ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.258dup (p.Asn87fs) (rs761317813)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000790707 SCV000334520 pathogenic not provided 2015-08-18 criteria provided, single submitter clinical testing
Invitae RCV000291526 SCV000816240 pathogenic Glycogen storage disease, type II 2020-09-10 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Asn87Glnfs*9) in the GAA gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs761317813, ExAC 0.005%). This variant has been observed in several individuals affected with glycogen storage disease II (PMID: 16917947, 21484825, 10206684). ClinVar contains an entry for this variant (Variation ID: 282842). Loss-of-function variants in GAA are known to be pathogenic (PMID: 2252923, 18425781, 22252923). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000291526 SCV001338289 pathogenic Glycogen storage disease, type II 2020-02-09 criteria provided, single submitter clinical testing Variant summary: GAA c.258dupC (p.Asn87GlnfsX9) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 1.2e-05 in 246016 control chromosomes. c.258dupC has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) (example, Beesley_1998, Montalvo_2006, Bali_2011, Nallamilli_2018, Kishnani_2019). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Broad Institute Rare Disease Group, Broad Institute RCV000291526 SCV001422880 pathogenic Glycogen storage disease, type II 2020-01-22 no assertion criteria provided curation The heterozygous p.Asn87GlnfsTer9 variant in GAA has been reported in 5 individuals (including 1 from the UK and 1 Italian individual) with Glycogen Storage Disease II (PMID: 16917947, 26873529, 21484825, 10206684), and has also been reported pathogenic by EGL Genetic Diagnostics and Invitae in ClinVar (Variation ID: 282842). Data from large population studies is insufficient to assess the frequency of this variant. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 87 and leads to a premature termination codon 9 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the GAA gene is a moderately established disease mechanism in autosomal recessive Glycogen Storage Disease II. The presence of this variant in combination with a pathogenic variant and in an individual with Glycogen Storage Disease II increases the likelihood that the p.Asn87GlnfsTer9 variant is pathogenic (PMID: 26873529). The phenotype of an individual heterozygous for this variant is highly specific for Glycogen Storage Disease II with less than 5% of normal GAA activity detected in their fibroblasts (PMID: 21484825, 26873529). In summary, this variant meets criteria to be classified as pathogenic for Glycogen Storage Disorder II in an autosomal recessive manner based on the predicted impact of the variant and an occurrence with a pathogenic GAA variant in an individual with Glycogen Storage Disorder II. ACMG/AMP Criteria applied: PVS1, PM3_Supporting, PP4 (Richards 2015).
Natera, Inc. RCV000291526 SCV001453579 pathogenic Glycogen storage disease, type II 2020-09-16 no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000790707 SCV001807617 pathogenic not provided no assertion criteria provided clinical testing

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