Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • See Evidence submitted by expert panel for details.

Variant: NM_000152.3(GAA):c.118C>T (p.Arg40Ter)

CA8814791

426593 (ClinVar)

Gene: GAA
Condition: glycogen storage disease II
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: 79019119-b26c-4336-8958-b3272cd7e778
Approved on: 2020-04-06
Published on: 2020-05-28

HGVS expressions

NM_000152.3:c.118C>T
NM_000152.3(GAA):c.118C>T (p.Arg40Ter)
NC_000017.11:g.80104704C>T
CM000679.2:g.80104704C>T
NC_000017.10:g.78078503C>T
CM000679.1:g.78078503C>T
NC_000017.9:g.75693098C>T
NG_009822.1:g.8149C>T
NM_001079803.1:c.118C>T
NM_001079804.1:c.118C>T
NM_000152.4:c.118C>T
NM_001079803.2:c.118C>T
NM_001079804.2:c.118C>T
NM_000152.5:c.118C>T
NM_001079803.3:c.118C>T
NM_001079804.3:c.118C>T
ENST00000302262.7:c.118C>T
ENST00000390015.7:c.118C>T
ENST00000570803.5:c.118C>T
ENST00000577106.5:c.118C>T
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Pathogenic

Met criteria codes 4
PM2 PP4 PVS1 PM3_Supporting

Evidence Links 5

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Lysosomal Diseases VCEP
This nonsense variant, c.118C>T (p.Arg40Ter), is expected to result in a premature termination codon, nonsense mediated decay, and absence of gene product, meeting PVS1. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00007 in the South Asian population, meeting PM2. The variant was found in compound heterozygosity with c.-32-13T>G, phase unknown, in two patients with Pompe disease who also meet the ClinGen LSD VCEP's PP4 criterion (PMID 22676651, 22958975), meeting PM3_Supporting. In addition, a large family has been reported with 7 affected siblings who are compound heterozygous for the variant and a variant of unknown significance, c.2647-7G>A (PMID 24107549). Additional cases with this variant have been reported but were not included because residual enzyme activity was not provided and therefore PP4 could not be assessed. There is a ClinVar entry for this variant (Variation ID: 426593, 2 star review status) with two submitters classifying the variant as pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1, PM2, PM3_Supporting, PP4.
Met criteria codes
PM2
The highest population minor allele frequency in gnomAD v2.1.1 is 0.00007 (S. Asian) which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2, meeting this criterion.
PP4
Multiple individuals have been reported with this variant and GAA activity <10% normal in lymphocytes, leukocytes or muscle samples, or <30% normal in cultured fibroblasts, or in the affected range in a clinically validated dried blood spot assay (PMIDs 24107549, 22958975, 22676651). This data meets the ClinGen LSD VCEP's specifications for PP4.
Patient 7 is compound heterozygous for c.118C>T (p.Arg40Ter) and c-32-13T>G and has 3.6% residual GAA activity (presumably in fibroblasts but tissue not stated). PubMed:22958975
Report of a family with 10 out of 13 siblings affected by late-onset Pompe disease. Three variants segregated in the family. One sibling, with a progressive undefined myopathy, was deceased. Seven siblings were compound heterozygous for c.118C > T [p.R40X] and c.2647-7G>A [p.N882fs] in GAA. Six siblings with this genotype had muscle GAA activity ranging from 2.3-3.1 pmol/min/mg protein (normal range 34 – 138) (<10% the lower limit of normal) and one (II-4) had GAA activity of 4.2 pmol/min/mg protein). In dried blood spots, the value was 0.09-0.31 (normal 1.86-219 nmol/h/l) in 6 siblings and 4.2 in II-4. PubMed:24107549
Patient 12 is compound heterozygous for c.118C>T (p.Arg40Ter) and c.-32-13T>G. The phase of the variants is unknown. GAA activity in lymphocytes is 0.5 (normal range of 9-42 nmole/mg/hr). (0.5 points) PubMed:22676651
PVS1
This is a nonsense variant which is predicted to cause nonsense mediated decay resulting in no gene product. Therefore, PVS1 can be applied.
PM3_Supporting
The variant was found in compound heterozygosity with c.-32-13T>G, phase unknown, in two patients with Pompe disease who also meet the ClinGen LSD VCEP's PP4 criterion (PMID 22676651, 22958975). Additional compound heterozygous cases have been reported but were not included because the residual GAA activity was not provided and therefore PP4 cannot be assessed. In addition, a large sibship is reported with 7 affected siblings who are compound heterozygous for the variant and a variant of unknown significance, c.2647-7G>A (PMID 24107549). Based on the ClinGen LSD VCEP's specifications, this data was given a total of 0.5 points which meets PM3_Supporting.
Patient 7 is compound heterozygous for c.118C>T (p.Arg40Ter) and c-32-13T>G and has 3.6% residual GAA activity (presumably in fibroblasts but tissue not stated). The phase of the variants is unknown. This data is not included because another patient with the same genotype, phase not confirmed, has already been included. PubMed:22958975
Report of a family with 10 out of 13 siblings affected by late-onset Pompe disease. Three variants segregated in the family. One sibling, with a progressive undefined myopathy, was deceased. Seven siblings were compound heterozygous for c.118C>T (p.Arg40X) and c.2647-7G>A [p.Asn882fs] (VOUS based on the guidelines of the ClinGen LSD VCEP) in GAA. Of note, two other siblings are compound heterozygous for c.2276G>A (p.Gly759Arg) and c.2647-7G>A, and one unaffected sibling is heterozygous for c.2276G>C. While it is highly likely that the variants are in trans, parental testing results are unavailable. Six siblings with the p.Arg40X/c.2647-7G>A genotype had muscle GAA activity <10% the lower limit of normal. PubMed:24107549
Patient PD10 is compound heterozygous for c.118C>T (p.Arg40Ter) and c.2815_2816del p.Val939fsX78. The diagnosis was based on clinical presentation and reduced GAA enzyme activity in leukocytes or dried blood spots. The phase of the variants is unknown. This data was not included because specific values for GAA activity were not provided. PubMed:24269976
Patient CD_7 is compound heterozygous for c.188C>T and c.2015G>A, p.(Arg672Gln). The phase of the variants is unknown. The patient has reduced GAA activity but the level is not available. PubMed:29869463
Patient 12 is compound heterozygous for c.118C>T (p.Arg40Ter) and c.-32-13T>G. The phase of the variants is unknown. GAA activity in lymphocytes is 0.5 (normal range of 9-42 nmole/mg/hr). (0.5 points) PubMed:22676651
Curation History
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