Variant: NM_000152.5(GAA):c.546+5G>T

CA8814901

557811 (ClinVar)

Gene: GAA

Condition: glycogen storage disease II

Inheritance Mode: Autosomal recessive inheritance

UUID: 4b3a2c5d-4eb5-4cb8-885a-fdc9ee0ee377

Approved on: 2022-10-04

Published on: 2022-12-20

HGVS expressions

NM_000152.5:c.546+5G>T
NM_000152.5(GAA):c.546+5G>T
NC_000017.11:g.80105137G>T
CM000679.2:g.80105137G>T
NC_000017.10:g.78078936G>T
CM000679.1:g.78078936G>T
NC_000017.9:g.75693531G>T
NG_009822.1:g.8582G>T
ENST00000302262.8:c.546+5G>T
ENST00000302262.7:c.546+5G>T
ENST00000390015.7:c.546+5G>T
ENST00000570803.5:c.546+5G>T
ENST00000577106.5:c.546+5G>T
NM_000152.3:c.546+5G>T
NM_001079803.1:c.546+5G>T
NM_001079804.1:c.546+5G>T
NM_000152.4:c.546+5G>T
NM_001079803.2:c.546+5G>T
NM_001079804.2:c.546+5G>T
NM_001079803.3:c.546+5G>T
NM_001079804.3:c.546+5G>T

Uncertain Significance

• Met criteria codes: PM2_Supporting PS3_Supporting

• Not Met criteria codes: PM3 PP4 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.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).

Met criteria codes

• PM2_Supporting: The highest population minor allele frequency in gnomAD v2.1.1 (exomes) is 0.0004978 (9/18078 alleles) in the East Asian population, which is lower than the ClinGen LSD VCEP’s threshold for PM2_Supporting (<0.001), meeting the criterion of PM2_Supporting.
• PS3_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).

Not Met criteria codes

• PM3: The variant has been found in multiple patients identified by newborn screening programs in Taiwan and Japan (PMID: 20080426, 21232767, 31076647, 34995642). One patient was compound heterozygous for the variant and c.10.80C>G (p.Tyr360Ter), and another 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. Of note, the variant occurs in cis with psuedodeficiency variants and none of the individuals in whom it has been identified have clear symptoms of Pompe disease. Therefore, PM3 was not applied.
• PP4: This variant has been identified in multiple patients in newborn screening programs in Taiwan and Japan (PMID: 20080426, 21232767, 31076647, 34995642). However, because the variant always occurs in cis with pseudodeficiency variants, the patients in whom it has been identified typically do not have symptoms of Pompe disease, PP4 has not been applied. One patient was reported to have initial CK elevation, and hypotonia for the first few years of life, but later reported as "normal" by the family at age 13 (PMID: 34995642).
• PP3: The computational splicing predictor SpliceAl gives a score of 0.42 for donor loss which is below the threshhold score value of 0.5 predicting the damaging effect. PP3 not met.