Variant: NM_000152.5(GAA):c.1375G>A (p.Asp459Asn)

CA198786

188480 (ClinVar)

Gene: GAA

Condition: glycogen storage disease II

Inheritance Mode: Autosomal recessive inheritance

UUID: a13f5909-eb8f-4d45-a198-4758c4612e8e

Approved on: 2024-03-05

Published on: 2024-03-28

HGVS expressions

NM_000152.5:c.1375G>A
NM_000152.5(GAA):c.1375G>A (p.Asp459Asn)
NC_000017.11:g.80109993G>A
CM000679.2:g.80109993G>A
NC_000017.10:g.78083792G>A
CM000679.1:g.78083792G>A
NC_000017.9:g.75698387G>A
NG_009822.1:g.13438G>A
ENST00000570803.6:c.1375G>A
ENST00000572080.2:c.1375G>A
ENST00000577106.6:c.1375G>A
ENST00000302262.8:c.1375G>A
ENST00000302262.7:c.1375G>A
ENST00000390015.7:c.1375G>A
NM_000152.3:c.1375G>A
NM_001079803.1:c.1375G>A
NM_001079804.1:c.1375G>A
NM_000152.4:c.1375G>A
NM_001079803.2:c.1375G>A
NM_001079804.2:c.1375G>A
NM_001079803.3:c.1375G>A
NM_001079804.3:c.1375G>A

Uncertain Significance

• Met criteria codes: PP4_Moderate PM2_Supporting PM3

• Not Met criteria codes: BP4 PP3

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.1375G>A variant in GAA is a missense variant predicted to cause substitution of Asp by Asn at amino acid 459 (p.Asp459Asn). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00041 (14/34538 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). At least 4 patients have been identified with this variant. Two had documented GAA deficiency, one with <30% of normal mean control level of GAA activity in skin fibroblasts (PMID: 21757382; 18458862) and one within affected range in dried blood spot (Clinical diagnostic laboratory). (PP4_Moderate). Of these patients, one was compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic by the ClinGen Lysosomal Diseases Variant Curation Expert Panel, and confirmed to be in trans, c.2173C>T (p.Arg725Trp) (ClinVar Variation ID: 4024, SCV004227911.1). 1 point (PM3). Additional patients had evidence of pseudodeficiency variants with (PMID: 21484825, 28302345). The computational predictor REVEL gives a score of 0.531 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: 188480). 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, PP4_Moderate, PM3. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on March 5, 2024).

Met criteria codes

• PP4_Moderate: At least 1 patient(s) with this variant had documented GAA deficiency with <30% of normal mean control level of GAA activity in skin fibroblasts (PMID: 21757382; 18458862) or within affected range by NBS (Duke). Thus met PP4_Moderate.
• PM2_Supporting: The highest population minor allele frequency in gnomAD v2.1.1 is 0.00041 (14/34538 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).
• PM3: This variant has been detected in at least 4 individuals with Pompe disease (Duke data; Pubmed ID: 21757382, 28302345, 21484825, 18458862). Of these patients, one was compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic by the ClinGen Lysosomal Diseases Variant Curation Expert Panel, and confirmed to be in trans, c.2173C>T (p.Arg725Trp) (ClinVar Variation ID: 4024, SCV004227911.1). 1 point (PM3).

Not Met criteria codes

• BP4: The computational predictor REVEL gives a score of 0.531 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 0.531 which is neither above nor below the thresholds predicting a damaging (>0.7) or benign (<0.5) impact on GAA function.