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

gnomAD frequency: 0.00004  dbSNP: rs770427750

Total submissions: 14

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.
Labcorp Genetics (formerly Invitae), Labcorp	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	2025-01-10	criteria provided, single submitter	clinical testing	Observed heterozygous in an individual with glycogen storage disease type IV, however no second GBE1 variant was identified (PMID: 27107456); 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, 36830903, 38164512, 27107456, 36628840, 30569318, 37152446)
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	2024-03-30	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005027476	SCV005657837	likely pathogenic	Adult polyglucosan body disease; Glycogen storage disease, type IV	2024-05-24	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
Solve-RD Consortium	RCV001147053	SCV005091243	likely pathogenic	Glycogen storage disease, type IV	2022-06-01	no assertion criteria provided	provider interpretation	Variant confirmed as disease-causing by referring clinical team