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.1556T>C (p.Met519Thr)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA274402

189124 (ClinVar)

Gene: GAA

Condition: glycogen storage disease II

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: f4330a30-6672-4c82-87de-66870f00f6d2

Approved on: 2024-05-07

Published on: 2024-05-08

HGVS expressions

NM_000152.5:c.1556T>C

NM_000152.5(GAA):c.1556T>C (p.Met519Thr)

NC_000017.11:g.80110945T>C

CM000679.2:g.80110945T>C

NC_000017.10:g.78084744T>C

CM000679.1:g.78084744T>C

NC_000017.9:g.75699339T>C

NG_009822.1:g.14390T>C

ENST00000570803.6:c.1556T>C

ENST00000572080.2:c.1556T>C

ENST00000577106.6:c.1556T>C

ENST00000302262.8:c.1556T>C

ENST00000302262.7:c.1556T>C

ENST00000390015.7:c.1556T>C

NM_000152.3:c.1556T>C

NM_001079803.1:c.1556T>C

NM_001079804.1:c.1556T>C

NM_000152.4:c.1556T>C

NM_001079803.2:c.1556T>C

NM_001079804.2:c.1556T>C

NM_001079803.3:c.1556T>C

NM_001079804.3:c.1556T>C

Pathogenic

PP4_Moderate PM2_Supporting PS3_Moderate PP3 PM3_Strong PM1

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.1556T>C variant in GAA is a missense variant predicted to cause substitution of methionine by threonine at amino acid 519 (p.Met519Thr). This variant has been detected in at least 4 individuals with Pompe disease. Of those individuals, 3 were compound heterozygous for the variant and a variant that has been classified as pathogenic by the ClinGen LD VCEP, phase unconfirmed, either c.525del (ClinVar Variation ID: 4033, SCV001443331.1) (PMID: 14695532), c.1441T>C (p.Trp481Arg) (ClinVar Variation ID: 189007, SCV004227917.1) (PMID: 31086307), or c.[752C>T;761C>T] (p.[Ser251Leu;Ser254Leu] (ClinVar Variation ID 325781/325782) (Clinical laboratory data); One individual was homozygous for the variant (PMID: 33741225) (PM3_Strong). At least 1 patient with this variant had documented GAA deficiency with <10% of normal mean control level of GAA activity in dried blood spot (PMID: 33741225) and 2 patients were reported to have symptoms consistent with infantile onset Pompe disease (PMID: 14695532) (PP4_Moderate). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003 (1/30616 alleles) in the South Asian population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.983 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Expression of the variant in COS-7 resulted in <2% wild type GAA activity with western blot data showing decreased level of mature protein, indicating that this variant may impact protein function (PMIDs: 19862843, 14695532) (PS3_Moderate). This variant alters amino acid M519, a residue that crystallography studies have shown to be important in the active site of GAA, and therefore has been defined as a critical residue by the ClinGen Lysosomal Diseases VCEP (https://www.biorxiv.org/content/10.1101/212837v1.full.pdf, PMID: 29061980) (PM1). There is a ClinVar entry for this variant (Variation ID: 189124). In summary, this variant meets the criteria to be classified as Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specification of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PM3_strong, PP4_moderate, PM1, PS3_moderate, PP3, PM2_supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on May 7, 2024)

PP4_Moderate

At least 1 patient with this variant had documented GAA deficiency with <10% of normal mean control level of GAA activity in dried blood spot (PMID: 33741225) and 2 patients were reported to have IOPD (PMID: 14695532) (PP4_Moderate).

PM2_Supporting

The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003 (1/30616 alleles) in the South Asian population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting).

PS3_Moderate

Expression of the variant in COS-7 resulted in <2% wild type GAA activity with western blot data showing reduction in level of mature protein, indicating that this variant may impact protein function (PMIDs: 19862843, 14695532) (PS3_Moderate).

PP3

The computational predictor REVEL gives a score of 0.983 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3).

PM3_Strong

This variant has been detected in at least 5 individuals with Pompe disease. Of those individuals, 3 were compound heterozygous for the variant and a variant that has been classified as pathogenic by the ClinGen LD VCEP, phase unconfirmed, either c.525del (ClinVar Variation ID: 4033, SCV001443331.1) (PMID: 14695532), c.1441T>C (p.Trp481Arg) (ClinVar Variation ID: 189007, SCV004227917.1) (PMID: 31086307), or c.[752C>T;761C>T] (p.[Ser251Leu;Ser254Leu] (ClinVar Variation ID 325781/325782) (Clinical laboratory data), 3 x 0.5 points. One individual was homozygous for the variant (0.5 point, PMID: 33741225). Total 2 points (PM3_Strong).

PM1

This variant alters amino acid M519, a residue that crystallography studies have shown to be important in the active site of GAA, and therefore has been defined as a critical residue by the ClinGen Lysosomal Diseases VCEP (https://www.biorxiv.org/content/10.1101/212837v1.full.pdf, PMID: 29061980) (PM1).

Curation History

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