Variant: NM_000152.5(GAA):c.1326+1G>A

CA401365436

597944 (ClinVar)

Gene: GAA

Condition: glycogen storage disease II

Inheritance Mode: Autosomal recessive inheritance

UUID: 80a3c16d-9b7a-4a55-98de-bbb6d5a6dbcb

Approved on: 2022-10-17

Published on: 2022-12-21

HGVS expressions

NM_000152.5(GAA):c.1326+1G>A
NM_000152.5:c.1326+1G>A
NC_000017.11:g.80108829G>A
CM000679.2:g.80108829G>A
NC_000017.10:g.78082628G>A
CM000679.1:g.78082628G>A
NC_000017.9:g.75697223G>A
NG_009822.1:g.12274G>A
ENST00000302262.8:c.1326+1G>A
ENST00000302262.7:c.1326+1G>A
ENST00000390015.7:c.1326+1G>A
NM_000152.3:c.1326+1G>A
NM_001079803.1:c.1326+1G>A
NM_001079804.1:c.1326+1G>A
NM_000152.4:c.1326+1G>A
NM_001079803.2:c.1326+1G>A
NM_001079804.2:c.1326+1G>A
NM_001079803.3:c.1326+1G>A
NM_001079804.3:c.1326+1G>A

Pathogenic

• Met criteria codes: PP4_Moderate PVS1 PM2_Supporting

• Not Met criteria codes: 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.1326+1G>A variant in GAA is a canonical splice site variant in the donor splice site of intron 8. RT-PCR evidence suggests that the variant results in nonsense-mediated decay (PMID: 10189220) (PVS1). Two African-American patients with infantile-onset Pompe disease have been reported with this variant. GAA activity is available for one of these patients and was 0.35% in fibroblasts (PMID: 10189220) (PP4_Moderate). These patients are compound heterozygous for the variant and either c.1441T>C (p.Trp481Arg) or c.1555A>G (p.Met519Val) (PMID: 10189220, 25256446). The allelic data from these patients will be used in the classification of the second variant and is not included here to avoid circular logic. Therefore, PM3 is not met at the current time. The highest population minor allele frequency in gnomAD v2.1.1 is 0.000114 (1/8708 alleles) in the African/ African American population, which is lower than the ClinGen LSD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). There is ClinVar entry to this variant (Variant ID: 597944). In summary, this variant meets the criteria to be classified as Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by ClinGen Lysosomal Storage Disorders Variant Curation Expert Panel (Specifications Version 2.0): PVS1, PP4_moderate, PM2_supporting. (Classification approved by the ClinGen LSD VCEP on October 17, 2022).

Met criteria codes

• PP4_Moderate: Two African-American patients with infantile-onset Pompe disease have been reported with this variant. GAA activity is available for one of these patients and was 0.35% in fibroblasts (PMID: 10189220) (PP4_Moderate).
• PVS1: The NM_000152.5:c.1326+1G>A variant in GAA is a canonical splice site variant in the donor splice site of intron 8. RT-PCR evidence suggests that the variant results in nonsense-mediated decay (PMID: 10189220) (PVS1)
• PM2_Supporting: The highest population minor allele frequency in gnomAD v2.1.1 is 0.000114 (1/8708 alleles) in the African/ African American population, which is lower than the ClinGen LSD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting).

Not Met criteria codes

• PM3: Two African-American patients have been reported who are compound heterozygous for the variant and either c.1441T>C (p.Trp481Arg) or c.1555A>G (p.Met519Val) (PMID: 10189220, 25256446). The allelic data from these patients will be used in the classification of the second variant and is not included here to avoid circular logic. Therefore, PM3 is not met at the current time.