Variant: NM_000152.5(GAA):c.376del (p.Trp126fs)

CA658824773

556716 (ClinVar)

Gene: GAA

Condition: glycogen storage disease II

Inheritance Mode: Autosomal recessive inheritance

UUID: 77cefcaf-e1a1-4dfa-965e-1e3119d47550

HGVS expressions

NM_000152.5:c.376del
NM_000152.5(GAA):c.376del (p.Trp126fs)
NC_000017.11:g.80104962del
CM000679.2:g.80104962del
NC_000017.10:g.78078761del
CM000679.1:g.78078761del
NC_000017.9:g.75693356del
NG_009822.1:g.8407del
ENST00000570803.6:c.376del
ENST00000572080.2:c.376del
ENST00000577106.6:c.376del
ENST00000302262.8:c.376del
ENST00000302262.7:c.376del
ENST00000390015.7:c.376del
ENST00000570803.5:c.376del
ENST00000577106.5:c.376del
NM_000152.3:c.376del
NM_001079803.1:c.376del
NM_001079804.1:c.376del
NM_000152.4:c.376del
NM_001079803.2:c.376del
NM_001079804.2:c.376del
NM_001079803.3:c.376del
NM_001079804.3:c.376del

Likely Pathogenic

• Met criteria codes: PVS1 PM2_Supporting

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.376del (p.Trp126GlyfsTer16) variant in GAA is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 2 of 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 the literature in individuals with Pompe disease. There is a ClinVar entry for this variant (Variation ID: 556716). In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease. 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 ). The classification was first approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on September 7, 2021. Since then, the data for this variant have been re-evaluated - no new data were identified. The classification of likely pathogenic was reapproved on April 5, 2024. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PVS1, PM2_Supporting.

Met criteria codes

• PVS1: The NM_000152.5:c.376del (p.Trp126GlyfsTer16) variant in GAA is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 2 of 20, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1).
• PM2_Supporting: This variant is absent in gnomAD v2.1.1 (PM2_Supporting).

Approved on: 2024-04-05

Published on: 2024-04-05