Variant: NM_000152.5(GAA):c.2704C>T (p.Gln902Ter)

370241 (ClinVar)

Gene: GAA

Condition: glycogen storage disease II

Inheritance Mode: Autosomal recessive inheritance

UUID: 758c50e3-1f35-4df3-8818-b0d9703e7699

Approved on: 2023-03-08

Published on: 2023-03-08

HGVS expressions

NM_000152.5:c.2704C>T
NM_000152.5(GAA):c.2704C>T (p.Gln902Ter)

Likely Pathogenic

• Met criteria codes: PVS1 PM2

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.2704C>T (p.Gln902Ter) variant in GAA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 19/20. Although exon 19 is the penultimate exon of GAA, the variant occurs in the region where nonsense-mediated decay is predicted to occur, in a gene in which loss-of-function is an established disease mechanism (PVS1). The variant is absent in gnomAD v.2.1.1, meeting PM2. To our knowledge, this variant has not been reported in the literature in individuals with Pompe disease, and results of experimental studies are not available. There is a ClinVar entry for this variant (Variation ID: 370241). The classification of this variant has been upgraded from Variant of Uncertain Significance to Likely Pathogenic based on the recommendations of the ClinGen Sequence Variant Interpretation Working Group, that a variant meeting PVS1 and PM2_Supporting is classified as Likely Pathogenic (https://clinicalgenome.org/site/assets/files/5182/pm2_-_svi_recommendation_-_approved_sept2020.pdf ). In summary, this variant meets the criteria to be classified as a likely pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP (Specifications version 2.0): PVS1, PM2_Supporting.

Met criteria codes

• PVS1: The NM_000152.5:c.2704C>T (p.Gln902Ter) variant in GAA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 19/20. Although exon 19 is the penultimate exon of GAA, the variant occurs in the region where nonsense-mediated decay is predicted to occur, in a gene in which loss-of-function is an established disease mechanism (PVS1).
• PM2: This variant is absent in gnomAD v2.1.1, meeting PM2.