Variant: NM_000152.5(GAA):c.2783A>G (p.Tyr928Cys)

CA401327377

1048589 (ClinVar)

Gene: GAA

Condition: glycogen storage disease II

Inheritance Mode: Autosomal recessive inheritance

UUID: 80721787-4e71-4d2f-9804-0d2ab2dbdef2

Approved on: 2023-12-20

Published on: 2023-12-22

HGVS expressions

NM_000152.5:c.2783A>G
NM_000152.5(GAA):c.2783A>G (p.Tyr928Cys)
NC_000017.11:g.80118789A>G
CM000679.2:g.80118789A>G
NC_000017.10:g.78092588A>G
CM000679.1:g.78092588A>G
NC_000017.9:g.75707183A>G
NG_009822.1:g.22234A>G
ENST00000302262.8:c.2783A>G
ENST00000302262.7:c.2783A>G
ENST00000390015.7:c.2783A>G
ENST00000573556.1:n.736A>G
NM_000152.3:c.2783A>G
NM_001079803.1:c.2783A>G
NM_001079804.1:c.2783A>G
NM_000152.4:c.2783A>G
NM_001079803.2:c.2783A>G
NM_001079804.2:c.2783A>G
NM_001079803.3:c.2783A>G
NM_001079804.3:c.2783A>G

Uncertain Significance

• Met criteria codes: PM2_Supporting PP4_Moderate PM3

• Not Met criteria codes: BP4 PP3

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

Evidence submitted by expert panel

Lysosomal Diseases VCEP

The NM_000152.5:c.2783A>G in GAA is predicted to result in the substitution of tyrosine by cysteine at amino acid 928 (p.Tyr928Cys). The variant has been identified in at least four individuals (all Indian where the country of origin is known). One of these patients has symptoms consistent with late onset Pompe disease and documented laboratory values showing deficient GAA activity (PMID: 33741225) (PP4_Moderate). Three individuals are homozygous for the variant (PMID: 33301762, clinical diagnostic laboratory), and one individual is compound heterozygous for the variant and a variant of uncertain significance, c.2015G>T (p.Arg672Leu) (PMID: 29122469, 33741225). The allelic data for this patient will be used in the classification of p.Arg672Leu and is not included here to avoid circular logic (PM3). The highest population minor allele frequency in gnomAD v4.0 is 0.00003294 (3/91080 alleles) in the S. 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 0.664 which is neither above nor below the thresholds predicting a damaging (>0.7) or benign (<0.5) impact on GAA function. There is a ClinVar entry for this variant (Variation ID: : 1048589). In summary, this variant meets the criteria to be classified as a variant of unceratin significance for Pompe disease. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel: PM3, PP4_Moderate, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 20, 2023).

Met criteria codes

• PM2_Supporting: The highest population minor allele frequency in gnomAD v4.0 is 0.00003294 (3/91080 alleles) in the S. Asian population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting).
• PP4_Moderate: The variant has been identified in at least four individuals (all Indian where the country of origin is known). One of these patients has symptoms consistent with late onset Pompe disease and documented laboratory values showing deficient GAA activity (PMID: 33741225) (PP4_Moderate).
• PM3: Three individuals are homozygous for the variant (max 2 x 0.5) (PMID: 33301762, clinical diagnostic laboratory), and one individual is compound heterozygous for the variant and a variant of uncertain significance, c.2015G>T (p.Arg672Leu) (PMID: 29122469, 33741225). The allelic data for this patient will be used in the classification of p.Arg672Leu and is not included here to avoid circular logic. Total 1 point (PM3).

Not Met criteria codes

• BP4: The computational predictor REVEL gives a score of 0.664 which is neither above nor below the thresholds predicting a damaging (>0.7) or benign (<0.5) impact on GAA function.
• PP3: The computational predictor REVEL gives a score of 0.664 which is neither above nor below the thresholds predicting a damaging (>0.7) or benign (<0.5) impact on GAA function.