ClinVar Miner

Submissions for variant NM_000158.4(GBE1):c.771T>A (p.Phe257Leu)

gnomAD frequency: 0.00003  dbSNP: rs137852887
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000433912 SCV000521030 pathogenic not provided 2016-12-08 criteria provided, single submitter clinical testing The F257L variant in the GBE1 gene has previously been reported in association with glycogen storage disorder type IV in a individual who was also compound heterozygous for a nonsense variant (Bao et al., 1996). Functional analysis of F257L found that it is associated with significantly reduced enzyme activity (Bao et al., 1996). Therefore we interpret F257L to be a pathogenic variant.
Broad Institute Rare Disease Group, Broad Institute RCV000056143 SCV002097115 likely pathogenic Glycogen storage disease, type IV 2022-01-27 criteria provided, single submitter curation The p.Phe257Leu variant in GBE1 has been reported in 1 individual, in the compound heterozygous state, with glycogen storage disease type IV (GSD IV) (PMID: 8613547) and has been identified in 0.004% (1/23832) of African/African American chromosomes by the Genome Aggregation Database (gnomAD,; dbSNP ID: rs137852887). 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#: 2780) and has been interpreted as pathogenic by OMIM, GeneDx, and GeneReviews. In vitro functional studies provide some evidence that the p.Phe257Leu variant may slightly impact protein function (PMID: 8613547). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive GSD IV. ACMG/AMP Criteria applied: PP3, PM3, PM2, PS3_supporting (Richards 2015).
Invitae RCV001851594 SCV002114226 likely pathogenic Glycogen storage disease, type IV; Glycogen storage disease IV, classic hepatic 2021-08-29 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with leucine at codon 257 of the GBE1 protein (p.Phe257Leu). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and leucine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with glycogen storage disease IV (PMID: 8613547). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 2780). 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. Experimental studies have shown that this missense change affects GBE1 protein function (PMID: 8613547). 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.
OMIM RCV000002912 SCV000023070 pathogenic Glycogen storage disease IV, classic hepatic 1996-02-15 no assertion criteria provided literature only
GeneReviews RCV000056143 SCV000087224 pathologic Glycogen storage disease, type IV 2009-04-02 no assertion criteria provided curation Converted during submission to Pathogenic.

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