Variant: NM_000152.5(GAA):c.2281delinsAT (p.Ala761fs)

CA16041905

370993 (ClinVar)

Gene: GAA

Condition: glycogen storage disease II

Inheritance Mode: Autosomal recessive inheritance

UUID: 0899d978-84e4-42d9-b219-e67e8b3e226a

Approved on: 2021-08-27

Published on: 2021-09-28

HGVS expressions

NM_000152.5:c.2281delinsAT
NM_000152.5(GAA):c.2281delinsAT (p.Ala761fs)
NC_000017.11:g.80117059delinsAT
CM000679.2:g.80117059delinsAT
NC_000017.10:g.78090858delinsAT
CM000679.1:g.78090858delinsAT
NC_000017.9:g.75705453delinsAT
NG_009822.1:g.20504delinsAT
ENST00000570803.6:c.2281delinsAT
ENST00000572080.2:c.*419delinsAT
ENST00000577106.6:c.2281delinsAT
ENST00000302262.8:c.2281delinsAT
ENST00000302262.7:c.2281delinsAT
ENST00000390015.7:c.2281delinsAT
ENST00000572080.1:c.700delinsAT
ENST00000573556.1:n.234delinsAT
NM_000152.3:c.2281delinsAT
NM_001079803.1:c.2281delinsAT
NM_001079804.1:c.2281delinsAT
NM_000152.4:c.2281delinsAT
NM_001079803.2:c.2281delinsAT
NM_001079804.2:c.2281delinsAT
NM_001079803.3:c.2281delinsAT
NM_001079804.3:c.2281delinsAT

Pathogenic

• Met criteria codes: PM3 PVS1 PM2_Supporting PP4_Moderate

Expert Panel

Lysosomal Diseases VCEP

Criteria Specification Information

Evidence submitted by expert panel

Lysosomal Diseases VCEP

The NM_000152.5: c.2281delinsAT (p.Ala761IlefsTer35) variant in GAA is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 17/20, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been reported in 3 patients with Pompe disease including one individual with documentation of laboratory values showing GAA deficiency, meeting the ClinGen LSD VCEP’s specifications for PP4_Moderate (PMID 17056254), and another stated to have deficient GAA activity (laboratory values not available) and on enzyme replacement therapy, meeting PP4 (PMID 29181627)(PP4_Moderate was applied). Both of these patients are compound heterozygous for the variant and a pathogenic variant in GAA, c.-32-13T>G, phase unknown (2 x 0.5 points = 1 point, PM3). Another patient was identified by newborn screening and was compound heterozygous for the variant, c.2238G>C (p.Trp746Cys), and a pseudodeficiency variant, c.2065G>A (PMID 33202836). This data may be used in the assessment of p.Trp746Cys and was not included here to avoid circular logic. The c.2281delinsAT variant is absent in gnomAD v2.1.1 (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 370993, 2 star review status) with one submitter 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 (Specifications Version 2.0): PVS1, PM3, PP4_Moderate, PM2_Supporting.

Met criteria codes

• PM3: Two patients are compound heterozygous for the variant and a pathogenic variant in GAA, c.-32-13T>G, phase unknown (2 x 0.5 points = 1 point, PM3). Another patient was identified by newborn screening and was compound heterozygous for the variant, c.2238G>C (p.Trp746Cys), and a pseudodeficiency variant, c.2065G>A (PMID 33202836). This data may be used in the assessment of p.Trp746Cys and was not included here to avoid circular logic.
• PVS1: The NM_000152.5: c.2281delinsAT (p.Ala761IlefsTer35) variant in GAA is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 17/20, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1).
• PM2_Supporting: This variant is absent in gnomAD v2.1.1 (PM2_Supporting).
• PP4_Moderate: This variant has been reported in 3 patients, one with documentation of laboratory values showing GAA deficiency, meeting the ClinGen LSD VCEP’s specifications for PP4_Moderate (PMID 17056254), another stated to have deficient GAA activity (laboratory values not available) and on enzyme replacement therapy, meeting PP4 (PMID 29181627), and another identified by newborn screening without sufficient data to apply PP4 (PMID 33202836). PP4_Moderate can be applied.