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.258dup (p.Asn87fs)

CA8814826

282842 (ClinVar)

Gene: GAA
Condition: glycogen storage disease II
Inheritance Mode: Autosomal recessive inheritance
UUID: 081e8068-c40d-4647-8006-fbecab5b6d86

HGVS expressions

NM_000152.5:c.258dup
NM_000152.5(GAA):c.258dup (p.Asn87fs)
ENST00000302262.8:c.258dup
ENST00000302262.7:c.258dup
ENST00000390015.7:c.258dup
ENST00000570803.5:c.258dup
ENST00000577106.5:c.258dup
NM_000152.3:c.258dup
NM_001079803.1:c.258dup
NM_001079804.1:c.258dup
NM_000152.4:c.258dup
NM_001079803.2:c.258dup
NM_001079804.2:c.258dup
NM_001079803.3:c.258dup
NM_001079804.3:c.258dup
NC_000017.11:g.80104844dup
CM000679.2:g.80104844dup
NC_000017.10:g.78078643dup
CM000679.1:g.78078643dup
NC_000017.9:g.75693238dup
NG_009822.1:g.8289dup

Pathogenic

Met criteria codes 4
PM3 PM2_Supporting PVS1 PP4_Moderate

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Lysosomal Diseases VCEP
The NM_000152.5:c.258dup (p.Asn87GlnfsTer9) variant in GAA is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 2/20, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). At least 10 patients with this variant and reported to have Pompe disease have been reported. This includes two patients with documented laboratory values showing GAA deficiency meeting the ClinGen LSD VCEP’s specifications for PP4_Moderate; one of them on enzyme replacement therapy (PMID 21484825, 31467850), a further 7, at least, patients on enzyme replacement therapy, without documented values for GAA activity, meeting specifications for PP4 (PMID 26873529, 31086307, 31392188, 31676142, 32248831), and additional patients with insufficient details to meet the requirements for PP4 (PMID 10206684, 16917947, 29961517, 30564623). At least 7 patients are compound heterozygous for the variant and a pathogenic variant, c.-32-13T>G, in GAA (PM3). Another two patients are compound heterozygous for the variant and either c.1195-8G>A (PMID 21484825) or c.1115A>T (p.His372Leu) (PMID 31467850). The in trans data from both of these patients will be used in the assessment of the other variant and is, therefore, not included here in order to avoid circular logic. The variant is absent in gnomAD v2.1.1 (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 282842, 2 star review status) with five submitters classifying the variant as pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific GAA criteria met, as specified by the ClinGen LSD VCEP (Specification Version 2.0): PVS1, PM3, PP4_Moderate, PM2_Supporting.
Met criteria codes
PM3
At least 7 patients have been reported who are compound heterozygous for the variant and a pathogenic variant, c.-32-13T>G, in GAA. Based on the ClinGen LSD VCEP’s specifications, a maximum of 2 cases with the same genotype can be counted if the phase is not confirmed (2 x 0.5 points = 1 point). Another two patients are compound heterozygous for the variant and either c.1195–8G>A (PMID 21484825) or c.1115A>T (p.His372Leu) (PMID 31467850). The in trans data from both of these patients will be used in the assessment of the other variant and is, therefore, not included here in order to avoid circular logic. Total 1 point (PM3).
PM2_Supporting
This variant is absent in gnomAD v2.1.1 (PM2_Supporting).
PVS1
The NM_000152.5:c.258dup (p.Asn87GlnfsTer9) variant in GAA is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 2/20, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1).
PP4_Moderate
Two patients with this variant have documented laboratory values showing GAA deficiency meeting the ClinGen LSD VCEP’s specifications for PP4_Moderate; one of these patients is on enzyme replacement therapy (PMID 21484825, 31467850). Another 9 patients are on enzyme replacement therapy, without documented values for GAA activity, meeting specifications for PP4 (PMID 26873529, 31086307, 31392188, 31676142, 32248831). There are additional patients with insufficient details to meet the requirements for PP4 (PMID 10206684, 16917947, 29961517, 30564623).
Approved on: 2021-09-28
Published on: 2021-09-28
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