Variant: NM_001079804.3:c.40_47del

CA913184761

Gene: GAA

Condition: glycogen storage disease II

Inheritance Mode: Autosomal recessive inheritance

UUID: 05073273-f7f5-49d8-b9fc-820d4c0d1b90

HGVS expressions

NM_001079804.3:c.40_47del
NC_000017.11:g.80104626_80104633del
CM000679.2:g.80104626_80104633del
NC_000017.10:g.78078425_78078432del
CM000679.1:g.78078425_78078432del
NC_000017.9:g.75693020_75693027del
NG_009822.1:g.8071_8078del
ENST00000302262.8:c.40_47del
ENST00000302262.7:c.40_47del
ENST00000390015.7:c.40_47del
ENST00000570803.5:c.40_47del
ENST00000577106.5:c.40_47del
NM_000152.3:c.40_47del
NM_001079803.1:c.40_47del
NM_001079804.1:c.40_47del
NM_000152.4:c.40_47del
NM_001079803.2:c.40_47del
NM_001079804.2:c.40_47del
NM_000152.5:c.40_47del
NM_001079803.3:c.40_47del

Pathogenic

• Met criteria codes: PM2_Supporting PP4_Moderate PVS1

• Not Met criteria codes: PM3

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.40_47del (p.Ala14ArgfsTer18) variant in GAA is a frameshift 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). One patient with infantile onset Pompe disease has been reported in multiple publications. Features include increased left ventricular mass, GAA activity <1% normal in skin fibroblasts, and improvement on enzyme replacement therapy (PP4_Moderate) (PMIDs: 17151339, 22658377, 29422078, 31193175). This patient is compound heterozygous for c.40_47del8 and c.1465G>A (p.Asp489Asn). The in trans data will be used in the assessment of p.Asp489Asn and is not included here to avoid circular logic (PMID: 29422078). The variant in absent in gnomAD v2.1.1. (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Storage Disorders Variant Curation Expert Panel (specifications version 2.0): PVS1, PP4_Moderate, PM2_Supporting. (Classification approved by the ClinGen LSD VCEP, February 7, 2023).

Met criteria codes

• PM2_Supporting: The variant in absent in gnomAD v2.1.1. (PM2_Supporting).
• PP4_Moderate: One patient, with infantile onset Pompe disease, has been reported in multiple publications. Features include increased left ventricular mass, GAA activity <1% normal in skin fibroblasts, and improvement on enzyme replacement therapy (PP4_Moderate) (PMIDs: 17151339, 22658377, 29422078, 31193175).
• PVS1: The NM_000152.5:c.40_47del (p.Ala14ArgfsTer18) variant in GAA is a frameshift 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).

Not Met criteria codes

• PM3: One patient, compound heterozygous for c.40_47del8 and c.1465G>A (p.Asp489Asn), has been reported. The in trans data for this patient will be used in the assessment of p.Asp489Asn and is not included here to avoid circular logic (PMID: 29422078).

Approved on: 2023-02-07

Published on: 2023-03-03