CM000679.1:g.78090790G>A
NC_000017.9:g.75705385G>A
NG_009822.1:g.20436G>A
ENST00000570803.6:c.2213G>A
ENST00000572080.2:c.*351G>A
ENST00000577106.6:c.2213G>A
ENST00000302262.8:c.2213G>A
ENST00000302262.7:c.2213G>A
ENST00000390015.7:c.2213G>A
ENST00000572080.1:c.632G>A
ENST00000573556.1:n.166G>A
NM_000152.3:c.2213G>A
NM_001079803.1:c.2213G>A
NM_001079804.1:c.2213G>A
NM_000152.4:c.2213G>A
NM_001079803.2:c.2213G>A
NM_001079804.2:c.2213G>A
NM_001079803.3:c.2213G>A
NM_001079804.3:c.2213G>A

Pathogenic

• Met criteria codes: PM2_Supporting PVS1 PP4

• Not Met criteria codes: BA1 BS1

Expert Panel

Lysosomal Diseases VCEP

Criteria Specification Information

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

Evidence submitted by expert panel

Lysosomal Diseases VCEP

The NM_000152.5:c.2213G>A (p.Trp738Ter) 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). This variant is absent in gnomAD v2.1.1. The highest population minor allele frequency in gnomAD v4.1.0 is 0.00001666 (1/60024 alleles) in the Admixed American population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). One patient with this variant has been reported with infantile onset Pompe disease and has deficient GAA activity (PMID: 27927596) (PP4). There is a ClinVar entry for this variant (Variation ID: 370222). In summary, this variant meets the criteria to be classified as Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PVS1, PP4, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 19, 2024)

Met criteria codes

• PM2_Supporting: This variant is absent in gnomAD v2.1.1. The highest population minor allele frequency in gnomAD v4.1.0 is 0.00001666 (1/60024 alleles) in the Admixed American population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting).
• PVS1: The NM_000152.5:c.2213G>A (p.Trp738Ter) variant in GAA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 16 (GAA has 20 exons), leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1).
• PP4: One patient with this variant has been reported with infantile onset Pompe disease and has deficient GAA activity (PMID: 27927596) (PP4).

Not Met criteria codes

• BA1: This variant is absent in GnomAD.
• BS1: This variant is absent in GnomAD.