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]

Variant: NM_000152.5(GAA):c.1445C>T (p.Pro482Leu)

CA401366796

982297 (ClinVar)

Gene: GAA (HGNC:2548)

Condition: glycogen storage disease II (MONDO:0009290)

Inheritance Mode: Autosomal recessive inheritance

UUID: 0b43e608-9622-456f-a358-b4d29ab793e0

Approved on: 2025-10-28

Published on: 2025-10-28

HGVS expressions

NM_000152.5(GAA):c.1445C>T (p.Pro482Leu)

NM_000152.5:c.1445C>T

NC_000017.11:g.80110734C>T

CM000679.2:g.80110734C>T

NC_000017.10:g.78084533C>T

CM000679.1:g.78084533C>T

NC_000017.9:g.75699128C>T

NG_009822.1:g.14179C>T

ENST00000570803.6:c.1445C>T

ENST00000572080.2:c.1445C>T

ENST00000577106.6:c.1445C>T

ENST00000302262.8:c.1445C>T

ENST00000302262.7:c.1445C>T

ENST00000390015.7:c.1445C>T

NM_000152.3:c.1445C>T

NM_001079803.1:c.1445C>T

NM_001079804.1:c.1445C>T

NM_000152.4:c.1445C>T

NM_001079803.2:c.1445C>T

NM_001079804.2:c.1445C>T

NM_001079803.3:c.1445C>T

NM_001079804.3:c.1445C>T

Likely Pathogenic

PM2_Supporting PM5_Supporting PP3 PP4_Moderate PM3_Strong

Evidence Links 0

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

PDF

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Lysosomal Diseases VCEP

The NM_000152.5:c.1445C>T variant in GAA is a missense variant predicted to cause substitution of proline by leucine at amino acid 482 (p.Pro482Leu). At least 5 patient(s) with this variant had documented GAA deficiency with <10% of normal mean control level of GAA activity in leukocytes, activity in the affected range in muscle, cultured skin fibroblasts, leukocytes, lymphocytes, whole blood or dried blood spot, or were noted to have deficient GAA activity but results were not provided (PMID: 17616415, 31086307, 34530085, 33741225, 31931849) (PP4_Moderate). This variant has been detected in at least 6 individuals with Pompe disease. Of those individuals, 4 were compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic for Pompe disease by the ClinGen LD VCEP. The phase is unconfirmed in all cases. The second variant includes c.1674_1675delTG (ClinVar Variation ID: 1397833) (PMID: 38958145, 0.5 points), c.258dup (ClinVar Variation ID: 282842) (PMID: 31931849, 0.5 points), c.1210G>A (p.Asp404Asn) (ClinVar Variation ID: 657348) (PMID: 31086307, 0.5 points), and c.343C>T (p.Gln115Ter) (ClinVar Variation ID: 188996) (PMID: 17616415, 0.5 points). Two individuals from different geographical areas were homozygous for the variant (2 x 0.5 pt) (PMID: 33741225, 38958145). Total 3 points (PM3_Strong). The highest population minor allele frequency in gnomAD v4.1.0. is 8.475e-7 (1/1179992 alleles) in the non-Finnish European 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). Another missense variant c.1445C>G (p.Pro482Arg) (PMID: 31392188, 22644586, ClinVar Variation ID 1067574) in the same codon has been classified as likely pathogenic for Pompe disease by the ClinGen LD VCEP (PM5_Supporting). There is a ClinVar entry for this variant (Variation ID: 982297). In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen LD VCEP (Specifications Version 2.0): PM3_Strong, PP4_Moderate, PP3, PM2_Supporting, PM5_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on October 28, 2025).

PM2_Supporting

The highest population minor allele frequency in gnomAD v4.1.0. is 8.475e-7 (1/1179992 alleles) in the non-Finnish European population. which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting).

PM5_Supporting

Another missense variant c.1445C>G (p.Pro482Arg) (PMID: 31392188, 22644586, ClinVar Variation ID 1067574) in the same codon has been classified as likely pathogenic for Pompe disease by the ClinGen LD VCEP without requiring the use of PM5 data from p.Pro482Leu (PM5_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).

PP4_Moderate

At least 5 patient(s) with this variant had documented GAA deficiency with <10% of normal mean control level of GAA activity in leukocytes, lymphocytes, muscle samples, activity in the affected range in muscle, cultured skin fibroblasts, leukocytes, lymphocytes, whole blood or dried blood spot, or were noted to have deficient GAA activity but results were not provided (PMID: 17616415, 31086307, 34530085, 33741225, 31931849) (PP4_Moderate).

PM3_Strong

This variant has been detected in at least 6 individuals with Pompe disease. Of those individuals, 4 were compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic for Pompe disease by the ClinGen LD VCEP. The phase is unconfirmed in all cases. The second variant includes c.1674_1675delTG (ClinVar Variation ID: 1397833) (PMID: 38958145, 0.5 points), c.258dup (ClinVar Variation ID: 282842) (PMID: 31931849, 0.5 points), c.1210G>A (p.Asp404Asn) (ClinVar Variation ID: 657348) (PMID: 31086307, 0.5 points), and c.343C>T (p.Gln115Ter) (ClinVar Variation ID: 188996) (PMID: 17616415, 0.5 points). Two individuals from different geographical areas were homozygous for the variant (2 x 0.5 pt) (PMID: 33741225, 38958145). Total 3 points (PM3_Strong).

Curation History

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