Variant: NM_000152.5(GAA):c.546+5G>A

CA8814900

2151633 (ClinVar)

Gene: GAA

Condition: glycogen storage disease II

Inheritance Mode: Autosomal recessive inheritance

UUID: 929e0f6e-ab84-4745-940b-ae8a3ea39300

HGVS expressions

NM_000152.5:c.546+5G>A
NM_000152.5(GAA):c.546+5G>A
NC_000017.11:g.80105137G>A
CM000679.2:g.80105137G>A
NC_000017.10:g.78078936G>A
CM000679.1:g.78078936G>A
NC_000017.9:g.75693531G>A
NG_009822.1:g.8582G>A
ENST00000302262.8:c.546+5G>A
ENST00000302262.7:c.546+5G>A
ENST00000390015.7:c.546+5G>A
ENST00000570803.5:c.546+5G>A
ENST00000577106.5:c.546+5G>A
NM_000152.3:c.546+5G>A
NM_001079803.1:c.546+5G>A
NM_001079804.1:c.546+5G>A
NM_000152.4:c.546+5G>A
NM_001079803.2:c.546+5G>A
NM_001079804.2:c.546+5G>A
NM_001079803.3:c.546+5G>A
NM_001079804.3:c.546+5G>A

Uncertain Significance

• Met criteria codes: PM2_Supporting PP3 PM3

• Not Met criteria codes: PP4

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.546+5G>A variant is in intron 2 of GAA. This variant has been detected in one patient with Pompe disease reported to have deficient GAA activity, but results and clinical information were not provided. This variant has also been reported in one individual with a positive newborn screen for Pompe disease and confirmed deficient GAA enzyme in DBS; while this technically meets criteria for PP4_moderate, we cannot apply this evidence code as there has not been a confirmed phenotype in this individual. This individual was compound heterozygous for this variant and the common c.-32-13T>G variant confirmed in trans (PM3). The highest population minor allele frequency in gnomAD v4.0 is 0.00006714 (5/74860 alleles) in the African/African-American subpopulation, which is lower than the ClinGen Lysosomal Disorders VCEP's threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). The computational splicing predictor SpliceAI gives a score of 0.57 for donor loss, predicting that the variant disrupts the donor splice site of intron 2 of GAA (PP3). There is another variant at the same location with a different amino acid change (NM_000152.5:c.546+5G>T) classified as a variant of uncertain significance by the ClinGen Lysosomal Disorders VCEP. There is a ClinVar entry for this variant (Variation ID: 2151633, 2 star review status) with two submitters classifying the variant as a uncertain significance. In summary, this variant has been classified as a VUS for Pompe disease by the ClinGen Lysosomal Disorders VCEP. GAA-Specific ACMG-AMP criteria applied, as specified by the ClinGen LSD VCEP (Specifications Version 2.0): PM3, PM2_Supporting, PP3. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 5, 2023).

Met criteria codes

• PM2_Supporting: The highest population minor allele frequency in gnomAD v4.0.0 is 0.000067 (5/74806 alleles) in the African/African-American subpopulation, which is lower than the ClinGen Lysosomal Diseases VCEP's threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting).
• PP3: The computational splicing predictor SpliceAI gives a score of 0.57] for donor loss, predicting that the variant disrupts the donor splice site of intron 2 of GAA (PP3).
• PM3: This variant has been detected in one individual with Pompe disease who was compound heterozygous for the variant and a pathogenic variant (c.-32-13T>G) confirmed in trans via maternal testing.

Not Met criteria codes

• PP4: One patient with this variant had reported GAA deficiency was noted to have deficient GAA activity but results were not provided. (0.5 pts for PP4)

Approved on: 2023-12-05

Published on: 2023-12-07