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]
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CA891862619

Gene: GAA
Condition: glycogen storage disease II
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: 653d5c53-5922-457b-8ce8-380f486c193e

HGVS expressions

NM_001079804.3:c.1057del
ENST00000302262.8:c.1057del
ENST00000302262.7:c.1057del
ENST00000390015.7:c.1057del
NM_000152.3:c.1057del
NM_001079803.1:c.1057del
NM_001079804.1:c.1057del
NM_000152.4:c.1057del
NM_001079803.2:c.1057del
NM_001079804.2:c.1057del
NM_000152.5:c.1057del
NM_001079803.3:c.1057del
NC_000017.11:g.80108391del
CM000679.2:g.80108391del
NC_000017.10:g.78082190del
CM000679.1:g.78082190del
NC_000017.9:g.75696785del
NG_009822.1:g.11836del

Pathogenic

Met criteria codes 4
PM3_Supporting 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 c.1057del (p.Gln353SerfsTer39) variant in GAA is a frameshift variant predicted to cause a premature stop codon and to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). One patient with this variant displayed clinical features consistent with infantile-onset Pompe disease and was treated with enzyme replacement therapy (PP4_Moderate)(PMID: 29181627). This individual is compound heterozygous for the variant and a pathogenic variant, c.1057del, phase unconfirmed (PM3_Supporting)(PMID 29181627). The variant is absent from gnomAD v2.1.1 (PM2_Supporting). There is no ClinVar entry for this variant. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen LSD VCEP (Specification Version 2.0): PVS1, PP4_Moderate, PM2_Supporting, PM3_Supporting. (Classification approved on August 17th, 2021)
Met criteria codes
PM3_Supporting
This variant has been detected in an individual with Pompe disease who is compound heterozygous for the variant and a variant classified as pathogenic by the ClinGen LSD VCEP, c.784G>A (p.Glu262Lys), phase unconfirmed (PMID 29181627)(0.5 points; PM3_Supporting).
PM2_Supporting
This variant is absent from gnomAD v2.1.1 (PM2_Supporting).
PVS1
The c.1057del (p.Gln353SerfsTer39) variant in GAA is a frameshift variant predicted to cause a premature stop codon and to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1).
PP4_Moderate
One patient has been reported with this variant and displayed clinical features consistent with infantile-onset Pompe disease, including muscle weakness cardiomyopathy (1 point), and was treated with enzyme replacement therapy (1 point) (Total 2 points, PP4_Moderate)(PMID: 29181627).
Approved on: 2021-08-19
Published on: 2021-09-07
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