ClinVar Miner

Submissions for variant NM_000158.4(GBE1):c.760A>G (p.Thr254Ala)

gnomAD frequency: 0.00004  dbSNP: rs770427750
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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Center for Human Genetics Tuebingen RCV000416121 SCV000493291 likely pathogenic not provided 2018-09-01 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV001147052 SCV001307824 uncertain significance Adult polyglucosan body disease 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina RCV001147053 SCV001307825 uncertain significance Glycogen storage disease, type IV 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Invitae RCV001245740 SCV001419045 pathogenic Glycogen storage disease, type IV; Glycogen storage disease IV, classic hepatic 2024-01-02 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 254 of the GBE1 protein (p.Thr254Ala). This variant is present in population databases (rs770427750, gnomAD 0.009%). This missense change has been observed in individual(s) with glycogen storage disease IV (PMID: 30569318, 33332610). ClinVar contains an entry for this variant (Variation ID: 374517). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GBE1 protein function. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000416121 SCV001793167 likely pathogenic not provided 2023-09-20 criteria provided, single submitter clinical testing Observed heterozygous in an individual with glycogen storage disease type IV, however no second GBE1 variant was identified (Said et al., 2016); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20058079, 33332610, 30228975, 27243974, 27107456, 36628840, 30569318, 36830903)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001584110 SCV001821319 uncertain significance not specified 2021-08-20 criteria provided, single submitter clinical testing Variant summary: GBE1 c.760A>G (p.Thr254Ala) results in a non-conservative amino acid change located in the Glycosyl hydrolase, family 13, catalytic domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.4e-05 in 242554 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in GBE1 causing Glycogen Storage Disease, Type IV (5.4e-05 vs 0.0013), allowing no conclusion about variant significance. c.760A>G has been reported in the literature in two individuals affected with Glycogen Storage Disease, Type IV who have reported second mutations (Schene_2018) along with one patient who had only one mutation reported (Said_2016). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Two classified as VUS while one classified as likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center RCV000416121 SCV002061657 uncertain significance not provided 2021-10-26 criteria provided, single submitter clinical testing PM2
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV001147053 SCV002097116 uncertain significance Glycogen storage disease, type IV 2022-01-27 criteria provided, single submitter curation The p.Thr254Ala variant in GBE1 has been reported in 2 individuals with glycogen storage disease type IV (GSD IV) (PMID: 30569318), segregated with disease in 1 individual from 1 family (PMID: 33332610) and has been identified in 0.01% (13/111154) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs770427750). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. Of the 3 affected individuals, 1 was a compound heterozygote that carried a reported pathogenic variant in trans, which increases the likelihood that the p.Gly264Glu variant is pathogenic (VariationID: 208584; PMID: 30569318). This variant has also been reported in ClinVar (Variation ID#: 374517) and has been interpreted as likely pathogenic by CeGaT Praxis fuer Humangenetik Tuebingen, and as a variant of uncertain significance by Illumina Clinical Services Laboratory (Illumina), Invitae, GeneDx, and Women's Health and Genetics (Laboratory Corporation of America, LabCorp). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Thr254Ala variant is uncertain. ACMG/AMP Criteria applied: PP3, PM3 (Richards 2015).
MGZ Medical Genetics Center RCV001147053 SCV002581806 likely pathogenic Glycogen storage disease, type IV 2022-08-22 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV001147052 SCV004100752 pathogenic Adult polyglucosan body disease 2023-09-28 criteria provided, single submitter clinical testing Criteria applied: PM3_VSTR,PM2_SUP,PP3
Baylor Genetics RCV001147053 SCV004198660 pathogenic Glycogen storage disease, type IV 2023-10-23 criteria provided, single submitter clinical testing
Natera, Inc. RCV001147053 SCV002082387 uncertain significance Glycogen storage disease, type IV 2021-04-02 no assertion criteria provided clinical testing

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