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

  • See Evidence submitted by expert panel for details.

Variant: NM_000152.5(GAA):c.2512C>T (p.Gln838Ter)

CA220400

92479 (ClinVar)

Gene: GAA
Condition: glycogen storage disease II
Inheritance Mode: Autosomal recessive inheritance
UUID: 044f7823-3980-446c-97fd-236867eecdaf

HGVS expressions

NM_000152.5:c.2512C>T
NM_000152.5(GAA):c.2512C>T (p.Gln838Ter)
NC_000017.11:g.80118223C>T
CM000679.2:g.80118223C>T
NC_000017.10:g.78092022C>T
CM000679.1:g.78092022C>T
NC_000017.9:g.75706617C>T
NG_009822.1:g.21668C>T
NM_000152.3:c.2512C>T
NM_001079803.1:c.2512C>T
NM_001079804.1:c.2512C>T
NM_000152.4:c.2512C>T
NM_001079803.2:c.2512C>T
NM_001079804.2:c.2512C>T
NM_001079803.3:c.2512C>T
NM_001079804.3:c.2512C>T
ENST00000302262.7:c.2512C>T
ENST00000390015.7:c.2512C>T
ENST00000573556.1:n.465C>T

Pathogenic

Met criteria codes 3
PP4 PM2 PVS1

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Lysosomal Diseases VCEP
This variant, c.2512C>T (p.Gln838Ter), is a nonsense variant that is predicted to result in nonsense mediated decay and lack of gene product, meeting PVS1. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006 in the African population, meeting PM2. It has been reported in two siblings with infantile onset Pompe disease who meet the ClinGen LSD VCEP’s specifications for PP4, and who are compound heterozygous for the variant and c.2105G>T (p.Arg702Leu) (PMID 26167453). However, this in trans data will be used in the assessment of p.Arg702Leu and is not included here in order to avoid a circular argument. Another patient, with limb girdle muscular dystrophy, has been reported to be compound heterozygous for the variant and c.-32-13T>G. However, residual GAA activity was not provided, and therefore this data was not included (PMID 30564623). There is a ClinVar entry for this variant (Variation ID: 92479, 1 star review status) with one submitter classifying the variant as 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, PP4.
Met criteria codes
PP4
Two siblings are reported with GAA activity ≤1% of normal GAA activity (in skin fibroblasts and/or muscle biopsy, meeting the specifications for PP4.
PM2
The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006 (African) which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2, meeting this criterion.
PVS1
This is a nonsense variant which is predicted to cause nonsense mediated decay resulting in no gene product. Therefore, PVS1 can be applied.
Approved on: 2020-05-04
Published on: 2020-05-27
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