Description
The NM_000152.5: c.1537G>A variant in GAA is a missense variant predicted to cause substitution of aspartic acid by asparagine at amino acid 513 (p.Asp513Asn). This variant has been detected in at least five individuals with Pompe disease. One patient of late-onset Pompe disease had documented GAA deficiency as 8.7% of the normal control level of GAA activity (PMID 33301762). Three siblings from one family had documented reduced GAA enzyme activity within the deficient range (clinical laboratory data). Patient(s) with this variant had documented in a Pompe Registry with the onset of symptoms less than 12 years of age (PMID 31342611). (PP4_Moderate). Of those individuals, one individual was homozygous for the variant, and three siblings were compound heterozygous for the variant and the pathogenic c.-32-13T>G variant (PM3 2.0 points, PMID 33301762, clinical laboratory data) (PM3_Strong). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006533 (2/30616 alleles) in the South Asian population, which is lower than the ClinGen LSD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.861 which is above the threshold of 0.7, evidence that correlates with impact on GAA function (PP3). Another missense variant c.1538A>G (p.Asp513Gly) (PMID 31510962, 33560568; ClinVar Variation ID: 638014) in the same codon has been classified as likely pathogenic for Pompe disease by the ClinGen LSD VCEP (PM5_Supporting). There is a ClinVar entry for this variant (Variation ID: 960182). In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP (specifications version 2.0): PP4_Moderate, PM3_Strong, PM2_Supporting, PP3, PM5_Supporting. (Classification approved by the ClinGen Lysosomal Diseases VCEP on July 18, 2023).
| # | Sample | Method | Observation |
|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences |
|---|
| 1 | germline | unknown | not provided | not provided | not provided | | not provided | not provided | not provided | not provided |
