Variant: NM_000152.5(GAA):c.1567del (p.Ser523fs)

CA16041894

371433 (ClinVar)

Gene: GAA

Condition: glycogen storage disease II

Inheritance Mode: Autosomal recessive inheritance

UUID: cbc7bf67-c0ec-4500-ae60-6483c93d64bb

Approved on: 2023-03-10

Published on: 2023-03-10

HGVS expressions

NM_000152.5:c.1567del
NM_000152.5(GAA):c.1567del (p.Ser523fs)
NC_000017.11:g.80110956del
CM000679.2:g.80110956del
NC_000017.10:g.78084755del
CM000679.1:g.78084755del
NC_000017.9:g.75699350del
NG_009822.1:g.14401del
ENST00000302262.8:c.1567del
ENST00000302262.7:c.1567del
ENST00000390015.7:c.1567del
NM_000152.3:c.1567del
NM_001079803.1:c.1567del
NM_001079804.1:c.1567del
NM_000152.4:c.1567del
NM_001079803.2:c.1567del
NM_001079804.2:c.1567del
NM_001079803.3:c.1567del
NM_001079804.3:c.1567del

Likely Pathogenic

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

• 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.1567del (p.Ser523ProfsTer55) variant in GAA is a frameshift variant predicted to cause a premature stop codon, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The 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, and results of experimental studies are not available. There is a ClinVar entry for this variant (Variation ID: 371433). 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

• PVS1: The NM_000152.5:c.1567del (p.Ser523ProfsTer55) variant in GAA is a frameshift variant predicted to cause a premature stop codon, 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).