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.1390A>T (p.Arg464Trp)

CA401366487

843677 (ClinVar)

Gene: GAA (HGNC:2548)

Condition: glycogen storage disease II (MONDO:0009290)

Inheritance Mode: Autosomal recessive inheritance

UUID: 1fefc9e3-dd55-4aef-8e78-9cb27fd5bc81

Approved on: 2025-10-30

Published on: 2025-10-30

HGVS expressions

NM_000152.5:c.1390A>T

NM_000152.5(GAA):c.1390A>T (p.Arg464Trp)

NC_000017.11:g.80110008A>T

CM000679.2:g.80110008A>T

NC_000017.10:g.78083807A>T

CM000679.1:g.78083807A>T

NC_000017.9:g.75698402A>T

NG_009822.1:g.13453A>T

ENST00000570803.6:c.1390A>T

ENST00000572080.2:c.1390A>T

ENST00000577106.6:c.1390A>T

ENST00000302262.8:c.1390A>T

ENST00000302262.7:c.1390A>T

ENST00000390015.7:c.1390A>T

NM_000152.3:c.1390A>T

NM_001079803.1:c.1390A>T

NM_001079804.1:c.1390A>T

NM_000152.4:c.1390A>T

NM_001079803.2:c.1390A>T

NM_001079804.2:c.1390A>T

NM_001079803.3:c.1390A>T

NM_001079804.3:c.1390A>T

Uncertain Significance

PM2_Supporting

PP3 PM3 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.1390A>T variant in GAA is a missense variant predicted to cause substitution of arginine by tryptophan at amino acid 464 (p.Arg464Trp). To our knowledge, this variant has not been reported in the literature in any individuals with Pompe disease and functional studies have not been performed. This variant is absent in gnomAD v4.1.0. (PM2_Supporting). The computational predictor REVEL gives a score of 0.694 which is neither above nor below the thresholds predicting a damaging (>0.7) or benign (<0.5) impact on GAA function. There is a ClinVar entry for this variant (Variation ID: 843677). In summary, this variant meets the criteria to be classified as Uncertain Significance for Pompe disease based on the GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on October 30, 2025)

PM2_Supporting

This variant is absent in gnomAD v4.1.0. (PM2_Supporting).

PP3

The computational predictor REVEL gives a score of 0.694 which is neither above nor below the thresholds predicting a damaging (>0.7) or benign (<0.5) impact on GAA function.

PM3

To our knowledge, this variant has not been reported in the literature in any individuals with Pompe disease.

PM5

Another missense variant c.1392G>C, p.Arg464Ser in the same codon has been reported in a patient with Pompe disease (ClinVar Variation ID: 432217). However, this variant has not yet met the criteria to be classified as pathogenic or likely pathogenic by the ClinGen LSD VCEP (PM5 not met).

Curation History

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