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:c.1106T>C

CA401364964

1034639 (ClinVar)

Gene: GAA (HGNC:2548)

Condition: glycogen storage disease II (MONDO:0009290)

Inheritance Mode: Autosomal recessive inheritance

UUID: 58c05f56-40b8-4963-87f3-9720ac6f893c

Approved on: 2025-10-21

Published on: 2025-12-02

HGVS expressions

NM_000152.5:c.1106T>C

NC_000017.11:g.80108519T>C

CM000679.2:g.80108519T>C

NC_000017.10:g.78082318T>C

CM000679.1:g.78082318T>C

NC_000017.9:g.75696913T>C

NG_009822.1:g.11964T>C

ENST00000570803.6:c.1106T>C

ENST00000572080.2:c.1106T>C

ENST00000577106.6:c.1106T>C

ENST00000302262.8:c.1106T>C

ENST00000302262.7:c.1106T>C

ENST00000390015.7:c.1106T>C

NM_000152.3:c.1106T>C

NM_001079803.1:c.1106T>C

NM_001079804.1:c.1106T>C

NM_000152.4:c.1106T>C

NM_001079803.2:c.1106T>C

NM_001079804.2:c.1106T>C

NM_001079803.3:c.1106T>C

NM_001079804.3:c.1106T>C

Likely Pathogenic

PP4_Moderate PP3 PM3_Supporting PS3_Moderate PM2_Supporting

PM5

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.1106T>C variant in GAA is a missense variant predicted to cause substitution of leucine by proline at amino acid 369 (p.Leu369Pro). At least 2 patients with a diagnosis of Pompe disease have been reported to have this variant, including one individual with documented GAA activity in the affected range in dried blood spot. This patient was also treated with enzyme replacement therapy for Pompe disease (Duke University; PMID: 23430493) (PP4_Moderate). This individual was compound heterozygous for this variant, c.2704C>T (p.Gln902Ter) (likely pathogenic based on classification by the ClinGen Lysosomal Diseases VCEP), and c.2064C>G (p.Ser688Arg) (not yet evaluated by the ClinGen Lysosomal Diseases VCEP); phase unconfirmed (Duke University). Another individual was compound heterozygous for this variant and c.1064T>C (p.Leu355Pro) (pathogenic based on classification by the ClinGen Lysosomal Diseases VCEP); phase unconfirmed (PMID: 23430493) (PM3_Supporting). The highest population minor allele frequency in gnomAD v4.1.0. is 0.00001666 (1/60010 alleles) in the Admixed American population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). Additionally, expression of the variant in HEK293 cells resulted in 3.1% wild type GAA activity and evidence of abnormal GAA synthesis and processing, leading the variant to be described as Class B (“potentially less severe”), indicating that this variant may impact protein function (PMID: 23430493) (PS3_Moderate). The computational predictor REVEL gives a score of 0.976, which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Another missense variant in the same codon, c.1106T>A (p.Leu369Gln), has been reported in a patient with Pompe disease (PMID: 31342611). However, this variant has not yet met the criteria to be classified as pathogenic or likely pathogenic by the ClinGen Lysosomal Diseases VCEP (PM5 not met). In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (specifications Version 2.0): PS3_Moderate, PM2_Supporting, PM3_Supporting, PP3, PP4_Moderate. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on October 21, 2025).

PP4_Moderate

At least 2 patients with a diagnosis of Pompe disease have been reported to have this variant, including one individual with documented GAA activity in the affected range in dried blood spot. This patient was also treated with enzyme replacement therapy for Pompe disease (Duke University; PMID: 23430493) (PP4_Moderate).

PP3

The computational predictor REVEL gives a score of 0.976, which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3).

PM3_Supporting

This variant has been detected in at least 2 individuals with Pompe disease. Of those individuals, one was compound heterozygous for this variant and c.1064T>C (p.Leu355Pro) (pathogenic based on classification by the ClinGen Lysosomal Diseases VCEP); phase unconfirmed (PMID: 23430493) (0.5 points). Another individual was compound heterozygous for this variant, c.2704C>T (p.Gln902Ter) (likely pathogenic based on classification by the ClinGen Lysosomal Diseases VCEP), and c.2064C>G (p.Ser688Arg) (not yet evaluated by the ClinGen Lysosomal Diseases VCEP); phase unconfirmed (Duke University) (PM3_Supporting).

PS3_Moderate

Expression of the variant in HEK293 cells resulted in 3.1% wild type GAA activity and evidence of abnormal GAA synthesis and processing, leading the variant to be described as Class B (“potentially less severe”), indicating that this variant may impact protein function (PMID: 23430493) (PS3_Moderate).

PM2_Supporting

The highest population minor allele frequency in gnomAD v4.1.0. is 0.00001666 (1/60010 alleles) in the Admixed American population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting).

PM5

Another missense variant in the same codon, c.1106T>A (p.Leu369Gln), has been reported in a patient with Pompe disease (PMID: 31342611). However, this variant has not yet met the criteria to be classified as pathogenic or likely pathogenic by the ClinGen Lysosomal Diseases VCEP (PM5 not met).

Curation History

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