ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.118C>T (p.Arg40Ter) (rs767409395)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel, ClinGen RCV000589039 SCV001371737 pathogenic Glycogen storage disease, type II 2020-04-06 reviewed by expert panel curation 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.
GeneDx RCV000489843 SCV000577073 pathogenic not provided 2018-11-22 criteria provided, single submitter clinical testing The R40X pathogenic variant in the GAA gene has been reported previously in multiple individuals with glycogen storage disease type II in the homozygous state, as well as in the heterozygous state in the presence of a second GAA variant (McCready et al., 2007; Sampaolo et al., 2013; Reuser et al., 1995). Additionally, functional studies in transfected COS cells and patient fibroblast cells showed that R40X resulted in reduced enzyme activity and impacts the function of the protein (Reuser et al., 1995). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. We interpret R40X as a pathogenic variant.
Integrated Genetics/Laboratory Corporation of America RCV000589039 SCV000695642 pathogenic Glycogen storage disease, type II 2016-02-03 criteria provided, single submitter clinical testing Variant summary: The c.118C>T variant in GAA is a nonsense mutation. The mutation is predicted to lead to a truncated/absent protein. It has been reported in multiple affected individuals with Pompe disease, including homozygous pt with classic infantile onset and nearly absent residual enzyme activity. The variant is present in ExAC at low frequency (0.0009%) which does not exceed the maximum frequency for a pathogenic variant in GAA gene (0.42%). Lastly, it has been classified as pathogenic via publications and/or reputable databases/clinical laboratories. Taken together, the variant was classified as Pathogenic.
Broad Institute Rare Disease Group,Broad Institute RCV000589039 SCV001422669 pathogenic Glycogen storage disease, type II 2019-11-18 no assertion criteria provided curation The p.Arg40Ter variant in GAA has been reported in at least 12 individuals (7 Italian, 1 German, 1 French, 1 Portuguese, and 1 Pakistani individuals) with Glycogen Storage Disease II, segregated with disease in 7 affected relatives from 1 family (PMID: 17723315, 9266392, 22676651, 11071489, 20559845, 24107549), and has been identified in 0.001% (4/275242) of chromosomes by the Genome Aggregation Database (gnomAD,; dbSNP rs767409395). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported pathogenic in ClinVar by GeneDx and Integrated Genetics/Laboratory Corporation of America (Variation ID: 426593). This nonsense variant leads to a premature termination codon at position 40, which is predicted to lead to a truncated or absent protein. Loss of function of the GAA gene is an established disease mechanism in autosomal recessive Glycogen Storage Disease II. The presence of this variant in combination with a reported pathogenic variant and in the homozygous state in individuals with Glycogen Storage Disease II increases the likelihood that the p.Arg40Ter variant is pathogenic (PMID: 17723315, 22958975, 22676651). The phenotype of individuals homozygous and compound heterozygous for this variant is highly specific for Glycogen Storage Disease II based on low relative GAA activity consistent with disease (PMID: 22676651, 22958975, 24107549, 17723315). In summary, this variant meets criteria to be classified as pathogenic for Glycogen Storage Disease II in an autosomal recessive manner based on the predicted impact of this variant and multiple occurrences with pathogenic variants in individuals with Glycogen Storage Disease II. ACMG/AMP Criteria applied: PVS1, PM3, PP4, PM2 (Richards 2015).

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