Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data

Variant: NM_000152.4(GAA):c.1336_1356dup (p.Ala452_Gly453insIleSerSerSerGlyProAla)

CA658824782

556985 (ClinVar)

Gene: GAA
Condition: glycogen storage disease II
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: fd73eed8-5074-4948-b8e9-139cf8a36027
Approved on: 2024-06-17
Published on: 2024-06-17

HGVS expressions

NM_000152.4:c.1336_1356dup
NM_000152.4(GAA):c.1336_1356dup (p.Ala452_Gly453insIleSerSerSerGlyProAla)
NC_000017.11:g.80109954_80109974dup
CM000679.2:g.80109954_80109974dup
NC_000017.10:g.78083753_78083773dup
CM000679.1:g.78083753_78083773dup
NC_000017.9:g.75698348_75698368dup
NG_009822.1:g.13399_13419dup
ENST00000570803.6:c.1336_1356dup
ENST00000572080.2:c.1336_1356dup
ENST00000577106.6:c.1336_1356dup
ENST00000302262.8:c.1336_1356dup
ENST00000302262.7:c.1336_1356dup
ENST00000390015.7:c.1336_1356dup
NM_000152.3:c.1336_1356dup
NM_001079803.1:c.1336_1356dup
NM_001079804.1:c.1336_1356dup
NM_001079803.2:c.1336_1356dup
NM_001079804.2:c.1336_1356dup
NM_000152.5:c.1336_1356dup
NM_001079803.3:c.1336_1356dup
NM_001079804.3:c.1336_1356dup
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Uncertain Significance

Met criteria codes 2
PM4 PM2_Supporting
Not Met criteria codes 2
PP3 BP4

Evidence Links 0

Expert Panel

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.1336_1356dup variant in GAA is predicted to cause a change in the length of the protein (p.Ile446_Ala452dup) due to an in-frame duplication of 7 amino acids in a non-repeat region (PM4). The variant is absent in gnomAD v2.1.1 (PM2_Supporting). To our knowledge, this variant has not been reported in the literature in individuals with Pompe disease, and results of experimental studies are not available. Computational evidence is conflicting; PROVEAN predicts that the variant will impact the function of GAA, while Mutation Taster predicts no impact. As a result, neither PP4 nor BP4 can be applied. There is a ClinVar entry for this variant (Variation ID: 556985). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PM4, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases VCEP on June 17, 2024)
Met criteria codes
PM4
The NM_000152.5:c.1336_1356dup variant in GAA is predicted to cause a change in the length of the protein (p.Ile446_Ala452dup) due to an in-frame duplication of 7 amino acids in a non-repeat region (PM4).
PM2_Supporting
This variant is absent in gnomAD v2.1.1 (PM2_Supporting).
Not Met criteria codes
PP3
Computational evidence is conflicting. The PROVEAN score is -14.56 (meeting the threshold of -2.5 for deleterious), and Mutation Taster predicts that this variant is a “polymorphism”. Because the results of these in silico prediction tools are conflicting, this criterion is not met.
BP4
Computational evidence is conflicting. The PROVEAN score is -14.56 (meeting the threshold of -2.5 for deleterious), and Mutation Taster predicts that this variant is a “polymorphism”. Because the results of these in silico prediction tools are conflicting, this criterion is not met.
Curation History
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