NM_000152.5:c.399C>A

CA401361056

Gene: GAA

Condition: glycogen storage disease II

Inheritance Mode: Autosomal recessive inheritance

UUID: 31db1a86-3a2d-4b40-ad3e-b72a3a3e4511

HGVS expressions

NM_000152.5:c.399C>A
NM_000152.3:c.399C>A
NM_001079803.1:c.399C>A
NM_001079804.1:c.399C>A
NM_000152.4:c.399C>A
NM_001079803.2:c.399C>A
NM_001079804.2:c.399C>A
NM_001079803.3:c.399C>A
NM_001079804.3:c.399C>A
ENST00000302262.7:c.399C>A
ENST00000390015.7:c.399C>A
ENST00000570803.5:c.399C>A
ENST00000577106.5:c.399C>A
NC_000017.11:g.80104985C>A
CM000679.2:g.80104985C>A
NC_000017.10:g.78078784C>A
CM000679.1:g.78078784C>A
NC_000017.9:g.75693379C>A
NG_009822.1:g.8430C>A

Pathogenic

• Met criteria codes: PP4 PM2 PVS1 PM3_Supporting

Expert Panel

Lysosomal Diseases VCEP

Criteria Specification Information

Evidence submitted by expert panel

Lysosomal Diseases VCEP

This variant, c.399C>A (p.Tyr133Ter), is a nonsense variant that is predicted to result in nonsense mediated decay and absence of gene product, meeting PVS1. When expressed in COS-1 cells, the variant results in no GAA activity and the mutant protein cannot be detected on Western blot, (PMID 14972326) supporting that it is a loss of function variant. The variant is absent in gnomAD v2.1.1, meeting PM2. A patient with infantile onset Pompe disease meeting the ClinGen LSD VCEP’s specifications for PP4 has been reported who is homozygous for the variant; both parents were confirmed to be heterozygotes (PMID 14972326), meeting PM3_Supporting. There is no ClinVar entry for this varint. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1, PM2, PM3_Supporting, PP4.

Met criteria codes

• PP4: Proband 1 has infantile onset Pompe disease and was reported who is homozygous for this variant. She has no detectable GAA activity in cultured fibroblasts (PMID 14972326). This meets the specifications for PP4.
• PM2: This variant is not in gnomAD v2.1.1.
• PVS1: This is a nonsense variant which is predicted to cause nonsense mediated decay resulting in no gene product. Therefore, PVS1 can be applied.
• PM3_Supporting: A patient with infantile onset Pompe disease and no detectable GAA activity in cultured fibroblasts (meeting PP4) was reported to be homozygous for this variant; both parents were confirmed to be heterozygotes (PMID 14972326). Based on the ClinGen LSD VCEP's specifications, this data was given a total of 0.5 points, which meets PM3_Supporting.

Approved on: 2020-02-14

Published on: 2020-05-28