Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Link to SEPIO compliant JSON-LD document

Variant: NM_000152.5(GAA):c.340_341insT (p.Lys114fs)

CA658795226

1068640 (ClinVar)

Gene: GAA

Condition: glycogen storage disease II

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 076d349a-770a-4b3a-9ec5-145101709b50

HGVS expressions

NM_000152.5:c.340_341insT

NM_000152.5(GAA):c.340_341insT (p.Lys114fs)

NC_000017.11:g.80104926_80104927insT

CM000679.2:g.80104926_80104927insT

NC_000017.10:g.78078725_78078726insT

CM000679.1:g.78078725_78078726insT

NC_000017.9:g.75693320_75693321insT

NG_009822.1:g.8371_8372insT

ENST00000570803.6:c.340_341insT

ENST00000572080.2:c.340_341insT

ENST00000577106.6:c.340_341insT

ENST00000302262.8:c.340_341insT

ENST00000302262.7:c.340_341insT

ENST00000390015.7:c.340_341insT

ENST00000570803.5:c.340_341insT

ENST00000577106.5:c.340_341insT

NM_000152.3:c.340_341insT

NM_001079803.1:c.340_341insT

NM_001079804.1:c.340_341insT

NM_000152.4:c.340_341insT

NM_001079803.2:c.340_341insT

NM_001079804.2:c.340_341insT

NM_001079803.3:c.340_341insT

NM_001079804.3:c.340_341insT

Pathogenic

PM2_Supporting PVS1 PM3_Supporting PP4_Moderate

Evidence Links 0

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

PDF

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Lysosomal Diseases VCEP

The NM_000152.5(GAA):c.340_341insT (p.Lys114Ilefs) 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 this variant has been reported with infantile onset Pompe disease and a GAA enzyme activity level from dried blood of 0.13 pmol/punch/hr (PMID: 20821053) (PP4_Moderate). This patient, in addition to two other patients, is homozygous for the c.340_341insT variant in GAA (PMIDs: 14695532, 20821053, 21483992) (PM3_Supporting). The variant is absent in gnomAD v2.1.1. (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 1068640). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease, based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel. ACMG/AMP criteria applied (specifications version 2.0): PVS1, PP4_Moderate, PM2_Supporting, PM3_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on February 6, 2024).

PM2_Supporting

This variant is absent in gnomAD v2.1.1. [PM2_Supporting]

PVS1

The NM_000152.5:c.340_341insT (p.Lys114fs) variant in GAA is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 2 out of 20 exons, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. Additionally, Sol8 cells nucleofected with ribonucleotide particles (RNPs) containing CRISPR/Cas9 targeting murine loci corresponding to the human c.340_341insT variant showed a partial reduction in GAA mRNA (Figure 2A) and almost a complete lack of GAA activity (Figure 2B) (PMID: 35682977).

PM3_Supporting

This variant has been detected in three individuals with Pompe disease. Of those individuals, all three were homozygous for this variant and two individuals may potentially be the same patient. [PM3_Supporting]

PP4_Moderate

This variant has been detected in at least three patients reported to have Pompe disease including one individual with a reported laboratory values demonstrating deficient GAA activity (PMID: 20821053), and two for whom GAA activity was not reported (PMID: 14695532, 21483992) (PP4_Moderate).

Approved on: 2024-02-06

Published on: 2024-04-05

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