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_000152.4(GAA):c.545C>G (p.Thr182Arg)

Curation Version - 1.1
Curation History
JSON LD for Version 1.1

CA8814893

499380 (ClinVar)

Gene: GAA

Condition: glycogen storage disease II

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: d02d78ca-2f3b-4475-b091-496e72e40826

Approved on: 2023-05-26

Published on: 2023-05-26

HGVS expressions

NM_000152.4:c.545C>G

NM_000152.4(GAA):c.545C>G (p.Thr182Arg)

NC_000017.11:g.80105131C>G

CM000679.2:g.80105131C>G

NC_000017.10:g.78078930C>G

CM000679.1:g.78078930C>G

NC_000017.9:g.75693525C>G

NG_009822.1:g.8576C>G

ENST00000302262.8:c.545C>G

ENST00000302262.7:c.545C>G

ENST00000390015.7:c.545C>G

ENST00000570803.5:c.545C>G

ENST00000577106.5:c.545C>G

NM_000152.3:c.545C>G

NM_001079803.1:c.545C>G

NM_001079804.1:c.545C>G

NM_001079803.2:c.545C>G

NM_001079804.2:c.545C>G

NM_000152.5:c.545C>G

NM_001079803.3:c.545C>G

NM_001079804.3:c.545C>G

NM_000152.5(GAA):c.545C>G (p.Thr182Arg)

Uncertain Significance

PM2_Supporting

BP4 PP4 PP3

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

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Lysosomal Diseases VCEP

The NM_000152.5(GAA):c.545C>G (p.Thr182Arg) variant in GAA has a highest population minor allele frequency in gnomAD v2.1.1 of 0.00010 (11/106436 alleles) in the European (Non-Finnish) population, which is lower than the ClinGen LD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). The variant has been reported in the literature but not in individuals diagnosed with Pompe disease (PMID: 29149851, 33552729) (PP4 is not met). The computational predictor REVEL gives a score of 0.395, a score which does not clearly predict an impact on GAA function (PMID: 36413997). There is a ClinVar entry for this variant (Variation ID: 499380). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases VCEP on May 26, 2023).

PM2_Supporting

The highest population minor allele frequency in gnomAD v2.1.1 is 0.00010 (11/106436 alleles) in the European (Non-Finnish) population, which is lower than the ClinGen LSD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting).

BP4

The computational predictor REVEL gives a score of 0.395 (which is above the cut-off recommended by Pejaver et al). The computational splicing predictor SpliceAI gives a score of 0.14 for donor loss.

PP4

The variant has been reported in the literature but there is not in individuals diagnosed with Pompe disease (PMID: 29149851, 33552729) (PP4 is not met).

PP3

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

Curation History

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.