ClinVar Miner

Submissions for variant NM_000158.4(GBE1):c.691+2T>C (rs192044702)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV001449661 SCV000245614 pathogenic Glycogen storage disease 2020-06-16 criteria provided, single submitter clinical testing The c.691+2T>C variant in GBE1 has been reported in at least 3 compound heterozygous individuals with glycogen storage disease IV and segregated with disease in at least 2 affected relatives from 1 family (Fernandez 2010 PMID:19813197, Ravenscroft 2013 PMID:23218673, Schene 2018 PMID:30569318). It has also been reported in ClinVar (Variation ID 208584) and has been identified in 0.14% (160/110918) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). 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 occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. Loss of function of the GBE1 gene is an established disease mechanism in autosomal recessive glycogen storage disease IV. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive glycogen storage disease IV. ACMG/AMP Criteria applied: PVS1, PM3_Strong, PP1_Moderate.
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000224184 SCV000280944 pathogenic not provided 2015-03-05 criteria provided, single submitter clinical testing
GeneDx RCV000224184 SCV000321703 pathogenic not provided 2018-12-11 criteria provided, single submitter clinical testing The c.691+2T>C pathogenic variant in the GBE1 gene has been reported previously in association with glycogen storage disorder, type IV (GSD IV) and with adult polyglucosan body disease in individuals who also had a second pathogenic GBE1 variant on the opposite allele (Fernandez et al., 2010; Ravenscroft et al., 2013; Lopez Chiriboga, 2017). The c.691+2T>C variant was observed with a frequency of 0.14% (153/110,290 alleles) in individuals of non-Finnish European background in large population cohorts (Lek et al., 2016). This splice site variant destroys the canonical splice donor site in intron 5. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. We interpret c.691+2T>C as a pathogenic variant.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000224184 SCV000342180 pathogenic not provided 2016-06-02 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000368399 SCV000446308 pathogenic GBE1-Related Disorders 2017-10-13 criteria provided, single submitter clinical testing The GBE1 c.691+2T>C splice donor variant has been reported in a total of seven individuals, including five with glycogen storage disease type IV (GSD IV) and two with adult polyglucosan body disease (APBD) (Fernandez et al. 2010; Ravenscroft et al. 2013; Bendroth-Asmussen et al. 2016; Kuhn et al. 2016; Franco-Palacios et al. 2016; Lopez Chiriboga 2017). All five individuals with GSD IV and one individual with APBD were compound heterozygous for the variant. In addition, one individual with APBD was heterozygous for the c.691+2T>C variant and homozygous for another intronic variant in the GBE1 gene (Franco-Palacios et al. 2016). The c.691+2T>C variant was also identified in a heterozygous state in two unaffected individuals (Ravenscroft et al. 2013; Dainese et al. 2014). Control data are unavailable for this variant, which is reported at a frequency of 0.00196 in the European (non-Finnish) population of the Exome Aggregation Consortium. Two studies noted significantly reduced GBE enzyme activity in individual fibroblasts (Fernandez et al. 2010; Ravenscroft et al. 2013). Based on the evidence and due to the potential impact of splice donor variants, the p.691+2T>C variant is classified as pathogenic for GBE1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Mayo Clinic Laboratories, Mayo Clinic RCV000660553 SCV000782662 pathogenic Adult polyglucosan body disease; Glycogen storage disease, type IV 2017-05-22 criteria provided, single submitter clinical testing
Counsyl RCV000190589 SCV000792913 pathogenic Glycogen storage disease, type IV 2017-08-03 criteria provided, single submitter clinical testing
Invitae RCV000706641 SCV000835705 pathogenic Glycogen storage disease, type IV; Glycogen storage disease IV, classic hepatic 2020-10-20 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 5 of the GBE1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs192044702, ExAC 0.2%). This variant has been reported in individuals affected with glycogen storage disease type IV (PMID: 19813197, 23218673, 26166723). ClinVar contains an entry for this variant (Variation ID: 208584). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and 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.
Fulgent Genetics,Fulgent Genetics RCV000660553 SCV000894328 pathogenic Adult polyglucosan body disease; Glycogen storage disease, type IV 2018-10-31 criteria provided, single submitter clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV000190589 SCV000996223 pathogenic Glycogen storage disease, type IV 2018-12-06 criteria provided, single submitter clinical testing This variant affects the canonical splice donor site of intron 5 of 15, and is therefore predicted to interfere with splicing and result in loss of normal protein function. This variant has been previously reported as a compound heterozygous change in patients with GBE1 glycogen storage disease (PMID: 23218673, 19813197). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.082% (183/223430; max AF: 0.0013 in European populations) and thus is presumed to be rare. Multiple splice prediction tools suggest this variant is likely to interfere with normal splicing. Based on the available evidence, the c.691+2T>C variant is classified as Pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000224184 SCV001248812 pathogenic not provided 2021-03-01 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000190589 SCV001366207 pathogenic Glycogen storage disease, type IV 2020-02-03 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP5.
Mayo Clinic Laboratories, Mayo Clinic RCV000224184 SCV001713290 pathogenic not provided 2021-02-18 criteria provided, single submitter clinical testing PVS1, PS3, PS4_moderate, PP1, PP3
Natera, Inc. RCV000190589 SCV001461486 pathogenic Glycogen storage disease, type IV 2020-09-16 no assertion criteria provided clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000224184 SCV001742769 pathogenic not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000224184 SCV001808499 pathogenic not provided no assertion criteria provided clinical testing

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