ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.2662G>T (p.Glu888Ter) (rs765718882)

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Total submissions: 5
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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 RCV000701656 SCV001371767 pathogenic Glycogen storage disease, type II 2020-05-04 reviewed by expert panel curation This variant, c.2662G>T (p.Glu888Ter), is a nonsense variant that is predicted to result in nonsense-mediated decay and lack of gene product, meeting PVS1. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00027 in the East Asian population, meeting PM2. At least 6 patients have been reported with this variant and deficiency of GAA activity meeting the ClinGen LSD VCEP's PP4 specifications. One of these individuals is compound heterozygous for the variant and c.-32-13T>G, phase unknown (PMID 16531044), and another is homozygous for the variant (PMID 17723315). This data meets PM3. Other individuals meeting PP4 specifications are compound heterozygous for the variant and either c.1574T>A (p.Phe525Tyr) (PMID 21232767), c.1935C>A (p.Asp645Glu) (PMID 18458862), or c.2238G>C (p.Trp746Cys) (PMID 25526786). However in each case, the in trans data from these patients will be used in the assessment of the other variant and was not used here in order to avoid a circular argument. Additional cases with the variant have been reported but were not included because the residual GAA activity was not provided, and therefore PP4 cannot be assessed (PMIDs 24269976, 25455803, 25626711, 27417441, 28394184, 31743840), or the patient carried a pseudodeficiency allele (PMID 21232767). There is a ClinVar entry for this variant (Variation ID: 578595) 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, PP4.
Invitae RCV000701656 SCV000830468 pathogenic Glycogen storage disease, type II 2019-05-16 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu888*) in the GAA gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs765718882, ExAC 0.02%). This variant has been reported as homozygous, or with a second variant, in several individuals affected with glycogen storage disease, type II (GSDII), also known as Pompe disease (PMID: 17723315, 16531044, 28394184, 21644219, 28032299, 18458862, 20080426). 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.
Integrated Genetics/Laboratory Corporation of America RCV000701656 SCV000919385 pathogenic Glycogen storage disease, type II 2018-12-20 criteria provided, single submitter clinical testing Variant summary: GAA c.2662G>T (p.Glu888X) 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. The variant allele was found at a frequency of 2e-05 in 245054 control chromosomes (gnomAD). The variant, c.2662G>T, has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) in both compound heterozygotes and homozygotes (Kostera-Pruszczyk_2006, Liu_2014, Chen_2017), and is one of the most common disease variant in Northern Chinese. These data indicate that the variant is likely to be associated with disease. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV001091540 SCV001247659 pathogenic not provided 2018-02-01 criteria provided, single submitter clinical testing
Broad Institute Rare Disease Group,Broad Institute RCV000701656 SCV001422961 pathogenic Glycogen storage disease, type II 2020-01-22 no assertion criteria provided curation The p.Glu888Ter variant in GAA has been reported in at least 8 individuals with glycogen storage disease (PMID: 25526786, 21232767, 18458862, 17723315, 16531044) and has been identified in 0.027% (5/18392) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs765718882). 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 in ClinVar as pathogenic by Invitae and Integrated Genetics (VariationID: 578595). This nonsense variant leads to a premature termination codon at position 888, 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. The phenotype of individuals homozygous for this variant is highly specific for glycogen storage disease based on GAA enzyme activity in lymphocytes and fibroblasts being <10% of wild type, consistent with disease (PMID: 25526786, 21232767, 17723315, 18458862). In addition, the presence of this variant in individuals with glycogen storage disease has been observed in combination with reported pathogenic and likely pathogenic variants (VariationID: 265160, 4027, 4029, 4032; PMID: 25526786, 21232767, 18458862, 17723315, 16531044). In summary, this variant meets criteria to be classified as pathogenic for glycogen storage disease II in an autosomal recessive manner based on the prediction that it will cause loss of function of the GAA gene and the presence of the variant in combination with numerous other pathogenic variants in affected individuals with phenotypes highly specific for GAA. ACMG/AMP Criteria applied: PVS1, PM3_supporting, PP4_moderate, PM2 (Richards 2015).

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