Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_000152.4(GAA):c.1687C>T (p.Gln563Ter)

CA16041895

370357 (ClinVar)

Gene: GAA (HGNC:2548)

Condition: glycogen storage disease II (MONDO:0009290)

Inheritance Mode: Autosomal recessive inheritance

UUID: 779d712a-8d04-4013-8f4b-68f5464ecb1b

Approved on: 2020-02-14

Published on: 2020-05-26

HGVS expressions

NM_000152.4(GAA):c.1687C>T (p.Gln563Ter)

NM_000152.4:c.1687C>T

NC_000017.11:g.80112033C>T

CM000679.2:g.80112033C>T

NC_000017.10:g.78085832C>T

CM000679.1:g.78085832C>T

NC_000017.9:g.75700427C>T

NG_009822.1:g.15478C>T

NM_000152.3:c.1687C>T

NM_001079803.1:c.1687C>T

NM_001079804.1:c.1687C>T

NM_001079803.2:c.1687C>T

NM_001079804.2:c.1687C>T

NM_000152.5:c.1687C>T

NM_001079803.3:c.1687C>T

NM_001079804.3:c.1687C>T

ENST00000302262.7:c.1687C>T

ENST00000390015.7:c.1687C>T

ENST00000572080.1:n.75C>T

ENST00000572803.1:n.301C>T

Pathogenic

PM2 PM3 PVS1 PP4

Evidence Links 2

Expert Panel

Lysosomal Diseases VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Lysosomal Diseases VCEP

This variant, c.1687C>T (p.Gln563Ter), is a nonsense variant that is predicted to result in nonsense-mediated decay and lack of gene product. Therefore, PVS1 can be applied. This variant is absent in gnomAD v2.1.1, meeting PM2. It has been reported in trans with a frameshift variant in GAA, c.722_723delTT, in an individual who meets the ClinGen LSD VCEP’s specifications for PP4 (PMID 19775921). This data meets PP4 and PM3. Additional patients with this variant have been reported but were not included because the residual GAA activity was not reported and therefore PP4 cannot be assessed (PMID 25741864). There is a ClinVar entry for this variant (Variation ID: 370357, one star review status) with one submitter classifying the variant as likely pathogenic. 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, PP4.

PM2

This variant is absent in gnomAD v2.1.1.

PM3

This variant was found in compound heterozygosity with a unique pathogenic variant in GAA, c.722_723delTT, in one patient with Pompe disease who also meets the ClinGen LSD VCEP's PP4 specifications. The phase was confirmed as in trans. Based on the ClinGen LSD VCEP's guidelines, this data was given a total of 1 point, which meets PM3.

PubMed:25741864

PubMed:19775921

PVS1

This is a nonsense variant which is predicted to cause nonsense mediated decay resulting in no gene product.

PP4

1 individual has been reported with this variant and GAA activity <10% normal in lymphocytes, leukocytes or muscle samples. This meets the criteria for PP4.

Patient has <1% of normal GAA activity (in skin fibroblasts and/or muscle biopsy). PubMed:19775921

Curation History

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