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 label mismatch: GAA vs undefined
  • 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.2221G>A (p.Asp741Asn)

CA8815660

571521 (ClinVar)

Gene: GAA
Condition: glycogen storage disease II
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: fb324baa-3e67-4d0b-abda-3f0ca72a19ed
Approved on: 2025-05-06
Published on: 2025-05-20

HGVS expressions

NM_000152.5:c.2221G>A
NM_000152.5(GAA):c.2221G>A (p.Asp741Asn)
NC_000017.11:g.80116999G>A
CM000679.2:g.80116999G>A
NC_000017.10:g.78090798G>A
CM000679.1:g.78090798G>A
NC_000017.9:g.75705393G>A
NG_009822.1:g.20444G>A
ENST00000570803.6:c.2221G>A
ENST00000572080.2:c.*359G>A
ENST00000577106.6:c.2221G>A
ENST00000302262.8:c.2221G>A
ENST00000302262.7:c.2221G>A
ENST00000390015.7:c.2221G>A
ENST00000572080.1:c.640G>A
ENST00000573556.1:n.174G>A
NM_000152.3:c.2221G>A
NM_001079803.1:c.2221G>A
NM_001079804.1:c.2221G>A
NM_000152.4:c.2221G>A
NM_001079803.2:c.2221G>A
NM_001079804.2:c.2221G>A
NM_001079803.3:c.2221G>A
NM_001079804.3:c.2221G>A
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Uncertain Significance

Met criteria codes 4
PM3_Supporting PP3 PP4_Moderate PM2_Supporting

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.2221G>A variant in GAA is a missense variant predicted to cause substitution of aspartic acid by asparagine at amino acid 741 (p.Asp741Asn). One proband with symptoms consistent with infantile-onset Pompe disease has been reported with this variant with documented deficiency of GAA activity (PMID: 29122469). This proband is compound heterozygous for the variant and a variant classified as pathogenic by the ClinGen Lysosomal Diseases VCEP, c.1978C>T (p.Arg660Cys) (PMID: 29122469) (PM3_supporting). Another proband with symptoms consistent with late-onset Pompe disease has been reported with this variant with documented deficiency of GAA activity (Duke University; PMID: 31904026, 32518148, 39983297). Additionally, both patients were treated with enzyme replacement therapy (PP4_Moderate). This proband is compound heterozygous for the variant, a variant classified as pathogenic by the ClinGen Lysosomal Diseases VCEP, c.1978C>T (p.Arg660Cys), and a variant classified as liekly pathogenic by the ClinGen Lysosomal Diseases VCEP, c.1477C>T (p.Pro493Ser). The c.2221G>A (p.Asp741Asn) and c.1477C>T (p.Pro493Ser) variants were confirmed in trans with the c.1978C>T (p.Arg660Cys) variant. The variants are confirmed in trans for this patient (Duke University). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00009603 (6/62480 alleles) in the Remaining 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 0.828 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3_met). Two other missense variants, c.2222A>T (p.Asp741Val) (ClinVar Variation ID: 291139) and c.2223C>G (p.Asp741Glu) (ClinVar Variation ID: 526539), in the same codon have been reported. However, these variants have not been classified by the ClinGen Lysosomal Diseases VCEP and, therefore, this evidence is not sufficient to meet PM5 at any strength. There is a ClinVar entry for this variant (Variation ID: 571521). 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): PM3_supporting, PP4_moderate, PM2_supporting, PP3_met). (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on May 6, 2025).
Met criteria codes
PM3_Supporting
This variant has been detected in at least two individuals with Pompe disease. One individual was compound heterozygous for the variant, c.2221G>A (p.Asp741Asn) and two other variants: a variant classified as pathogenic by the ClinGen LD VCEP, c.1978C>T (p.Arg660Cys) (ClinVar Variation ID: 558604, SCV002540656.1), and a variant classified as likely pathogenic by the by the ClinGen LD VCEP, c.1477C>T (p.Pro493Ser) (ClinVar Variation ID: 2160730) (Duke University; PMID: 31904026, 32518148, 39983297). The c.2221G>A (p.Asp741Asn) and c.1477C>T (p.Pro493Ser) variants were confirmed in trans with the c.1978C>T (p.Arg660Cys) variant. The phase of the variants was confirmed in trans by parental testing. 0 points. The other individual was compound heterozygous for the variant, c.2221G>A (p.Asp741Asn) and a variant classified as pathogenic by the ClinGen LD VCEP, c.1978C>T (p.Arg660Cys) (ClinVar Variation ID: 558604, SCV002540656.1) (PMID: 29122469). The phase of the variants was not confirmed. 0.5 points; PM3_supporting.
PP3
The computational predictor REVEL gives a score of 0.828 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3_met).
PP4_Moderate
This variant has been detected in at least 2 patients reported to have Pompe disease including one with reported laboratory values demonstrating deficient GAA activity. This patient was also treated with enzyme replacement therapy (Duke University; PMID: 31904026, 32518148). 2 points; PP4_moderate.
PM2_Supporting
The highest population minor allele frequency in gnomAD v4.1.0 is 0.00009603 (6/62480 alleles) in the Remaining population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_supporting).
Curation History
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