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]

x This classification has been retracted/unpublished!

Variant: NM_000152.4(GAA):c.1754+1G>A

Curation Version - 1.1
Curation History
JSON LD for Version 1.1

CA10605471

286458 (ClinVar)

Gene: GAA

Condition: glycogen storage disease II

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: e4c678f5-39e9-47cd-b721-a90452043ec4

Approved on: 2019-09-04

Published on: 2020-05-26

HGVS expressions

NM_000152.4:c.1754+1G>A

NM_000152.4(GAA):c.1754+1G>A

NC_000017.11:g.80112101G>A

CM000679.2:g.80112101G>A

NC_000017.10:g.78085900G>A

CM000679.1:g.78085900G>A

NC_000017.9:g.75700495G>A

NG_009822.1:g.15546G>A

ENST00000570803.6:c.1754+1G>A

ENST00000572080.2:c.1754+1G>A

ENST00000577106.6:c.1754+1G>A

ENST00000302262.8:c.1754+1G>A

ENST00000302262.7:c.1754+1G>A

ENST00000390015.7:c.1754+1G>A

ENST00000572080.1:c.142+1G>A

ENST00000572803.1:n.368+1G>A

NM_000152.3:c.1754+1G>A

NM_001079803.1:c.1754+1G>A

NM_001079804.1:c.1754+1G>A

NM_001079803.2:c.1754+1G>A

NM_001079804.2:c.1754+1G>A

NM_000152.5:c.1754+1G>A

NM_001079803.3:c.1754+1G>A

NM_001079804.3:c.1754+1G>A

Pathogenic

PM2 PM3 PVS1 PP4

Evidence Links 0

Expert Panel

Lysosomal Diseases VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Lysosomal Diseases VCEP

The c.1754+1G>A variant alters the canonical donor splice site of intron 12 and is predicted to causing skipping of exon 12, which would result in a frameshift causing a premature stop codon and nonsense-mediated decay. Therefore PVS1 can be applied. This is supported by negative results for cross reactive immunological material studies in fibroblasts from a patient with this variant (PMID: 22252923). The variant is absent in gnomAD. It has been reported in a patient with infantile onset Pompe disease in trans with a pathogenic frameshift variant (PMID 19775921). 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 LSD VCEP: PVS1, PM2, PM3, PP4.

PM2

This variant is absent in gnomAD.

PM3

This variant was found in trans with a pathogenic variant in GAA in a patient with infantile-onset Pompe disease with <1% GAA activity in fibroblasts or muscle (PMID 19775921). Based on the ClinGen LSD VCEP's guidelines, this data was given a total of 1 point, meeting PM3.

PVS1

This variant alters the canonical donor splice site of intron 12. It is predicted to disrupt normal splicing, causing skipping of exon 12, which would result in a frameshift causing a premature stop codon and nonsense mediated decay. This is supported by cross reactive immunological material (CRIM) analysis in cultured fibroblasts showing that c.1754+1G>A is a CRIM-negative allele (PMID 22252923).

PP4

This variant was identified in a patient with infantile onset Pompe disease with <1% of normal GAA activity in skin fibroblasts and/or muscle biopsy (tissue type(s) not stated for this patient) (PMID 19775921), meeting the specifications of the ClinGen LSD VCEP for PP4.

Curation History

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