Variant: NM_000152.4(GAA):c.1288G>A (p.Glu430Lys)

CA8815251

501777 (ClinVar)

Gene: GAA

Condition: glycogen storage disease II

Inheritance Mode: Autosomal recessive inheritance

UUID: 68d0c25e-977d-4211-b166-3f52d076d6b1

Approved on: 2023-04-06

Published on: 2024-04-12

HGVS expressions

NM_000152.4:c.1288G>A
NM_000152.4(GAA):c.1288G>A (p.Glu430Lys)
NC_000017.11:g.80108790G>A
CM000679.2:g.80108790G>A
NC_000017.10:g.78082589G>A
CM000679.1:g.78082589G>A
NC_000017.9:g.75697184G>A
NG_009822.1:g.12235G>A
ENST00000570803.6:c.1288G>A
ENST00000572080.2:c.1288G>A
ENST00000577106.6:c.1288G>A
ENST00000302262.8:c.1288G>A
ENST00000302262.7:c.1288G>A
ENST00000390015.7:c.1288G>A
NM_000152.3:c.1288G>A
NM_001079803.1:c.1288G>A
NM_001079804.1:c.1288G>A
NM_001079803.2:c.1288G>A
NM_001079804.2:c.1288G>A
NM_000152.5:c.1288G>A
NM_001079803.3:c.1288G>A
NM_001079804.3:c.1288G>A

Uncertain Significance

• Met criteria codes: PM2_Supporting

• Not Met criteria codes: BP4 PP3

Expert Panel

Lysosomal Diseases VCEP

Criteria Specification Information

Criteria Specification: ClinGen Lysosomal Storage Disorders Variant Curation Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2

Evidence submitted by expert panel

Lysosomal Diseases VCEP

The NM_000152.5:c.1288G>A (p.Glu430Lys) variant in GAA has a highest population minor allele frequency in gnomAD v2.1.1 of 0.00043 (10/23086 alleles) in the African population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.577 which is neither above nor below the thresholds predicting a damaging (>0.7) or benign (<0.5) impact on GAA function. SpliceAI predicts no impact on splicing. To our knowledge, this variant has not been reported in the literature in individuals with Pompe disease, and the results of functional studies are not available. However, there is a ClinVar entry for this variant (Variation ID: 501777). 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): PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel, April 6, 2023)

Met criteria codes

• PM2_Supporting: The highest population minor allele frequency in gnomAD v2.1.1 is 0.00043 (10/23086 alleles) in the African population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting).

Not Met criteria codes

• BP4: The computational predictor REVEL gives a score of 0.577 which is neither above nor below the thresholds predicting a damaging (>0.7) or benign (<0.5) impact on GAA function. SpliceAI predicts no impact on splicing.
• PP3: The computational predictor REVEL gives a score of 0.577 which is neither above nor below the thresholds predicting a damaging (>0.7) or benign (<0.5) impact on GAA function. SpliceAI predicts no impact on splicing.