ClinVar Miner

Submissions for variant NM_000158.4(GBE1):c.1804-2A>T

dbSNP: rs1224090803
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001378284 SCV001575821 likely pathogenic Glycogen storage disease, type IV; Glycogen storage disease IV, classic hepatic 2023-06-04 criteria provided, single submitter clinical testing Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. ClinVar contains an entry for this variant (Variation ID: 1067109). This variant has not been reported in the literature in individuals affected with GBE1-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change affects an acceptor splice site in intron 13 of the GBE1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site 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).
Broad Institute Rare Disease Group, Broad Institute RCV001826137 SCV002097081 likely pathogenic Glycogen storage disease, type IV 2022-01-27 criteria provided, single submitter curation The c.1804-2A>T variant in GBE1 has not been previously reported in the literature in individuals with GBE1-related disorders but has been identified in 0.0009% (1/107714) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs1224090803). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID#: 1067109) and has been interpreted as likely pathogenic by Invitae. This variant is located in the 5' splice region. Computational tools predict a splicing impact, though this information is not predictive enough to determine pathogenicity. Loss of function of the GBE1 gene is an established disease mechanism in autosomal recessive GBE1-related disorders. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive GBE1-related disorders. ACMG/AMP Criteria applied: PVS1, PM2 (Richards 2015).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003317492 SCV004020476 likely pathogenic GBE1-Related Disorders 2023-06-27 criteria provided, single submitter clinical testing Variant summary: GBE1 c.1804-2A>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4.3e-06 in 229908 control chromosomes. To our knowledge, no occurrence of c.1804-2A>T in individuals affected with GBE1-Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics RCV001826137 SCV004198738 likely pathogenic Glycogen storage disease, type IV 2022-09-20 criteria provided, single submitter clinical testing

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