Variant: NM_000152.5(GAA):c.365del (p.Met122fs)

CA274330

189059 (ClinVar)

Gene: GAA

Condition: glycogen storage disease II

Inheritance Mode: Autosomal recessive inheritance

UUID: b83fe932-df4f-401a-992c-c2a91488ea50

HGVS expressions

NM_000152.5:c.365del
NM_000152.5(GAA):c.365del (p.Met122fs)
ENST00000302262.8:c.365del
ENST00000302262.7:c.365del
ENST00000390015.7:c.365del
ENST00000570803.5:c.365del
ENST00000577106.5:c.365del
NM_000152.3:c.365del
NM_001079803.1:c.365del
NM_001079804.1:c.365del
NM_000152.4:c.365del
NM_001079803.2:c.365del
NM_001079804.2:c.365del
NM_001079803.3:c.365del
NM_001079804.3:c.365del
NC_000017.11:g.80104951del
CM000679.2:g.80104951del
NC_000017.10:g.78078750del
CM000679.1:g.78078750del
NC_000017.9:g.75693345del
NG_009822.1:g.8396del

Pathogenic

• Met criteria codes: PP4_Moderate PM2_Supporting PM3_Supporting PVS1

Expert Panel

Lysosomal Diseases VCEP

Criteria Specification Information

Evidence submitted by expert panel

Lysosomal Diseases VCEP

NM_000152.5:c.365del (p.Met122ArgfsTer20) 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). One patient with late onset Pompe disease has been reported with documentation of laboratory values showing GAA deficiency (~7% lower limit of normal) in cultured fibroblasts (2 points) and who is on enzyme replacement therapy (1 point)(PMID: 20638881). (Total 3 points, PP4_Moderate). This patient is compound heterozygous, with unknown phase, for the variant and a pathogenic variant in GAA, c.-32-13T>G (0.5 points, PM3_Supporting). The variant is absent in gnomAD v2.1.1 (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 189059, two star review status) with two submitters classifying the variant as pathogenic and one as likely 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, PP4_Moderate, PM3_Supporting, PM2_Supporting.

Met criteria codes

• PP4_Moderate: One patient with late onset Pompe disease has been reported with documentation of laboratory values showing GAA deficiency (~7% lower limit of normal) in cultured fibroblasts (2 points) and who is on enzyme replacement therapy (1 point)(PMID: 20638881). (Total 3 points, PP4_Moderate).
• PM2_Supporting: This variant is absent in gnomAD v2.1.1 (PM2_Supporting).
• PM3_Supporting: One patient with Pompe disease is compound heterozygous for the variant and c.-32-13T>G (PMID: 20638881). The phase is not confirmed. 0.5 points were given, meeting PM3_Supporting.
• PVS1: NM_000152.5:c.365del (p.Met122ArgfsTer20) 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).

Approved on: 2021-08-19

Published on: 2021-09-28