Variant: NM_000152.5(GAA):c.716del (p.Leu239fs)

CA658795234

556853 (ClinVar)

Gene: GAA

Condition: glycogen storage disease II

Inheritance Mode: Autosomal recessive inheritance

UUID: e32471b6-613c-46e4-a4cd-33dfe10d4b9a

HGVS expressions

NM_000152.5:c.716del
NM_000152.5(GAA):c.716del (p.Leu239fs)
NC_000017.11:g.80107580del
CM000679.2:g.80107580del
NC_000017.10:g.78081379del
CM000679.1:g.78081379del
NC_000017.9:g.75695974del
NG_009822.1:g.11025del
NM_000152.3:c.716del
NM_001079803.1:c.716del
NM_001079804.1:c.716del
NM_000152.4:c.716del
NM_001079803.2:c.716del
NM_001079804.2:c.716del
NM_001079803.3:c.716del
NM_001079804.3:c.716del
ENST00000302262.7:c.716del
ENST00000390015.7:c.716del
ENST00000570803.5:c.716del

Pathogenic

• Met criteria codes: PP4 PM2 PVS1

• Not Met criteria codes: PM3

Expert Panel

Lysosomal Diseases VCEP

Criteria Specification Information

Evidence submitted by expert panel

Lysosomal Diseases VCEP

This variant, c.716delT (p.Leu239ArgfsTer29), is a frameshift variant that is predicted to result in a premature termination codon, nonsense mediated decay, and lack of gene product, meeting PVS1. One patient with this variant meets the ClinGen LSD VCEP’s specifications for PP4. This patient is compound heterozygous for the variant and c.1447G>A (p.Gly483Arg) (PMID 31606152, personal communication). This in trans data will be used in the assessment of p.Gly483Arg and is not included here in order to avoid circular logic. Another patient who is compound heterozygous for the variant has been reported (PMID 14695532). However, residual GAA activity was not provided and this data was not included. Therefore, PM3 is not currently met. This variant is not in gnomAD v2.1.1, meeting PM2. There is a ClinVar entry for this variant (Variation ID: 556853, 2 star review status) with one submitter classifying the variant as pathogenic and two as likely 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: One patient with this variant has Pompe disease and deficient activity in fibroblasts (~0.5%) and dried blood spot, meeting PP4 (PMID 31606152 - personal communication).
• PM2: This variant is not in gnomAD v2.1.1.
• PVS1: This is a frameshift variant which is predicted to result in a premature termination codon, nonsense mediated decay, and lack of gene product. Therefore, PVS1 can be applied.

Not Met criteria codes

• PM3: One patient with this variant meets PP4. This patient is compound heterozygous for the variant and c.1447G>A (p.Gly483Arg) (PMID 31606152, personal communication). This in trans data will be used in the assessment of p.Gly483Arg and is not included here in order to avoid circular logic. Therefore, PM3 is not currently met, but could be met in the future, with additional data.

Approved on: 2020-09-20

Published on: 2020-11-12