Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computer assertion could be determined for this classification!

Variant: NM_000152.5:c.1A>T

CA401359799

984798 (ClinVar)

Gene: GAA
Condition: glycogen storage disease II
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: 49d3d2d1-50c1-40a9-ad86-9329acc9d719
Approved on: 2024-09-17
Published on: 2024-09-17

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
ENST00000570803.6:c.1A>T
ENST00000572080.2:c.1A>T
ENST00000577106.6:c.1A>T
ENST00000302262.8:c.1A>T
ENST00000302262.7:c.1A>T
ENST00000390015.7:c.1A>T
ENST00000570803.5:c.1A>T
ENST00000577106.5:c.1A>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
More

Likely Pathogenic

Met criteria codes 4
PM2_Supporting PP4 PVS1_Strong PM3_Supporting

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Lysosomal Storage Disorders Variant Curation Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2

PDF
Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Lysosomal Diseases VCEP
The NM_000152.5:c.1A>T (p.Met1?) variant in GAA may cause a truncated or absent protein by altering the start codon of the coding sequence. The next in-frame methionine is at position 122; if used, the gene product would be missing the signal sequence (PMID 22252923). 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 but 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). Based on the specifications of the ClinGen LD VCEP, PVS1_Strong was applied. The variant is absent in gnomAD v2.1.1 (PM2_Supporting). The variant has been reported in a patient with clinical features consistent with late onset Pompe disease on enzyme replacement therapy (PP4). This patient is compound heterozygous, phase unconfirmed, for the variant and another variant in GAA that has been classified as pathogenic by the ClinGen LD VCEP, c.-32-13T>G (ClinVar Variation ID: 4027) (PMID 27711114, 30022036) (PP4, PM3_Supporting). 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 Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PVS1_Strong, PP4, PM2_Supporting, PM3_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on September 17, 2024)
Met criteria codes
PM2_Supporting
This variant is absent in gnomAD v2.1.1 and v4.1.0 (PM2_Supporting).
PP4
One patient has been reported with the variant and late onset Pompe disease, on enzyme replacement therapy (PMID: 27711114) (PP4).
PVS1_Strong
The NM_000152.5:c.1A>T (p.Met1?) variant in GAA may cause a truncated or absent protein by altering the start codon of the coding sequence. The next in-frame methionine is at position 122; if used, the gene product would be missing the signal sequence (PMID 22252923). 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 but 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). Based on the specifications of the ClinGen LD VCEP, PVS1_Strong was applied.
PM3_Supporting
One patient has been reported who is compound heterozygous for the variant and a known pathogenic variant in GAA, c.-32-13T>G (ClinVar Variation ID: 4027) (PMID: 27711114). However, the phase is not known (0.5 points) (PM3_Supporting).
Curation History
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