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]

Link to SEPIO compliant JSON-LD document

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

CA8814893

499380 (ClinVar)

Gene: GAA

Condition: glycogen storage disease II

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

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

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

Approved on: 2023-05-26

Published on: 2023-05-26

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