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.1192dup (p.Leu398fs)

CA16041890

370510 (ClinVar)

Gene: GAA

Condition: glycogen storage disease II

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 588d5681-ac4f-4e84-afdc-e2962954e613

HGVS expressions

NM_000152.5:c.1192dup

NM_000152.5(GAA):c.1192dup (p.Leu398fs)

NC_000017.11:g.80108605dup

CM000679.2:g.80108605dup

NC_000017.10:g.78082404dup

CM000679.1:g.78082404dup

NC_000017.9:g.75696999dup

NG_009822.1:g.12050dup

NM_000152.3:c.1192dup

NM_001079803.1:c.1192dup

NM_001079804.1:c.1192dup

NM_000152.4:c.1192dup

NM_001079803.2:c.1192dup

NM_001079804.2:c.1192dup

NM_001079803.3:c.1192dup

NM_001079804.3:c.1192dup

ENST00000302262.7:c.1192dup

ENST00000390015.7:c.1192dup

Pathogenic

PM2 PVS1 PM3_Supporting PP4

Evidence Links 3

Expert Panel

Lysosomal Diseases VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Lysosomal Diseases VCEP

This variant, c.1192dup (p.Leu398ProfsTer108), is a frameshift variant that is predicted to result in a premature termination codon, nonsense mediated decay, and lack of gene product, meeting PVS1. This variant is not in gnomAD v2.1.1, meeting PM2. One patient has been reported who meets the ClinGen LSD VCEP’s specifications for PP4 and who is compound heterozygous with c.-32-13T>G pathogenic variant, phase unknown (PMID 17616415), meeting PM3_Supporting. The variant has been reported in additional publications but GAA activity was not provided and therefore the data was not included (PMIDs 22980766, 27711114). There is a ClinVar entry for this variant (Variation ID: 370510, 1 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_supporting, PP4.

PM2

This variant is not in gnomAD v2.1.1, meeting PM2

PVS1

This is a frameshift variant which is predicted to result in a premature termination codon, nonsense mediated decay, and lack of gene product. Therefore, PVS1 can be applied.

PM3_Supporting

One patient meeting the ClinGen LSD VCEP's PP4 specifications is compound heterozygous for the variant and c.-32-13T>G pathogenic variant, phase unknown (PMID 17616415), meeting PM3_Supporting. Additional patients have been reported but were not included because the GAA activity was not provided and therefore PP4 cannot be assessed (PMIDs 22980766, 27711114).

PubMed:22980766

PubMed:17616415

PubMed:27711114

PP4

One patient with the variant in compound heterozygosity with c.-32-13T>G is reported with adult onset Pompe disease and 28% residual GAA activity in fibroblasts (PMID 17616415), meeting PP4. Of note, additional publications report a patient with the same genotype, but different age of onset, which may be a different individual (PMIDs 22980766, 27711114). However, individual residual GAA activity was not provided.

Approved on: 2020-09-20

Published on: 2020-11-12

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