NM_000152.5:c.1A>T

CA401359799

Gene: GAA

Condition: glycogen storage disease II

Inheritance Mode: Autosomal recessive inheritance

UUID: 49d3d2d1-50c1-40a9-ad86-9329acc9d719

HGVS expressions

NM_000152.5:c.1A>T
NC_000017.11:g.80104587A>T
CM000679.2:g.80104587A>T
NC_000017.10:g.78078386A>T
CM000679.1:g.78078386A>T
NC_000017.9:g.75692981A>T
NG_009822.1:g.8032A>T
NM_000152.3:c.1A>T
NM_001079803.1:c.1A>T
NM_001079804.1:c.1A>T
NM_000152.4:c.1A>T
NM_001079803.2:c.1A>T
NM_001079804.2:c.1A>T
NM_001079803.3:c.1A>T
NM_001079804.3:c.1A>T
ENST00000302262.7:c.1A>T
ENST00000390015.7:c.1A>T
ENST00000570803.5:c.1A>T
ENST00000577106.5:c.1A>T

Likely Pathogenic

• Met criteria codes: PVS1_Strong PM2

Expert Panel

Lysosomal Diseases VCEP

Criteria Specification Information

Evidence submitted by expert panel

Lysosomal Diseases VCEP

The c.1A>T (p.Met1?) variant affects the initiator codon of GAA and is predicted to abolish the start codon. The next in-frame methionine is at position 122 but the likelihood of this start site being used is low and, even if used, the gene product would be missing the signal sequence (PMID 22252923). PVS1_Strong was applied based on the specifications of the ClinGen LSD VCEP. When expressed in HEK293T cells, a very low level of an approximately 85 kD protein was seen on Western blot, suggesting the use of a downstream ATG in this in vitro system. There was no detectable GAA activity in the cells (PMID 22644586). There is also evidence that this variant may result in skipping of exon 2 in about 40-50% of transcripts when compared to wild type (PMID: 31301153). The variant is absent in gnomAD v2.1.1, meeting PM2. The variant has been reported in a patient with late onset Pompe disease who is compound heterozygous for the variant and c.-32-13T>G (PMID 27711114, 30022036). However, the residual GAA activity was not provided, and therefore PP4 cannot be assessed and PM3 was not applied. This variant is not in ClinVar. Of note, additional initiator codon variants, including c.1A>G, c.2T>C, and c.3G>A, have been reported in patients with Pompe disease (see http://www.pompevariantdatabase.nl/). In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1_Strong, PM2.

Met criteria codes

• PVS1_Strong: c.1A>T is an initiator codon variant that is predicted to abolish the start codon (p.Met1?). The next in-frame methionine is at position 122 but the likelihood of this start site being used is low and, even if used, the gene product would be missing the signal sequence (PMID 22252923). Therefore, PVS1_Strong can be applied. When expressed in HEK293T cells, a very low level of an approximately 85 kD protein was seen on Western blot, suggesting the use of a downstream ATG in this in vitro system. There was no detectable GAA activity in the cells (PMID 22644586). There is also evidence that this variant may result in skipping of exon 2 in about 40-50% of transcripts when compared to wild type (PMID: 31301153).
• PM2: This variant is absent in gnomAD v2.1.1.

Approved on: 2020-06-16

Published on: 2020-11-11