ClinVar Miner

Submissions for variant NM_000158.4(GBE1):c.1492G>A (p.Glu498Lys)

gnomAD frequency: 0.00071  dbSNP: rs201758548
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Total submissions: 18
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000660623 SCV000791516 uncertain significance Glycogen storage disease, type IV 2017-05-17 criteria provided, single submitter clinical testing
Eurofins Ntd Llc (ga) RCV000728026 SCV000855546 uncertain significance not provided 2017-07-12 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000764514 SCV000895596 uncertain significance Adult polyglucosan body disease; Glycogen storage disease, type IV 2022-04-18 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV000779417 SCV000916032 uncertain significance Adult polyglucosan body disease 2018-01-17 criteria provided, single submitter clinical testing The GBE1 c.1492G>A (p.Glu498Lys) missense variant has been reported in a compound heterozygous state with a splice site variant in one individual with adult polyglucosan body disease, whose unaffected mother was noted to be a carrier of this variant (Naddaf et al. 2016). Analysis of patient's leukocytes showed only seven percent of normal GBE enzyme activity while the unaffected mother showed 62 percent of normal enzyme activity. Control data are unavailable for this variant, which is reported at a frequency of 0.001347 in the South Asian population of the Exome Aggregation Consortium database. Based on the limited evidence, the p.Glu498Lys variant is classified a variant of unknown significance but suspicious for pathogenicity for adult polyglucosan body disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Illumina Laboratory Services, Illumina RCV000660623 SCV001308701 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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Invitae RCV001240088 SCV001413011 uncertain significance Glycogen storage disease, type IV; Glycogen storage disease IV, classic hepatic 2022-10-24 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 498 of the GBE1 protein (p.Glu498Lys). This variant is present in population databases (rs201758548, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with GBE1-related conditions (PMID: 26789422). ClinVar contains an entry for this variant (Variation ID: 548007). 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) performed at Invitae indicates that this missense variant is expected to disrupt GBE1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Mayo Clinic Laboratories, Mayo Clinic RCV000728026 SCV001713289 uncertain significance not provided 2023-02-15 criteria provided, single submitter clinical testing BS1, PP3, PP4, PM3
CeGaT Center for Human Genetics Tuebingen RCV000728026 SCV001746775 uncertain significance not provided 2023-11-01 criteria provided, single submitter clinical testing GBE1: PM3, PM2:Supporting, PP3
GeneDx RCV000728026 SCV001767594 uncertain significance not provided 2022-03-24 criteria provided, single submitter clinical testing Reported in trans with a GBE1 splicing variant in a patient with an unusual manifestation of adult polyglucosan body disease, whose GBE enzyme activity in blood leukocytes was 7% of normal levels (Naddaf et al., 2016); 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: 26789422, 34946936, 34426522)
Broad Institute Rare Disease Group, Broad Institute RCV000779417 SCV002097094 uncertain significance Adult polyglucosan body disease 2022-01-27 criteria provided, single submitter curation The p.Glu498Lys variant in GBE1 has been reported in 1 individual. in the compound heterozygous state, with adult polyglucosan body disease (APBD) (PMID: 26789422) and has been identified in 0.1% (32/24784) of European (Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs201758548). 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. 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.Glu498Lys variant is uncertain. ACMG/AMP Criteria applied: PP3 (Richards 2015).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003117462 SCV003800663 uncertain significance not specified 2023-01-05 criteria provided, single submitter clinical testing Variant summary: GBE1 c.1492G>A (p.Glu498Lys) results in a conservative amino acid change located in the Glycosyl hydrolase, family 13, catalytic domain (IPR006047) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00073 in 240226 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in GBE1 causing Glycogen Storage Disease, Type IV (0.00073 vs 0.0013), allowing no conclusion about variant significance. c.1492G>A has been reported in the literature as a compound heterozygous genotype in at-least one individual affected with Adult polyglucosan body disease (APBD) (example, Naddaf_2016) and as a homozygous genotype in at-least one individual affected with Glycogen storage disease type IV (example, Ersoy_2021). 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. Twelve 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 uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Preventiongenetics, part of Exact Sciences RCV003403524 SCV004121536 uncertain significance GBE1-related condition 2023-08-05 criteria provided, single submitter clinical testing The GBE1 c.1492G>A variant is predicted to result in the amino acid substitution p.Glu498Lys. This variant has been reported in the compound heterozygous state in a patient with adult polyglucosan body disease (Naddaf et al. 2016. PubMed ID: 26789422). Of note, GBE1 exon 12 has previously been reported as a mutation “hotspot” (Moses and Parvari. 2002. PubMed ID: 11949934) and exon 12 mutations have been associated with a wide range of clinical phenotypes (for review, see Li et al. 2010. PubMed ID: 20058079). This variant is reported in 0.13% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-81627202-C-T) and is interpreted as uncertain by many outside laboratories in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/548007/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000728026 SCV001807261 uncertain significance not provided no assertion criteria provided clinical testing
Clinical Genetics, Academic Medical Center RCV000728026 SCV001918609 uncertain significance not provided no assertion criteria provided clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000728026 SCV001963216 uncertain significance not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000728026 SCV001972924 uncertain significance not provided no assertion criteria provided clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV000728026 SCV002035822 uncertain significance not provided no assertion criteria provided clinical testing
Natera, Inc. RCV000660623 SCV002082379 uncertain significance Glycogen storage disease, type IV 2020-01-13 no assertion criteria provided clinical testing

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