Variant: NM_000152.5(GAA):c.615G>A (p.Pro205=)

CA243111

196223 (ClinVar)

Gene: GAA

Condition: glycogen storage disease II

Inheritance Mode: Autosomal recessive inheritance

UUID: 4066d189-e5a2-4f99-82a1-3913da100053

Approved on: 2025-02-18

Published on: 2025-02-28

HGVS expressions

NM_000152.5:c.615G>A
NM_000152.5(GAA):c.615G>A (p.Pro205=)
NC_000017.11:g.80105817G>A
CM000679.2:g.80105817G>A
NC_000017.10:g.78079616G>A
CM000679.1:g.78079616G>A
NC_000017.9:g.75694211G>A
NG_009822.1:g.9262G>A
ENST00000570803.6:c.615G>A
ENST00000572080.2:c.615G>A
ENST00000577106.6:c.615G>A
ENST00000302262.8:c.615G>A
ENST00000302262.7:c.615G>A
ENST00000390015.7:c.615G>A
ENST00000570803.5:c.615G>A
ENST00000577106.5:c.615G>A
NM_000152.3:c.615G>A
NM_001079803.1:c.615G>A
NM_001079804.1:c.615G>A
NM_000152.4:c.615G>A
NM_001079803.2:c.615G>A
NM_001079804.2:c.615G>A
NM_001079803.3:c.615G>A
NM_001079804.3:c.615G>A

Uncertain Significance

• Met criteria codes: PM2_Supporting BP7 BP4

• Not Met criteria codes: PP4

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.615G>A variant in GAA is a synonymous (silent) variant (p.Pro205=) that is not predicted to impact splicing based on the computational splice predictor SpliceAI (BP4). Further, it is not in a position that is highly conserved (BP7). This variant has not been reported in a patient with Pompe disease to our knowledge. The highest population minor allele frequency in gnomAD v4.0. is 0.0004172 (38/91082 alleles) in the South Asian population. This is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (ClinVar Variation ID: 196223). Due to conflicting evidence, this variant is classified as a variant of uncertain significance for Pompe disease based on the GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications version 2.0): BP4, BP7, PM2_supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on February 18, 2025)

Met criteria codes

• PM2_Supporting: The highest population minor allele frequency in gnomAD v4.0. is 0.0004172 (38/91082 alleles) in the South Asian population. This is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting).
• BP7: The computational splicing predictor SpliceAI gives a score of 0.01 for acceptor gain suggesting that the variant has no impact on splicing (BP4). Additionally, this variant is at a nucleotide position that is not predicted to be highly conserved (PhyloP100 score: -2.893). Thus, BP7 can be applied.
• BP4: The computational splicing predictor SpliceAI gives a score of 0.01 for acceptor gain suggesting that the variant has no impact on splicing (BP4).

Not Met criteria codes

• PP4: This variant has been reported in one individual in the Duke Molecular Genetics Laboratory with a second silent change (phase unknown) that is classified as a VUS. GAA enzyme is in the normal range. No clinical information available.