Variant: NM_000152.5(GAA):c.2655_2656del (p.Val886fs)

CA913191011

597005 (ClinVar)

Gene: GAA

Condition: glycogen storage disease II

Inheritance Mode: Autosomal recessive inheritance

UUID: 73dc276a-44f8-4f4e-ad99-3769378ea110

Approved on: 2021-09-01

Published on: 2021-09-28

HGVS expressions

NM_000152.5:c.2655_2656del
NM_000152.5(GAA):c.2655_2656del (p.Val886fs)
ENST00000302262.8:c.2655_2656del
ENST00000302262.7:c.2655_2656del
ENST00000390015.7:c.2655_2656del
ENST00000573556.1:n.608_609del
NM_000152.3:c.2655_2656del
NM_001079803.1:c.2655_2656del
NM_001079804.1:c.2655_2656del
NM_000152.4:c.2655_2656del
NM_001079803.2:c.2655_2656del
NM_001079804.2:c.2655_2656del
NM_001079803.3:c.2655_2656del
NM_001079804.3:c.2655_2656del
NC_000017.11:g.80118661_80118662del
CM000679.2:g.80118661_80118662del
NC_000017.10:g.78092460_78092461del
CM000679.1:g.78092460_78092461del
NC_000017.9:g.75707055_75707056del
NG_009822.1:g.22106_22107del

Pathogenic

• Met criteria codes: PM3_Supporting PP4_Moderate PM2_Supporting PVS1

Expert Panel

Lysosomal Diseases VCEP

Criteria Specification Information

Evidence submitted by expert panel

Lysosomal Diseases VCEP

The NM_000152.5:c.2655_2656del (p.Val886GlufsTer2) 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). Two siblings with this variant and late-onset Pompe disease have been reported with GAA activity in dried blood spots below the normal range, and both are on enzyme replacement therapy (PMID 31392188, personal communication)(PP4_Moderate). These individuals are compound heterozygous for the variant and a pathogenic variant in GAA, c.-32-13T>G, phase unknown (PM3_Supporting). The variant is absent in gnomAD v2.1.1 (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 597005; 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 met, based on the specifications of the ClinGen LSD VCEP (Specifications Version 2.0): PVS1, PP4_Moderate, PM2_Supporting, PM3_Supporting.

Met criteria codes

• PM3_Supporting: Two siblings with late-onset Pompe disease are compound heterozygous for the variant and c.-32-13T>G, a known pathogenic variant in GAA (PMID 31392188). The phase is unknown. Total 0.5 points (PM3_Supporting).
• PP4_Moderate: Two siblings with Pompe disease who are compound heterozygous have documented GAA activity in dried blood spot below the normal range, and both are on enzyme replacement therapy (PMID 31392188, personal communication)meeting the ClinGen LSD VCEP's specifications for PP4_Moderate.
• PM2_Supporting: This variant is absent in gnomAD v2.1.1 (PM2_Supporting).
• PVS1: The NM_000152.5:c.2655_2656del (p.Val886GlufsTer2) 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).