ClinVar Miner

Submissions for variant NM_000158.4(GBE1):c.1570C>T (p.Arg524Ter)

gnomAD frequency: 0.00006  dbSNP: rs137852888
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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000490013 SCV000577268 pathogenic not provided 2021-11-26 criteria provided, single submitter clinical testing Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate GBE activity is inactivated (Bao Y et al., 1996); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 26166723, 15452297, 22305237, 29379554, 31589614, 30094188, 33332610, 8613547)
Invitae RCV001052971 SCV001217211 pathogenic Glycogen storage disease, type IV; Glycogen storage disease IV, classic hepatic 2020-09-17 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg524*) in the GBE1 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs137852888, ExAC 0.003%). This variant has been observed in individuals affected with GBE1-related disease (PMID: 8613547, 15452297). ClinVar contains an entry for this variant (Variation ID: 2781). Loss-of-function variants in GBE1 are known to be pathogenic (PMID: 9851430, 15452297, 20058079, 23034915). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000056093 SCV001520378 pathogenic Glycogen storage disease, type IV 2019-04-30 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing in patients [PMID 8613547, 25525159] and is predicted to cause nonsense mediated decay
Kasturba Medical College, Manipal, Manipal Academy of Higher Education RCV000056093 SCV002053833 likely pathogenic Glycogen storage disease, type IV criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000056093 SCV002074257 pathogenic Glycogen storage disease, type IV 2022-01-14 criteria provided, single submitter clinical testing Variant summary: GBE1 c.1570C>T (p.Arg524X) 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 3.7e-05 in 243478 control chromosomes. c.1570C>T has been reported in the literature in individuals affected with Glycogen Storage Disease, Type IV (example, Bao_1996, Bruno_2004, Bendroth-Asmussen_2016). At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (example, Bao_1996). Five 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 RCV000056093 SCV002097091 pathogenic Glycogen storage disease, type IV 2022-01-27 criteria provided, single submitter curation The p.Arg524Ter variant in GBE1 has been reported in 4 individuals with glycogen storage disease type IV (GSD IV) (PMID: 29379554, 15452297, 8613547, 26166723) and has been identified in 0.007% (8/111504) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs137852888). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. Of the 4 affected individuals, 1 was a compound heterozygote that carried a reported pathogenic variant in trans, and 1 was a compound heterozygote that carried a variant of uncertain significance in trans, which increases the likelihood that the p.Arg524Ter variant is pathogenic (Variation ID#: 208584; PMID: 29379554, 26166723). This variant has also been reported in ClinVar (Variation ID#: 2781) and has been interpreted as pathogenic by OMIM, GeneDx, Baylor Genetics, Invitae, GeneReviews, and Natera. This nonsense variant leads to a premature termination codon at position 524, which is predicted to lead to a truncated or absent protein. Loss of function of the GBE1 gene is an established disease mechanism in autosomal recessive GSD IV. The phenotype of individuals homozygous or compound heterozygous for this variant is highly specific for GSD IV based on strict biochemical investigations consistent with disease (PMID: 8613547). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive GSD IV. ACMG/AMP Criteria applied: PVS1, PM2_supporting, PM3, PP4 (Richards 2015).
OMIM RCV000002913 SCV000023071 pathogenic Glycogen storage disease IV, classic hepatic 2004-09-28 no assertion criteria provided literature only
OMIM RCV000002914 SCV000023072 pathogenic Glycogen storage disease due to glycogen branching enzyme deficiency, childhood neuromuscular form 2004-09-28 no assertion criteria provided literature only
GeneReviews RCV000056093 SCV000087164 pathologic Glycogen storage disease, type IV 2009-04-02 no assertion criteria provided curation Converted during submission to Pathogenic.
Natera, Inc. RCV000056093 SCV001460445 pathogenic Glycogen storage disease, type IV 2020-09-16 no assertion criteria provided clinical testing
PerkinElmer Genomics RCV000490013 SCV002024210 pathogenic not provided 2019-09-23 no assertion criteria provided clinical testing

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