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]

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

Curation Version - 1.2
Curation History
JSON LD for Version 1.2

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: 2020-02-05

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

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

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

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

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

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

Pathogenic

PVS1 PP4 PM2 PM3

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 cause skipping of exon 12, which would result in a frameshift, creation of a premature stop codon, and nonsense-mediated decay. This is supported by the finding of no cross reactive immunological material in fibroblasts from a patient with this variant (PMID: 22252923). Therefore PVS1 can be applied. The variant is absent in gnomAD v2.1.1, meeting PM2. It has been reported in a patient with infantile onset Pompe disease in trans with a frameshift variant, c.722_723delTT (PMID 19775921), meeting PM3. There is a ClinVar entry for this variant (Variant ID: 286458; one star review status) with one submitter classifying the variant as likely pathogenic. 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.

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.

PM2

This variant is absent in gnomAD v2.1.1.

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.

Curation History

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