Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_000152.5(GAA):c.1A>G (p.Met1Val)

Curation Version - 1.1
Curation History
JSON LD for Version 1.1

CA273952

188785 (ClinVar)

Gene: GAA

Condition: glycogen storage disease II

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: b5fb2272-c9ba-42b5-977c-4a141c31891a

Approved on: 2024-06-08

Published on: 2024-12-06

HGVS expressions

NM_000152.5:c.1A>G

NM_000152.5(GAA):c.1A>G (p.Met1Val)

NC_000017.11:g.80104587A>G

CM000679.2:g.80104587A>G

NC_000017.10:g.78078386A>G

CM000679.1:g.78078386A>G

NC_000017.9:g.75692981A>G

NG_009822.1:g.8032A>G

ENST00000570803.6:c.1A>G

ENST00000572080.2:c.1A>G

ENST00000577106.6:c.1A>G

ENST00000302262.8:c.1A>G

ENST00000302262.7:c.1A>G

ENST00000390015.7:c.1A>G

ENST00000570803.5:c.1A>G

ENST00000577106.5:c.1A>G

NM_000152.3:c.1A>G

NM_001079803.1:c.1A>G

NM_001079804.1:c.1A>G

NM_000152.4:c.1A>G

NM_001079803.2:c.1A>G

NM_001079804.2:c.1A>G

NM_001079803.3:c.1A>G

NM_001079804.3:c.1A>G

Pathogenic

PVS1_Strong PP4_Moderate PM3_Strong PM2_Supporting

Evidence Links 0

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

PDF

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Lysosomal Diseases VCEP

The NM_000152.5:c.1A>G (p.Met1Val, aka p.Met1?) start loss variant in GAA may cause a truncated or absent protein by altering the start codon of the coding sequence and is predicted to lead to the omission of a critical region of the protein (PVS1_Strong; PMIDs 22644586, 30192042, 22252923). This variant is absent in gnomAD v2.1.1. (PM2_Supporting). This variant has been detected in at least 5 individuals with Pompe disease. Three individuals are compound heterozygous for the variant and another pathogenic or likely pathogenic variant in GAA, including c.2608T>C (pArg870Ter) (pathogenic based on classification by the ClinGen LD VCEP, confirmed in trans, 1 point, PMID: 33301762), exon 6-10 deletion (pathogenic, phase confirmed, 1 point, PMID: 37542277), and c.1831G>A (p.Gly611Ser), LP based on classification by the ClinGen LD VCEP; phase unconfirmed, 0.25 points, PMID:33250842). One individual was homozygous for the variant (0.5 point, 29422078). Another patient is compound heterozygous for the variant and another variant in GAA, either c.1714C>G (p.His572Asp) (PMID: 33301762). The allelic data from this patient will be used in the assessment of the second variant and is not included here to avoid circular logic. Total 2.75 points (PM3_Strong). At least two patients with this variant had documented GAA deficiency with <10% of the normal mean control level of GAA activity in dried blood spots (PMID: 33301762, 37542277). One homozygous patient had documented symptoms of severe infantile onset of the disease and was reported to be on enzyme replacement therapy for Pompe disease, and CRIM negative (PMID: 29422078) (PP4_Moderate). Three different missense variants (c.2T>C, c.1A>T, c.3G>A) (ClinVar Variation IDs: 984802, 984798, 972816, respectively], in the same codon have been classified as Pathogenic/Likely pathogenic for Pompe disease by the ClinGen Lysosomal Diseases VCEP. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PVS1_Strong, PM3_Strong, PP4_Moderate, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on June 8, 2024)

PVS1_Strong

The NM_000152.5: c.1A>G (p.Met1?) variant in GAA may cause a truncated or absent protein by altering the start codon of the coding sequence and is predicted to lead to the omission of a critical region of the protein (PVS1_Strong; PMIDs 22644586, 30192042, 22252923).

PP4_Moderate

At least two patients with this variant had documented GAA deficiency with <10% of the normal mean control level of GAA activity in dried blood spots (PMID: 33301762, 37542277). One homozygous patient had documented symptoms of severe infantile onset of the disease and was reported to be on enzyme replacement therapy for Pompe disease, and CRIM negative (PMID: 29422078) (PP4_Moderate).

PM3_Strong

Three individuals are compound heterozygous for the variant and another pathogenic or likely pathogenic variant in GAA, including c.2608T>C (pArg870Ter) (pathogenic based on classification by the ClinGen LD VCEP, confirmed in trans, 1 point, PMID: 33301762), exon 6-10 deletion (pathogenic, phase confirmed, 1 point, PMID: 37542277), and c.1831G>A (p.Gly611Ser), LP based on classification by the ClinGen LD VCEP; phase unconfirmed, 0.25 points, PMID:33250842). One individual was homozygous for the variant (0.5 point, 29422078). Another patient is compound heterozygous for the variant and another variant in GAA, either c.1714C>G (p.His572Asp) (PMID: 33301762). The allelic data from this patient will be used in the assessment of the second variant and is not included here to avoid circular logic. Total 2.75 points (PM3_Strong).

PM2_Supporting

This variant is absent in gnomAD v4.0.1 (PM2_Supporting).

Curation History

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