Variant: NM_000152.5(GAA):c.4G>T (p.Gly2Ter)

CA401359822

560377 (ClinVar)

Gene: GAA

Condition: glycogen storage disease II

Inheritance Mode: Autosomal recessive inheritance

UUID: c365a331-1b7f-48ef-814e-1feff0f64f2b

HGVS expressions

NM_000152.5:c.4G>T
NM_000152.5(GAA):c.4G>T (p.Gly2Ter)
NC_000017.11:g.80104590G>T
CM000679.2:g.80104590G>T
NC_000017.10:g.78078389G>T
CM000679.1:g.78078389G>T
NC_000017.9:g.75692984G>T
NG_009822.1:g.8035G>T
ENST00000302262.8:c.4G>T
ENST00000302262.7:c.4G>T
ENST00000390015.7:c.4G>T
ENST00000570803.5:c.4G>T
ENST00000577106.5:c.4G>T
NM_000152.3:c.4G>T
NM_001079803.1:c.4G>T
NM_001079804.1:c.4G>T
NM_000152.4:c.4G>T
NM_001079803.2:c.4G>T
NM_001079804.2:c.4G>T
NM_001079803.3:c.4G>T
NM_001079804.3:c.4G>T

Likely Pathogenic

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Insufficient Evidence"

• Met criteria codes: PM2_Supporting PVS1

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.4G>T (p.Gly2Ter) variant in GAA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 2/20, 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 (PM2_Supporting). To our knowledge, this variant has not been reported in individuals with Pompe disease in the literature and functional studies are unavailable. There is a ClinVar entry for this variant (Variation ID: 560377). 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 Likely 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, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases VCEP, March 10, 2023).

Met criteria codes

• PM2_Supporting: This variant is absent in gnomADv2.1.1. (PM2_Supporting)
• PVS1: The NM_000152.5:c.4G>T (p.Gly2Ter) variant in GAA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 2/20, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1).

Approved on: 2023-03-10

Published on: 2023-03-10