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
  • No CSPEC computed assertion could be determined for this classification!

Variant: NM_000152.5(GAA):c.2467A>T (p.Ile823Phe)

CA401325518

456406 (ClinVar)

Gene: GAA
Condition: glycogen storage disease II
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: f94a2b44-f698-49ab-8738-d9ee2a316872
Approved on: 2025-06-17
Published on: 2025-07-03

HGVS expressions

NM_000152.5:c.2467A>T
NM_000152.5(GAA):c.2467A>T (p.Ile823Phe)
NC_000017.11:g.80117735A>T
CM000679.2:g.80117735A>T
NC_000017.10:g.78091534A>T
CM000679.1:g.78091534A>T
NC_000017.9:g.75706129A>T
NG_009822.1:g.21180A>T
ENST00000570803.6:c.2467A>T
ENST00000572080.2:c.*605A>T
ENST00000577106.6:c.2467A>T
ENST00000302262.8:c.2467A>T
ENST00000302262.7:c.2467A>T
ENST00000390015.7:c.2467A>T
ENST00000573556.1:n.420A>T
NM_000152.3:c.2467A>T
NM_001079803.1:c.2467A>T
NM_001079804.1:c.2467A>T
NM_000152.4:c.2467A>T
NM_001079803.2:c.2467A>T
NM_001079804.2:c.2467A>T
NM_001079803.3:c.2467A>T
NM_001079804.3:c.2467A>T
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Uncertain Significance

Met criteria codes 2
PM2_Supporting PP3
Not Met criteria codes 2
PP4 PM3

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

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Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Lysosomal Diseases VCEP
The NM_000152.5:c.2467A>T variant in GAA is a missense variant predicted to cause substitution of isoleucine by phenylalanine at amino acid 823 (p.Ile823Phe). The highest population minor allele frequency in gnomAD v4.1.0. is 0.000002 (2/1179156 alleles) in the European, non-Finnish 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 0.918 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Although this variant has been identified in several individuals with low GAA activity on newborn screen, it not been reported in any symptomatic individuals diagnosed with Pompe disease and, as such, there is insufficient data to apply PM3 and PP4. There is a ClinVar entry for this variant (Variation ID: 456406). In summary, this variant meets the criteria to be classified as a Variant of Uncertain Significance for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PP2, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on June 17, 2025)
Met criteria codes
PM2_Supporting
The highest population minor allele frequency in gnomAD v4.1.0. is 0.000002 (2/1179156 alleles) in the European, non-Finnish population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting).
PP3
The computational predictor REVEL gives a score of 0.918 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3).
Not Met criteria codes
PP4
This variant has been detected in at least 11 unrelated patients suspected to have Pompe disease or tested positive on NBS, 8 of which demonstrated deficient GAA activity (PMID: 33202836, Duke University, Revvity). None of these individuals were diagnosed with Pompe disease and there has been no follow-up. 0 points. Not Met.
PM3
This variant has been detected in at least 11 unrelated individuals with suspected Pompe disease. None of these individuals were reported to be diagnosed with Pompe disease. Of those individuals, 6 were compound heterozygous for the variant and a variant classified as pathogenic by the ClinGen LD VCEP. Three individuals were compound heterozygous for this variant and c.-32-13T>G (ClinVar Variation ID: 4027, SCV005382543.1) (PMID: 33202836; Clinical Diagnostic Laboratory). Two individuals were compound heterozygous for this variant and c.2238G>C (p.Trp746Cys) (ClinVar Variation ID: 265160, SCV002032122.1) (PMID: 33202836; clinical diagnostic laboratory). One individual was compound heterozygous for this variant and c.1504A>G (p.Met502Val) (ClinVar Variation ID: 439746, SCV004227907.1) (PMID: 33202836). The remaining 5 inidivduals were compound heterozygous for the variant, variants not classified as pathogenic by the ClinGen LD VCEP, and/or pseudodeficiency variants. One individual was compound heterozygous for this variant, c.2238G>C (p.Trp746Cys) (pathogenic based on classification by the ClinGen Lysosomal Diseases VCEP, ClinVar Variation ID: 265160, SCV002032122.1), and c.2065G>A (p.Glu689Lys) (pseudodeficiency variant) (clinical diagnostic laboratory). One individual was compound heterozygous for this variant, c.671G>A (p.Arg224Gln) (likely pathogenic based on classification by the ClinGen Lysosomal Diseases VCEP), and c.2065G>A (p.Glu689Lys) (pseudodeficiency variant) (clinical diagnostic laboratory). One individual was compound heterozygous for this variant and an unkown GAA variant (clinical diagnostic laboratory). The phase is not confirmed for any of these individuals. One individual is compound heterozygous for c.2467A>T (Ile823Phe) and c.1504A>G (p.Met502Val) (VUS based on classification by the ClinGen Lysosomal Diseases VCEP); the phase of the variants was confirmed in trans by familial testing (clinical diagnostic laboratory). 0 points. Not Met.
Curation History
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