Variant: NM_000152.5(GAA):c.1445C>T (p.Pro482Leu)

982297 (ClinVar)

Gene: GAA

Condition: glycogen storage disease II

Inheritance Mode: Autosomal recessive inheritance

UUID: 0b43e608-9622-456f-a358-b4d29ab793e0

Approved on: 2023-02-07

Published on: 2023-03-03

HGVS expressions

NM_000152.5:c.1445C>T
NM_000152.5(GAA):c.1445C>T (p.Pro482Leu)

Likely Pathogenic

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Insufficient Evidence"

• Met criteria codes: PP3 PM3 PP4_Moderate PM5_Supporting 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.1445C>T variant in GAA is a missense variant predicted to cause substitution of proline by leucine at amino acid 482 (p.Pro482Leu). At least 5 patient(s) with this variant had documented GAA deficiency with <10% of normal mean control level of GAA activity in leukocytes, activity in the affected range in muscle, cultured skin fibroblasts, leukocytes, lymphocytes, whole blood or dried blood spot, or were noted to have deficient GAA activity but results were not provided (PMID: 17616415, 31086307, 34530085, 33741225, 31931849) (PP4_Moderate). Of those individuals, 2 were compound heterozygous for the variant and a pathogenic or likely pathogenic variant (p.Asp404Asn, p.Asn87Glnfs*9) (PMID: 31086307, 31931849). One individual was homozygous for the variant (PMID: 33741225) (PM3). This variant is absent in gnomAD v2.1.1. (PM2_Supporting). The computational predictor REVEL gives a score of 0.918 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Another missense variant c.1445C>G (p.Pro482Arg) (PMID: 31392188, 22644586, ClinVar Variation ID 1067574) in the same codon has been classified as likely pathogenic for Pompe disease by the ClinGen LSD VCEP (PM5_Supporting). There is a ClinVar entry for this variant (Variation ID: 982297; 2 star review status) with two submitters classifying the variant as pathogenic, and two as likely pathogenic. In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen LSD VCEP (Specifications Version 2.0): PP4_Moderate, PM3, PP3, PM2_Supporting, PM5_Supporting. (Classification approved by the ClinGen LSD VCEP, February 7, 2023).

Met criteria codes

• PP3: The computational predictor REVEL gives a score of [0.918] which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3).
• PM3: This variant has been detected in at least 5 individuals with Pompe disease. Of those individuals, 2 were compound heterozygous for the variant and a pathogenic or likely pathogenic variant (p.Asp404Asn, p.Asn87Glnfs*9 - 1 pt) (PMID: 31086307, 31931849). One individual was homozygous for the variant (0.5 pt) (PMID: 33741225) (PM3).
• PP4_Moderate: At least 5 patient(s) with this variant had documented GAA deficiency with <10% of normal mean control level of GAA activity in leukocytes, lymphocytes, muscle samples, activity in the affected range in muscle, cultured skin fibroblasts, leukocytes, lymphocytes, whole blood or dried blood spot, or were noted to have deficient GAA activity but results were not provided (PMID: 17616415, 31086307, 34530085, 33741225, 31931849) (PP4_Moderate).
• PM5_Supporting: Another missense variant c.1445C>G (p.Pro482Arg) (PMID: 31392188, 22644586, ClinVar Variation ID 1067574) in the same codon has been classified as likely pathogenic for Pompe disease by the ClinGen LSD VCEP (PM5_Supporting).
• PM2_Supporting: This variant is absent in gnomAD v2.1.1 (PM2_Supporting).