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]

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Variant: NM_001079804.3:c.2411G>A

CA401325125

1693552 (ClinVar)

Gene: GAA

Condition: glycogen storage disease II

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 58b01f86-672c-430b-8d06-a40e3609d568

Approved on: 2024-03-06

Published on: 2024-03-26

HGVS expressions

NM_001079804.3:c.2411G>A

NC_000017.11:g.80117679G>A

CM000679.2:g.80117679G>A

NC_000017.10:g.78091478G>A

CM000679.1:g.78091478G>A

NC_000017.9:g.75706073G>A

NG_009822.1:g.21124G>A

ENST00000570803.6:c.2411G>A

ENST00000572080.2:c.*549G>A

ENST00000577106.6:c.2411G>A

ENST00000302262.8:c.2411G>A

ENST00000302262.7:c.2411G>A

ENST00000390015.7:c.2411G>A

ENST00000573556.1:n.364G>A

NM_000152.3:c.2411G>A

NM_001079803.1:c.2411G>A

NM_001079804.1:c.2411G>A

NM_000152.4:c.2411G>A

NM_001079803.2:c.2411G>A

NM_001079804.2:c.2411G>A

NM_000152.5:c.2411G>A

NM_001079803.3:c.2411G>A

NM_000152.5(GAA):c.2411G>A (p.Trp804Ter)

Pathogenic

PVS1 PM3_Supporting PM2_Supporting

PP4

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:c.2411G>A (p.Trp804Ter) variant in GAA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 17 )out of 20, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). One patient reported to have infantile-onset Pompe disease is compound heterozygous for the variant and a variant that has been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP, c.1802C>T (p.Ser601Leu) (ClinVar Variation ID: 194154, SCV002032130.1); the phase is unconfirmed (PMID: 28394184) (PM3_Supporting). There is insufficient data to apply PP4. The variant is absent in gnomAD v2.1.1. (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. Initially, the variant was classified a likely pathogenic by the ClinGen Lysosomal Diseases VCEP on August 17, 2021, but it was reclassified as pathogenic on Jan 15, 2024, due to the application of PM3_Supporting. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PVS1, PM2_Supporting, PM3_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Panel on Feb 6, 2024).

PVS1

The NM_000152.5: c.2411G>A (p.Trp804Ter) variant in GAA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 17 out of 20, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1).

PM3_Supporting

One patient reported to have infantile-onset Pompe disease is compound heterozygous for the variant and a variant that has been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP, c.1802C>T (p.Ser601Leu) (ClinVar Variation ID: 194154, SCV002032130.1); the phase is unconfirmed (PMID: 28394184) (0.5 points) (PM3_Supporting). Note that the pathogenic classification of p.Ser601Leu does not require the allelic data from this patient.

PM2_Supporting

This variant is absent in gnomAD v2.1.1. and v4.0. (PM2_Supporting).

PP4

Insufficient details provided to apply PP4.

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