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Variant: NM_000152.5(GAA):c.546G>T (p.Thr182=)

CA16041884

370637 (ClinVar)

Gene: GAA
Condition: glycogen storage disease II
Inheritance Mode: Autosomal recessive inheritance
UUID: 9490a55c-4cd0-44b3-859b-a915cd935f7e

HGVS expressions

NM_000152.5:c.546G>T
NM_000152.5(GAA):c.546G>T (p.Thr182=)
NC_000017.11:g.80105132G>T
CM000679.2:g.80105132G>T
NC_000017.10:g.78078931G>T
CM000679.1:g.78078931G>T
NC_000017.9:g.75693526G>T
NG_009822.1:g.8577G>T
ENST00000302262.8:c.546G>T
ENST00000302262.7:c.546G>T
ENST00000390015.7:c.546G>T
ENST00000570803.5:c.546G>T
ENST00000577106.5:c.546G>T
NM_000152.3:c.546G>T
NM_001079803.1:c.546G>T
NM_001079804.1:c.546G>T
NM_000152.4:c.546G>T
NM_001079803.2:c.546G>T
NM_001079804.2:c.546G>T
NM_001079803.3:c.546G>T
NM_001079804.3:c.546G>T

Pathogenic

Met criteria codes 5
PM2_Supporting PM3_Strong PS3 PP4_Moderate PP3
Not Met criteria codes 1
BP7

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Lysosomal Diseases VCEP
The NM_000152.5:c.546C>T (p.Thr182=) variant in GAA is a synonymous (silent) variant that alters the last nucleotide of exon 2 and has been found to impact splicing of intron 2 (PMID 19609281, 21757382, 33168984). At least 20 patients with Pompe disease and this variant have been reported including 17 patients with documented laboratory values for GAA activity <10% of normal mean control level of GAA activity in leukocytes, <30% of normal mean control level of GAA activity in cultured fibroblasts or activity in the affected range in cultured skin fibroblasts, leukocytes, lymphocytes, or dried blood spot (PMID 19609281, 21982629, 25388776, 28433475, 29124014, 30093193); pseudodeficiency variants are confirmed absent in one of these patients (PMID 28433475)(PP4_Moderate). The patients typically have late onset Pompe disease and are of East Asian descent. Of these patients, two are compound heterozygous for the variant and a variant that has been classified as pathogenic by the ClinGen LSD VCEP, including c.118C>T (p.Arg40Ter) (PMID 29124014, ClinVar SCV SCV001371737.1), and c.1935C>A (p.Asp645Glu)(PMID 21757382), and seven patients are homozygous for the variant (PMID 20202878, 21982629, 29124014, 30093193). Additional patients are compound heterozygous for the variant and a missense variant - c.796C>T (p.Pro266Ser) (PMID 29124014), c.1099T>G (p.Trp367Gly) (PMID 29124014), c.1316T>A (p.Met439Lys)(PMID 28433475), p.Arg600Cys (PMID 19609281, 20202878, 21982629), c.2171C>A (p.Ala724Asp)(PMID 25388776), c.2481G>A (p.Gln827His) (PMID 29124014); the in trans data from these patients will be used in assessment of these variants and is not included here in order to avoid circular logic (PM3_Strong). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). Results of RT-PCR and subsequent sequencing of cDNA from patient skin fibroblasts from multiple studies are consistent with c.546G>T being a leaky splice variant, with production of some normal transcript in addition to skipping of exon 2 and use of a cryptic splice site in intron 2 (PMID 19609281, 21757382, 33168984)(PS3). Consistent with this finding, the computational splicing predictor SpliceAI gives a score of 0.69 for donor loss, predicting that the variant disrupts the donor splice site of intron 2 of GAA (PP3). Of note, additional variants at this position, c.546G>A (ClinVar Variation ID: 280955) and c.546G>C (ClinVar Variation ID: 281056), have also been reported in patients with Pompe disease. There is a ClinVar entry for this variant (Variation ID: 370637, 1 star review status) with one submitter classifying the variant as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Storage Disorders Variant Curation Expert Panel (ACMG/AMP specifications version 2.0): PS3, PM3_Strong, PP4_Moderate, PP3, PM2_Supporting.
Met criteria codes
PM2_Supporting
This variant is absent in gnomAD v2.1.1 (PM2_Supporting)
PM3_Strong
At least 20 patients with Pompe disease and this variant have been reported. Of these patients, two are compound heterozygous for the variant and a variant that has been classified as pathogenic by the ClinGen LSD VCEP, including c.118C>T (p.Arg40Ter) (PMID 29124014, ClinVar SCV SCV001371737.1, 0.5 points), c.1935C>A (p.Asp645Glu)(PMID 21757382, 0.5 points), and (p.Arg608Ter)(PMID 20202878, 21982629, 0.5 points). Seven patients are homozygous for the variant (PMID 20202878, 21982629, 29124014, 30093193; exceeds maximum 1 point). Additional patients are compound heterozygous for the variant and a missense variant - c.796C>T (p.Pro266Ser) (PMID 29124014), c.1099T>G (p.Trp367Gly) (PMID 29124014), c.1316T>A (p.Met439Lys)(PMID 28433475), p.Arg600Cys (PMID 19609281, 20202878, 21982629), c.2171C>A (p.Ala724Asp)(PMID 25388776), c.2481G>A (p.Gln827His) (PMID 29124014); the in trans data from these patients will be used in assessment of these variants and is not included here in order to avoid circular logic. Total 2.5 points (PM3_Strong).
PS3
Results of RT-PCR and subsequent sequencing of cDNA from patient skin fibroblasts from multiple studies are consistent with c.546G>T being a leaky splice variant, with production of some normal transcript in addition to skipping of exon 2 and use of a cryptic splice site in intron 2 (PMID 19609281, 21757382, 33168984)(PS3).
PP4_Moderate
There are at least 17 patients with Pompe disease and this variant who have a documented laboratory values for GAA activity <10% of normal mean control level of GAA activity in leukocytes, <30% of normal mean control level of GAA activity in cultured fibroblasts or activity in the affected range in cultured skin fibroblasts, leukocytes, lymphocytes, or dried blood spot (PMID 19609281, 21982629, 25388776, 28433475, 29124014, 30093193) of which pseudodeficiency variants are confirmed absent in one (PMID 28433475)(PP4_Moderate).
PP3
The computational splicing predictor SpliceAI gives a score of 0.69 for donor loss, predicting that the variant disrupts the donor splice site of intron 2 of GAA (PP3).
Not Met criteria codes
BP7
HumansSplicing Finder, NNSPLICE and MaxEntScan all predict the donor splice site to be lost.
Approved on: 2021-12-02
Published on: 2021-12-02
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