NM_000152.5:c.1317GAT[1]

526518 (ClinVar)

Gene: GAA

Condition: glycogen storage disease II

Inheritance Mode: Autosomal recessive inheritance

UUID: a98b509a-813f-4fa4-a2b8-d777c8deae09

Approved on: 2022-11-03

Published on: 2022-11-28

HGVS expressions

NM_000152.5:c.1317GAT[1]
NM_000152.5:c.1320_1322delGAT
NM_000152.5(GAA):c.1317GAT[1] (p.Met440del)

Uncertain Significance

• Met criteria codes: PM3_Supporting PM4_Supporting PP4_Moderate PM2_Supporting

• Not Met criteria codes: PS3 PP3

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.1317delGAT or c.1320_1322delGAT variant is predicted to cause a change in the length of protein due to inframe deletion of one amino acid, Met440 in a non repeat region (PM4_Supporting). This variant is documented in NBS-Pompe program from Japan (PMID: 31076647). One LOPD patient from China was reported to be compound heterozygous for the variant and a variant in GAA that has been classified as pathogenic by the ClinGen LSD VCEP, c.2238G>C (p.Trp746Cys)(PM3_supporting). This patient had documented deficiency of GAA activity (PMID: 35071497) (PP4_moderate). The variant is absent in gnomAD v2.1.1 (PM2_supporting). The results of in silico predictors were conflicting. To our knowledge, no functional studies have been performed on this variant. There is a ClinVar entry for this variant (Variant ID: 526518). Due to insufficient evidence this variant is classified as of uncertain significance for Pompe disease based on ACMG/AMP criteria applied, as specified by LSD VCEP (specification version 2.0). Criteria applied: criteria: PM2_supporting; PM3_supporting, PM4_Supporting, PP4_moderate. (Classification approved by the ClinGen LSD VCEP on Nov 3, 2022).

Met criteria codes

• PM3_Supporting: The variant c.1320_1322delGAT has been detected in one late onset pompe patient from China. Patient is compound heterozygous for the variant and a pathogenic c.2238G>C(p.Trp746Cys)VCV000265160.38 . PMID: 35071497 Phase unknown, 0.5 point, meets PM3_supporting
• PM4_Supporting: The NM_000152.5:c.1317delGAT or c.1320_1322delGAT is predicted to cause a change in the length of protein due to inframe deletion of one amino acid, Met440 in a non repeat region (PM4_Supporting).
• PP4_Moderate: One late onset Pompe patient from China on ventilator support ( female with age of onset-12 years, diagnosis-23 years) had documented GAA deficiency with 0.16micro mol/L/h ( reference range1.46-20.34).PMID: 35071497 meets PP4_moderate
• PM2_Supporting: GAA c.1317GAT[1] (p.Met440del) is absent at gnomAD.

Not Met criteria codes

• PS3: To our knowledge, no functional studies have been performed.
• PP3: MutationTaster scored it as benign, and MutPredIndel is right at 0.5 which is deleterious with a 10% false positive rate. Due to conflicting in silico predictions, neither PP3 nor BP4 is met.