Variant: NM_000152.5(GAA):c.766_767insC (p.Tyr256fs)

CA658824780

550104 (ClinVar)

Gene: GAA

Condition: glycogen storage disease II

Inheritance Mode: Autosomal recessive inheritance

UUID: d5329ec3-79f1-4fc7-a4db-66c65f93d1be

HGVS expressions

NM_000152.5:c.766_767insC
NM_000152.5(GAA):c.766_767insC (p.Tyr256fs)
NC_000017.11:g.80107630_80107631insC
CM000679.2:g.80107630_80107631insC
NC_000017.10:g.78081429_78081430insC
CM000679.1:g.78081429_78081430insC
NC_000017.9:g.75696024_75696025insC
NG_009822.1:g.11075_11076insC
ENST00000302262.8:c.766_767insC
ENST00000302262.7:c.766_767insC
ENST00000390015.7:c.766_767insC
ENST00000570803.5:c.766_767insC
NM_000152.3:c.766_767insC
NM_001079803.1:c.766_767insC
NM_001079804.1:c.766_767insC
NM_000152.4:c.766_767insC
NM_001079803.2:c.766_767insC
NM_001079804.2:c.766_767insC
NM_001079803.3:c.766_767insC
NM_001079804.3:c.766_767insC

Likely Pathogenic

• Met criteria codes: PVS1 PM2_Supporting

Expert Panel

Lysosomal Diseases VCEP

Criteria Specification Information

Criteria Specification: ClinGen Lysosomal Storage Disorders Variant Curation Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2

Evidence submitted by expert panel

Lysosomal Diseases VCEP

The NM_000152.5:c.766_767insC (p.Tyr256SerfsTer74) variant in GAA is a frameshift variant that is predicted to cause a premature stop codon, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is not in gnomAD v2.1.1 (PM2_Supporting). To our knowledge, this variant has not been reported in a patient with Pompe disease in the literature, and results of functional studies are not available. There is a ClinVar entry for this variant (Variation ID: 550104. In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease. The classification of this variant has been upgraded from Variant of Uncertain Significance to Likely Pathogenic based on the recommendations of the ClinGen Sequence Variant Interpretation Working Group, that a variant meeting PVS1 and PM2_Supporting is classified as Likely Pathogenic (https://clinicalgenome.org/site/assets/files/5182/pm2_-_svi_recommendation_-_approved_sept2020.pdf ) GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PVS1, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases VCEP on May 26, 2023).

Met criteria codes

• PVS1: The NM_000152.5:c.766_767insC (p.Tyr256SerfsTer74) variant in GAA is a frameshift variant that is predicted to cause a premature stop codon, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1).
• PM2_Supporting: This variant is not in gnomAD v2.1.1.

Approved on: 2023-05-26

Published on: 2023-05-26