Variant: NM_000152.5(GAA):c.236_246del (p.Pro79fs)

CA16041880

371302 (ClinVar)

Gene: GAA

Condition: glycogen storage disease II

Inheritance Mode: Autosomal recessive inheritance

UUID: dc90ac1d-ebd6-428f-bb4a-d24b6f97f6a9

HGVS expressions

NM_000152.5:c.236_246del
NM_000152.5(GAA):c.236_246del (p.Pro79fs)
NC_000017.11:g.80104822_80104832del
CM000679.2:g.80104822_80104832del
NC_000017.10:g.78078621_78078631del
CM000679.1:g.78078621_78078631del
NC_000017.9:g.75693216_75693226del
NG_009822.1:g.8267_8277del
NM_000152.3:c.236_246del
NM_001079803.1:c.236_246del
NM_001079804.1:c.236_246del
NM_000152.4:c.236_246del
NM_001079803.2:c.236_246del
NM_001079804.2:c.236_246del
NM_001079803.3:c.236_246del
NM_001079804.3:c.236_246del
ENST00000302262.7:c.236_246del
ENST00000390015.7:c.236_246del
ENST00000570803.5:c.236_246del
ENST00000577106.5:c.236_246del

Pathogenic

• Met criteria codes: PVS1 PP4 PM2 PM3

Expert Panel

Lysosomal Diseases VCEP

Criteria Specification Information

Evidence submitted by expert panel

Lysosomal Diseases VCEP

This variant, c.236_246del (p.Pro79ArgfsTer13), has been reported in multiple patients with Pompe disease. For two of these patients, residual GAA activity is reported and meets the ClinGen LSD VCEP's specifications for PP4 (PMID 17056254, 30778879). Both of these patients are compound heterozygous for the variant and a unique pathogenic variant; one with c.377G>A (p.Trp126Ter), in trans (PMID 17056254), and the other with c.1655T>C (p.Leu552Pro), phase unknown (PMID 30778879). This data meets PM3. Additional cases, both homozygous and compound heterozygous, have been reported but were not included because the residual GAA activity was not provided, and therefore PP4 cannot be assessed (PMIDs, 19588081, 22194990, 22980766, 23825616, 25998610, 26913919, 29143201, 30022036, 32125626). There is a ClinVar entry for this variant (Variation ID: 371302, 1 star review status) with 1 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 applied, as specified by the ClinGen LSD VCEP: PVS1, PM2, PM3, PP4.

Met criteria codes

• 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.
• PP4: Two individuals have been reported with this variant and GAA activity in the affected range when compared to the laboratory’s control range (PMIDs 17056254, 30778879) . This meets the criteria for PP4.
• PM2: This variant is absent in gnomAD v2.1.1, meeting PM2.
• PM3: This variant was found in compound heterozygosity with a unique pathogenic variant in GAA in 2 patients with Pompe disease who also meet the ClinGen LSD VCEP's PP4 specifications, with either c.377G>A (p.Trp126Ter), in trans (PMID 17056254), or c.1655T>C (p.Leu552Pro), phase unknown (PMID 30778879). Based on the ClinGen LSD VCEP's specifications, this data was given a total of 1.5 points which meets PM3. Additional cases, both homozygous and compound heterozygous, have been reported but were not included because the residual GAA activity was not provided, and therefore PP4 cannot be assessed (PMIDs, 19588081, 22194990, 22980766, 23825616, 25998610, 26913919, 29143201, 30022036, 32125626).

Approved on: 2020-06-16

Published on: 2020-11-11