NM_000152.5:c.722_723del

CA658795235

Gene: GAA

Condition: glycogen storage disease II

Inheritance Mode: Autosomal recessive inheritance

UUID: 1b742d4e-033e-469e-b02a-e368ad095141

HGVS expressions

NM_000152.5:c.722_723del
NC_000017.11:g.80107586_80107587del
CM000679.2:g.80107586_80107587del
NC_000017.10:g.78081385_78081386del
CM000679.1:g.78081385_78081386del
NC_000017.9:g.75695980_75695981del
NG_009822.1:g.11031_11032del
NM_000152.3:c.722_723del
NM_001079803.1:c.722_723del
NM_001079804.1:c.722_723del
NM_000152.4:c.722_723del
NM_001079803.2:c.722_723del
NM_001079804.2:c.722_723del
NM_001079803.3:c.722_723del
NM_001079804.3:c.722_723del
ENST00000302262.7:c.722_723del
ENST00000390015.7:c.722_723del
ENST00000570803.5:c.722_723del

Pathogenic

• Met criteria codes: PVS1 PP4 PM2 PM3_Strong

Expert Panel

Lysosomal Diseases VCEP

Criteria Specification Information

Evidence submitted by expert panel

Lysosomal Diseases VCEP

This variant, c.722_723del (p.Phe241CysfsTer), is a frameshift variant that is predicted to result in a premature termination codon, 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 found in at least two patients with Pompe disease who meet the ClinGen LSD VCEP’s specifications for PP4 (PMID 19775921). One of these patients is compound heterozygous for the variant and c.1687C>T (p.Gln563Ter), and the other is compound heterozygous for the variant and c.1754+1G>A. In both cases, the variants were confirmed to be in trans. This data meets PM3_Strong. Additional cases have been reported, but did not meet PP4 (PMID 28838325). 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 applied, as specified by the ClinGen LSD VCEP: PVS1, PM2, PM3_Strong, PP4.

Met criteria codes

• PVS1: This is a frameshift variant which is predicted to result in a premature termination codon and nonsense mediated decay resulting in no gene product.
• PP4: This variant has been found in at least two patients with <1% residual GAA activity in skin fibroblasts (PMID 19775921) meeting the ClinGen LSD VCEP's specifications for PP4.
• PM2: This variant is absent in gnomAD v2.1.1.
• PM3_Strong: This variant has been found in at least two patients with Pompe disease who meet the ClinGen LSD VCEP’s specifications for PP4 (PMID 19775921). One of these patients is compound heterozygous for the variant and c.1687C>T (p.Gln563Ter), and the other is compound heterozygous for the variant and c.1754+1G>A. In both cases, the variants were confirmed to be in trans. One point was given to each case (total 2 points), meeting PM3_Strong.

Approved on: 2020-01-21

Published on: 2020-05-26