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.1115A>T (p.His372Leu)

CA16041889

370483 (ClinVar)

Gene: GAA (HGNC:2548)

Condition: glycogen storage disease II (MONDO:0009290)

Inheritance Mode: Autosomal recessive inheritance

UUID: a67f8a03-785c-44c2-b912-13cdb9ffef8b

Approved on: 2026-04-07

Published on: 2026-04-08

HGVS expressions

NM_000152.5:c.1115A>T

NM_000152.5(GAA):c.1115A>T (p.His372Leu)

NC_000017.11:g.80108528A>T

CM000679.2:g.80108528A>T

NC_000017.10:g.78082327A>T

CM000679.1:g.78082327A>T

NC_000017.9:g.75696922A>T

NG_009822.1:g.11973A>T

ENST00000570803.6:c.1115A>T

ENST00000572080.2:c.1115A>T

ENST00000577106.6:c.1115A>T

ENST00000302262.8:c.1115A>T

ENST00000302262.7:c.1115A>T

ENST00000390015.7:c.1115A>T

NM_000152.3:c.1115A>T

NM_001079803.1:c.1115A>T

NM_001079804.1:c.1115A>T

NM_000152.4:c.1115A>T

NM_001079803.2:c.1115A>T

NM_001079804.2:c.1115A>T

NM_001079803.3:c.1115A>T

NM_001079804.3:c.1115A>T

Likely Pathogenic

PP3 PP4_Moderate PM3_Strong PM2_Supporting PS3_Supporting

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.1115A>T variant in GAA is a missense variant predicted to cause substitution of histidine by leucine at amino acid 557 (p.Ile557Phe). Five probands with symptoms consistent with Pompe disease have been reported with this variant (PMID: 15121988, 18607768, 24715333, 28196920, 28394184, 31467850), three with documented deficiency of GAA activity (PMID: 15121988, 24715333, 28196920, 31467850) (PP4_Moderate). Each of these individuals was compound heterozygous for the variant and another variant that has been classified as pathogenic for Pompe disease by the ClinGen LD VCEP, including c.-32-13T>G (ClinVar Variation ID: 4027) (PMID: 18607768, 28196920, 3 patients, max 2 x 0.5 points), c.258dup (ClinVar Variation ID: 282842) (0.5 points, PMID: 31467850), and c.525del (Variation ID: 4033) (0.5 points, PMID: 15121988, 24715333); phase was not confirmed for any of these individuals. Another patient was compound heterozygous for the variant and c.2563G>C (p.Gly855Arg). The allelic data will be used to classify the second variant and is not included here to avoid circular logic. Total 2 points (PM3_Strong). The highest population minor allele frequency for this variant in gnomAD v4.1.0. is 0.000007628 (9/1179890 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). Expression of the variant in COS7 or HEK293T cells resulted in evidence of abnormal synthesis and processing on Western blot, indicating that this variant may impact protein function (PMID: 15121988, 24715333) (PS3_Supporting). The computational predictor REVEL gives a score of 0.928 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). There is a ClinVar entry for this variant (Variation ID: 370483). 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 Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PP4_Moderate, PM2_Supporting, PM3_Strong, PP3, PS3_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on April 7, 2026)

PP3

The computational predictor REVEL gives a score of 0.928 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3).

PP4_Moderate

At least five patients with this variant had documented GAA deficiency. One patient showed <30% of normal mean control level of GAA activity in cultured fibroblasts and skeletal muscle. This patient was also reported to be on enzyme replacement therapy for Pompe disease (PMID: 15121988, 247153333). Two patients showed <30% normal mean control level of GAA activity in dried blood spot, one of which was reported to be on enzyme replacement therapy for Pompe disease (PMID: 28196920, 31467850). Two patients were noted to have deficient GAA activity but results were not reported (PMID: 18607768, 28394184). PP4_Moderate.

PM3_Strong

Five individuals were compound heterozygous for the variant and another variant that has been classified as pathogenic for Pompe disease by the ClinGen LD VCEP, including c.-32-13T>G (ClinVar Variation ID: 4027) (PMID: 18607768, 28196920, 3 patients, max 2 x 0.5 points), c.258dup (ClinVar Variation ID: 282842) (0.5 points, PMID: 31467850), and c.525del (Variation ID: 4033) (0.5 points, PMID: 15121988, 24715333); phase was not confirmed for any of these individuals. Another patient was compound heterozygous for the variant and c.2563G>C (p.Gly855Arg). The allelic data will be used to classify the second variant and is not included here to avoid circular logic. Total 2 points (PM3_Strong)

PM2_Supporting

The highest population minor allele frequency in gnomAD v4.1.0. is 0.000007628 (9/1179890 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).

PS3_Supporting

Expression of the variant in COS cells resulted in low-level synthesis of the 110 kDa precursor but did show some degradation. The mutant allele did not generate catalytically active α-glucosidase, despite overexpression (PMID: 15121988). Expression of the variant in HEK293T cells showed synthesis of the 110 kDa acid α-glucosidase precursor with normal molecular mass in cells. The c.1115A>T (p.His372Leu) encoded precursor was not present in culture medium when analyzed by Western blot (PMID: 24715333). PS3_Supporting.

Curation History

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.