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_000152.4(GAA):c.1222A>G (p.Met408Val)

Curation Version - 1.1
Curation History
JSON LD for Version 1.1

CA8815236

371235 (ClinVar)

Gene: GAA

Condition: glycogen storage disease II

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: e8e8f441-1f7e-4b2e-8c9f-940203b26cb8

Approved on: 2024-05-06

Published on: 2024-05-08

HGVS expressions

NM_000152.4:c.1222A>G

NM_000152.4(GAA):c.1222A>G (p.Met408Val)

NC_000017.11:g.80108724A>G

CM000679.2:g.80108724A>G

NC_000017.10:g.78082523A>G

CM000679.1:g.78082523A>G

NC_000017.9:g.75697118A>G

NG_009822.1:g.12169A>G

ENST00000570803.6:c.1222A>G

ENST00000572080.2:c.1222A>G

ENST00000577106.6:c.1222A>G

ENST00000302262.8:c.1222A>G

ENST00000302262.7:c.1222A>G

ENST00000390015.7:c.1222A>G

NM_000152.3:c.1222A>G

NM_001079803.1:c.1222A>G

NM_001079804.1:c.1222A>G

NM_001079803.2:c.1222A>G

NM_001079804.2:c.1222A>G

NM_000152.5:c.1222A>G

NM_001079803.3:c.1222A>G

NM_001079804.3:c.1222A>G

Likely Pathogenic

PP4_Moderate PM2_Supporting PM3 PS3_Supporting

BP4 PP3

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

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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.1222A>G variant in GAA is predicted to result in the substitution of methionine by valine at amino acid 408 (p.Met408Val). Four patients have been reported with this variant; three with infantile onset Pompe disease and documented values showing GAA deficiency, at least two of them treated with enzyme replacement therapy (PMID: 11738358, 26497565, 34995642). Another patient has later onset symptoms with reduction of urine Glc4 on enzyme replacement therapy (PMID: 21687968) (PP4_Moderate). One individual is compound heterozygous for the variant and a variant in GAA that has been classified as pathogenic by the ClinGen Lysosomal Diseases Variant Curation Expert Panel, c.1579del, confirmed in trans (PMID: 34995642) (ClinVar Variation ID: 952947). Another patient is homozygous for the variant (PMID: 26497565). Two patients are compound heterozygous for the variant and either c.1000G>A (p.Gly334Ser) (PMID: 21687968) or c.1408_1410del (PMID: 11738358); the allelic data for these two patients will be used in the classification of the other variant and is not included here to avoid circular logic (PM3). When expressed in COS-7 cells, this variant results in <2% wild type GAA activity (PMID 19862843) (PS3_Supporting). The computational predictor REVEL gives a score of 0.637 which is neither above nor below the thresholds predicting a damaging (>0.7) or benign (<0.5) impact on GAA function. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00002 (2/111716 alleles) in the European, non-Finnish population. There is a ClinVar entry for this variant (Variation ID: 371235). In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease. The classification was first approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on May 26, 2020. Since then, the data for this variant have been re-evaluated. The classification of likely pathogenic was reapproved on May 6, 2024. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PM3, PP4_Moderate, PS3_Supporting, PM2_Supporting.

PP4_Moderate

Four patients have been reported with this variant; three with infantile onset Pompe disease and documented GAA deficiency, at least two of them treated with enzyme replacement therapy (PMID: 11738358, 26497565, 34995642). Another patient has later onset symptoms with reduction of urine Glc4 on enzyme replacement therapy (PMID: 21687968) (PP4_Moderate). Another individual, identified by newborn screening, was heterozygous for the variant and homozygous for pseudodeficiency variants (PMID: 20080426).

PM2_Supporting

The highest population minor allele frequency in gnomAD v2.1.1 is 0.00002 (2/111716 alleles) in the European, non-Finnish population which is lower than the ClinGen Lysosomal Diseases VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting).

PM3

One individual is compound heterozygous for the variant and a variant in GAA that has been classified as pathogenic by the ClinGen Lysosomal Diseases Variant Curation Expert Panel, c.1579del (PMID: 34995642) (ClinVar Variation ID: 952947), confirmed in trans (1 point). Another patient is homozygous for the variant (0.5 points) (PMID: 26497565). Two patients are compound heterozygous for the variant and either c.1000G>A (p.Gly334Ser) (PMID: 21687968) or c.1408_1410del (PMID: 11738358); the allelic data for these patients will be used in the classification of the other variant and is not included here to avoid circular logic. Total 1.5 points (PM3).

PS3_Supporting

This variant results in <2% GAA activity when expressed in COS-7 cells (PMID: 19862843) (PS3_Supporting).

BP4

The computational predictor REVEL gives a score of 0.637 which is neither above nor below the thresholds predicting a damaging (>0.7) or benign (<0.5) impact on GAA function.

PP3

The computational predictor REVEL gives a score of 0.637 which is neither above nor below the thresholds predicting a damaging (>0.7) or benign (<0.5) impact on GAA function.

Curation History

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