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_000152.5(GAA):c.676C>G (p.Leu226Val)

CA198772

188476 (ClinVar)

Gene: GAA

Condition: glycogen storage disease II

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 1711ccb4-7228-406e-8a50-1b6cb6820adf

Approved on: 2024-05-07

Published on: 2024-05-08

HGVS expressions

NM_000152.5:c.676C>G

NM_000152.5(GAA):c.676C>G (p.Leu226Val)

NC_000017.11:g.80105878C>G

CM000679.2:g.80105878C>G

NC_000017.10:g.78079677C>G

CM000679.1:g.78079677C>G

NC_000017.9:g.75694272C>G

NG_009822.1:g.9323C>G

ENST00000570803.6:c.676C>G

ENST00000572080.2:c.676C>G

ENST00000577106.6:c.676C>G

ENST00000302262.8:c.676C>G

ENST00000302262.7:c.676C>G

ENST00000390015.7:c.676C>G

ENST00000570803.5:c.676C>G

NM_000152.3:c.676C>G

NM_001079803.1:c.676C>G

NM_001079804.1:c.676C>G

NM_000152.4:c.676C>G

NM_001079803.2:c.676C>G

NM_001079804.2:c.676C>G

NM_001079803.3:c.676C>G

NM_001079804.3:c.676C>G

Likely Benign

BS1 BP4

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.676C>G variant in GAA is a missense variant predicted to cause substitution of leucine by valine at amino acid 226 (p.Leu226Val). The highest population minor allele frequency of this variant in gnomAD v2.1.1. is 0.006298 (156/24770 alleles) in the African/African American population which is higher than the ClinGen Lysosomal Diseases VCEP’s threshold for BS1 (>0.005), and therefore meets this criterion (BS1). The computational predictor REVEL gives a score of 0.159 which is below the threshold of 0.5, evidence that does not predict a damaging effect on GAA function (BP4). There are ten ClinVar entries for this variant (Variation ID:188476; 2 star review status) with eight submitters classifying the variant as likely benign and two as benign. In summary, this variant meets the criteria to be classified as likely benign for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): BS1, BP4. (Classification approved by the ClinGen Lysosomal Diseases VCEP on May 7, 2024)

BS1

The highest population minor allele frequency in gnomAD v2.1.1 is 0.006298 (156/24770 alleles) in the African/African American population, which is higher than the ClinGen Lysosomal Diseases VCEP’s threshold for BS1 (>0.005), and therefore meets this criterion (BS1). The highest population minor allele frequency in gnomAD v4.1.0 is 0.006750 (506/74960 alleles) in the African/African American population, which is higher than the ClinGen Lysosomal Diseases VCEP’s threshold for BS1 (>0.005), and therefore meets this criterion (BS1).

BP4

The computational predictor REVEL gives a score of 0.159 which is below the threshold of 0.5, evidence that does not predict a damaging effect on GAA function (BP4).

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