Variant: NM_000152.5(GAA):c.379_380del (p.Cys127fs)

CA658795227

552747 (ClinVar)

Gene: GAA

Condition: glycogen storage disease II

Inheritance Mode: Autosomal recessive inheritance

UUID: a8a843c7-778f-4800-880e-7a226f2c5d60

HGVS expressions

NM_000152.5:c.379_380del
NM_000152.5(GAA):c.379_380del (p.Cys127fs)
NC_000017.11:g.80104965_80104966del
CM000679.2:g.80104965_80104966del
NC_000017.10:g.78078764_78078765del
CM000679.1:g.78078764_78078765del
NC_000017.9:g.75693359_75693360del
NG_009822.1:g.8410_8411del
ENST00000302262.8:c.379_380del
ENST00000302262.7:c.379_380del
ENST00000390015.7:c.379_380del
ENST00000570803.5:c.379_380del
ENST00000577106.5:c.379_380del
NM_000152.3:c.379_380del
NM_001079803.1:c.379_380del
NM_001079804.1:c.379_380del
NM_000152.4:c.379_380del
NM_001079803.2:c.379_380del
NM_001079804.2:c.379_380del
NM_001079803.3:c.379_380del
NM_001079804.3:c.379_380del

Pathogenic

• Met criteria codes: PM2_Supporting PM3_Strong PVS1 PP4_Moderate

Expert Panel

Lysosomal Diseases VCEP

Criteria Specification Information

Evidence submitted by expert panel

Lysosomal Diseases VCEP

NM_000152.5:c.379_380del (p.Cys127LeufsTer18) variant in GAA is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 2/20, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). At least 4 patients with Pompe disease and this variant have been reported that meet the ClinGen LSD VCEP’s specifications for PP4_Moderate. Of these patients, the available data includes documentation of laboratory values showing GAA deficiency (PMIDs 18757064, 24245577, 24715333, 30049495, 33162552). Furthermore, one of these patients had documented features consistent with infantile onset Pompe disease (PMID 24715333, 33162552) and another was on enzyme replacement therapy (PMID 30049495)(PP4_Moderate). These patients are all compound heterozygous for the variant and another pathogenic variant in GAA, phase unknown, including c.525delT (PMID 24715333, 33162552), “del exon 18” (PMID 9660056), and c.-32-13T>G (PMID 17573812, 17643989, 18757064, 24245577, 33458579; at least two patients). Total 2 points (PM3_Strong). Another patients is compound heterozygous for the variant and c.2104C>T (p.Arg702Cys); phase unconfirmed (PMID 30049495). The in trans data from this patient will be used in the assessment of p.Arg702Cys and was not included here in order to avoid circular logic. The variant is absent in gnomAD v2.1.1 (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 552747, two star review status) with two submitters 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, as specified by the ClinGen LSD VCEP Specification Version 2.0): PVS1, PM3_Strong, PP4_Moderate, PM2_Supporting.

Met criteria codes

• PM2_Supporting: This variant is absent in gnomAD v2.1.1 (PM2_Supporting).
• PM3_Strong: At least four patients have been reported who are compound heterozygous for the variant and another pathogenic variant in GAA, phase unknown, including c.525delT (PMID 24715333, 33162552; 0.5 points), “del exon 18” (PMID 9660056; 0.5 points), and c.-32-13T>G (PMID 17573812, 17643989, 18757064, 24245577, 33458579; at least two patients, 2 x 0.5 points). Total 2 points (PM3_Strong). Another patients is compound heterozygous for the variant and c.2104C>T (p.Arg702Cys); phase unconfirmed (PMID 30049495). The in trans data from this patient will be used in the assessment of p.Arg702Cys and was not included here in order to avoid circular logic.
• PVS1: NM_000152.5:c.379_380del (p.Cys127LeufsTer18) variant in GAA is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 2/20, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1).
• PP4_Moderate: At least 4 patients with Pompe disease and this variant have been reported that meet the ClinGen LSD VCEP’s specifications for PP4_Moderate. Of these patients, the available data includes documentation of laboratory values showing GAA deficiency (2 points) (PMIDs 18757064, 24245577, 24715333, 30049495, 33162552). One of these patients had documented features consistent with infantile onset Pompe disease (PMID 24715333, 33162552, add 1 point) and another was on enzyme replacement therapy (PMID 30049495, add 1 point). Additional patients have also been reported.

Approved on: 2021-08-19

Published on: 2021-09-28