Variant: NM_000152.5(GAA):c.1082C>G (p.Pro361Arg)

CA10606426

289367 (ClinVar)

Gene: GAA

Condition: glycogen storage disease II

Inheritance Mode: Autosomal recessive inheritance

UUID: 47ad62d9-cb93-4314-abed-a72383fae6e2

Approved on: 2023-11-21

Published on: 2023-12-07

HGVS expressions

NM_000152.5:c.1082C>G
NM_000152.5(GAA):c.1082C>G (p.Pro361Arg)
NC_000017.11:g.80108495C>G
CM000679.2:g.80108495C>G
NC_000017.10:g.78082294C>G
CM000679.1:g.78082294C>G
NC_000017.9:g.75696889C>G
NG_009822.1:g.11940C>G
ENST00000302262.8:c.1082C>G
ENST00000302262.7:c.1082C>G
ENST00000390015.7:c.1082C>G
NM_000152.3:c.1082C>G
NM_001079803.1:c.1082C>G
NM_001079804.1:c.1082C>G
NM_000152.4:c.1082C>G
NM_001079803.2:c.1082C>G
NM_001079804.2:c.1082C>G
NM_001079803.3:c.1082C>G
NM_001079804.3:c.1082C>G

Likely Pathogenic

• Met criteria codes: PP3 PP4_Moderate PM2_Supporting PM5 PM3

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

Evidence submitted by expert panel

Lysosomal Diseases VCEP

The NM_000152.5:c.1082C>G variant in GAA is a missense variant predicted to cause substitution of proline by arginine at amino acid 361 (p.Pro361Arg). This variant has been observed in the literature in two cases consistent with late-onset Pompe disease (PMID: 30312517, 32012848) with documented GAA deficiency. Both met PP4 specifications (PP4_Moderate), in compound heterozygosity with the known pathogenic variant c.-32-13T>G, phase not confirmed (PM3). The highest population minor allele frequency in gnomAD v4.0.0 is 0.0000008993 (1/1111956 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). The computational predictor REVEL gives a score of 0.945 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Another missense variant (c.1082C>T, p.Pro361Leu) (ClinVar Variation ID: 403712) in the same codon has been classified as pathogenic for Pompe disease by the ClinGen Lysosomal Diseases VCEP (PM5). There is a ClinVar entry for this variant (Variation ID: 289367, 1-star review status) with 2 submitter, classifying this variant as a VUS. 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): PP4_Moderate, PM3, PM2_Supporting, PP3, PM5. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on November 21, 2023).

Met criteria codes

• PP3: The computational predictor REVEL gives a score of 0.945 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3).
• PP4_Moderate: At least two patient(s) with this late-onset Pompe disease and variant had documented GAA deficiency. (PMID: 30312517, 32012848). (PP4_Moderate).
• PM2_Supporting: The highest population minor allele frequency in gnomAD v4.0.0 is 0.0000008993 (1/1111956 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).
• PM5: Another missense variant [c.1082C>T, p.Pro361Leu] [ClinVar Variation ID: 403712] in the same codon has been classified as pathogenic for Pompe disease by the ClinGen Lysosomal Diseases VCEP (PM5).
• PM3: This variant has been detected in two individuals with late-onset Pompe disease. Both individuals were compound heterozygous for this variant and a known pathogenic variant [c.-32-13T>G]. Phase is unknown. (PM3)