Description
The NM_000152.5:c.546+5G>T variant is an intronic variant in exon 2 of GAA. The variant has been found in multiple patients identified by newborn screening programs in Taiwan and Japan (PMID: 20080426, 21232767, 31076647, 34995642). However, the variant always occurs in cis with pseudodeficiency variants (including c.1726G>A) which could be responsible for the reduced GAA activity. One patient, who was compound heterozygous for the variant and c.1080C>G (p.Tyr360Ter), was reported to have initial CK elevation, and hypotonia for the first few years of life, but was later reported as "normal" by the family at age 13 years (PMID: 34995642). Another patient was homozygous for the variant (PMID: 21232767). In addition, patients who are heterozygous for the variant, with no second variant suspicious for causing Pompe disease, have been found. At the current time, the clinical significance of this variant is unclear. No patient with a clear diagnosis of Pompe disease has been found and it is unknown if this variant may contribute to later onset symptoms (neither PP4 nor PM3 were applied). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0004978 in the East Asian population which is lower than ClinGen LSD VCEP threshold of <0.001 (PM2_supporting). RT-PCR of RNA from primary fibroblasts a patient who is compound heterozygous for c.[546+5G>T; 1726G>A] and c.1080C>G (p.Tyr360Ter) revealed a normal-sized fragment containing 2 sequences (1 normal and 1 with a 3-bp insertion) and an aberrantly short fragment containing a deletion of exon 2 (PMID: 34995642). Another study also showed, based on RT-PCR, that the variant results in skipping of exon 2 (PMID: 31301153). RT-PCR shows that variant results in skipping of exon 2, and is expected to result in the loss of the initiator methionine (PMID: 31301153), meeting PS3_supporting. There is ClinVar entry to this variant (Variation ID : 557811, one star review status) with five submitters classifying the variant as Pathogenic (1); Likely Pathogenic (1); Uncertain significance (2). In summary, this variant has been classified as a variant of uncertain significance for Pompe disease by the ClinGen Lysosomal Storage Disorders Variant Curation Expert Panel. GAA-Specific ACMG-AMP criteria applied, as specified by the ClinGen LSD VCEP (Specifications Version 2.0): PS3_supporting, PM2_supporting. (Classification approved by the ClinGen LSD VCEP on October 4, 2022).
| # | 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 |
