Description
The NM_000152.5(GAA):c.1019A>G variant in GAA is a missense variant predicted to cause substitution of tyrosine by cysteine at amino acid 340 (p.Tyr340Cys). This variant has been detected in at least 4 individuals with Pompe disease and at least 2 patients with this variant had documented GAA deficiency with activity in the affected range in dried blood spot (internal lab data). Of those individuals, 3 were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and 1 was confirmed in trans by parental testing, including c.-32-13T>G (1 patient, internal lab data, confirmed in trans), c.2560C>T; p.Arg854* (1 patient, internal lab data, phase unknown), and c.1292_1295dup p.(Gln433Alafs *74) (1 patient, PMID: 32802993, phase unknown and no follow up to NBS). In addition, one patient is compound heterozygous for the variant and c.1725C>T (p.Tyr575Tyr) (internal lab data), which is not classified as P/LP and one patient was compound heterozygous for the variant and c.2432delT (p.Leu811Argfs*37) (internal lab data, confirmed in trans), but enzyme testing was in the carrier range (PM3 and PP4_Moderate). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00084 (28/282466 alleles) in the African 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 0.752 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). There is a ClinVar entry for this variant (Variation ID: 289356, 2 star review status) with 7 submitters classifying the variant as a variant of uncertain significance. In summary, while this variant meets the criteria to be classified as likely pathogenic for Pompe disease, the GAA VCEP does not believe there is insufficient phenotypic evidence to support this classification at this time. Therefore, this variant will be classified as a variant of uncertain significance until further evidence is available. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases VAriant Curation Expert Panel (Specifications Version 2.0): PM3, PP4_Moderate, PP3, PM2_Supporting. Classification approved by the ClinGen Lysosomal Diseases VCEP, August 1st, 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 |
