ClinVar Miner

Submissions for variant NM_000158.4(GBE1):c.555+1G>T

gnomAD frequency: 0.00006  dbSNP: rs759707498
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services,Illumina RCV000779419 SCV000916034 uncertain significance GBE1-Related Disorders 2018-11-16 criteria provided, single submitter clinical testing The GBE1 c.555+1G>T variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. A literature search was performed for the gene and cDNA change. No publications were found based on this search. The c.555+1G>T variant is reported at a frequency of 0.000790 in the Latino population of the Exome Aggregation Consortium. Based on the variant frequency, disease prevalence, disease penetrance, and inheritance mode, this variant could not be ruled out of causing disease. Due to the potential impact of splice donor variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for GBE1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV001377777 SCV001575200 likely pathogenic Glycogen storage disease, type IV; Glycogen storage disease IV, classic hepatic 2020-08-10 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 4 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 (rs759707498, ExAC 0.08%). This variant has not been reported in the literature in individuals with GBE1-related conditions. ClinVar contains an entry for this variant (Variation ID: 632422). Experimental studies and prediction algorithms are not available or were not evaluated, and the effect of this variant on mRNA splicing is currently unknown. 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: 15452297, 20058079). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Broad Institute Rare Disease Group, Broad Institute RCV001825518 SCV002097123 uncertain significance Glycogen storage disease, type IV 2022-01-27 criteria provided, single submitter curation The c.555+1G>T variant in GBE1 has not been previously reported in the literature in individuals with GBE1-related disorders but has been identified in 0.04% (14/31638) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs759707498). 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. This variant has also been reported in ClinVar (Variation ID#: 632422) and has been interpreted as likely pathogenic by Invitae. This variant is located in the 3' splice region. Computational tools predict a splicing impact, though this information is not predictive enough to determine pathogenicity. This variant is adjacent to an in-frame exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. Loss of function of the GBE1 gene is an established disease mechanism in autosomal recessive GBE1-related disorders. In summary, the clinical significance of the c.555+1G>T variant is uncertain. ACMG/AMP Criteria applied: PVS1_moderate (Richards 2015).
Natera, Inc. RCV001825518 SCV002082389 likely pathogenic Glycogen storage disease, type IV 2020-06-03 no assertion criteria provided clinical testing

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