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

CA401364293

Gene: GAA

Condition: glycogen storage disease II

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 8b8a4880-5d32-489b-a5d8-17af6b017a6d

Approved on: 2020-02-14

Published on: 2020-05-27

HGVS expressions

NM_000152.5:c.955+1G>A

NC_000017.11:g.80107897G>A

CM000679.2:g.80107897G>A

NC_000017.10:g.78081696G>A

CM000679.1:g.78081696G>A

NC_000017.9:g.75696291G>A

NG_009822.1:g.11342G>A

NM_000152.3:c.955+1G>A

NM_001079803.1:c.955+1G>A

NM_001079804.1:c.955+1G>A

NM_000152.4:c.955+1G>A

NM_001079803.2:c.955+1G>A

NM_001079804.2:c.955+1G>A

NM_001079803.3:c.955+1G>A

NM_001079804.3:c.955+1G>A

ENST00000302262.7:c.955+1G>A

ENST00000390015.7:c.955+1G>A

Pathogenic

PM3_Supporting PVS1 PP4 PM2

Evidence Links 1

Expert Panel

Lysosomal Diseases VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Lysosomal Diseases VCEP

This variant, c.955+1G>A, alters the donor splice site of intron 5 in the GAA gene. Assuming that skipping of exon 5 occurs, this would cause a frameshift, resulting in a premature termination codon and lack of GAA gene product, meeting PVS1. The variant is absent in gnomAD v2.1.1, meeting PM2. This variant was found in compound heterozygosity with a pathogenic variant in GAA, c.1438-2A>G, in a patient who also meets the ClinGen LSD VCEP's PP4 specifications (PMID 29422078). The phase is unknown. This data meets PM3_Supporting. There is no ClinVar entry for this variant. 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_Supporting, PP4.

PM3_Supporting

This variant was found in compound heterozygosity with a pathogenic variant in GAA, c.1438-2A>G, in a patient who meets the ClinGen LSD VCEP's PP4 specifications (PMID 29422078). The phase is unknown. Based on the ClinGen LSD VCEP's specifications, this data was given a total of 0.5 points which meets PM3_Supporting.

PVS1

This variant alters the donor splice site of intron 5. Assuming that this results in skipping of exon 5, this would cause a frameshift, resulting in a premature termination codon, and lack of GAA gene product, meeting PVS1.

PP4

One patient is reported with this variant and <2% normal GAA activity in either lymphocytes, fibroblasts, or muscle tissue (unspecified), meeting the ClinGen LSD VCEP's criteria for PP4.

PubMed:29422078

PM2

This variant is absent in gnomAD v2.1.1.

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