ClinVar Miner

Submissions for variant NM_000158.4(GBE1):c.671T>C (p.Leu224Pro)

gnomAD frequency: 0.00002  dbSNP: rs137852886
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000056134 SCV000797793 likely pathogenic Glycogen storage disease, type IV 2018-02-13 criteria provided, single submitter clinical testing
Invitae RCV001050904 SCV001215033 pathogenic Glycogen storage disease, type IV; Glycogen storage disease IV, classic hepatic 2020-09-01 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 224 of the GBE1 protein (p.Leu224Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been observed in combination with another GBE1 variant in individual with glycogen storage disease or polyglucosan body myopathy (PMID: 25665141, 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: 2778). This variant has been reported to affect GBE1 protein function (PMID: 8613547). For these reasons, this variant has been classified as Pathogenic.
Broad Institute Rare Disease Group, Broad Institute RCV000056134 SCV002097121 likely pathogenic Glycogen storage disease, type IV 2022-01-27 criteria provided, single submitter curation The p.Leu224Pro variant in GBE1 has been reported in at least 4 individuals with GBE1-related disorders (PMID: 8613547, 25665141, 23034915) and has been identified in 0.01% (1/9498) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs137852886). 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 4 affected individuals, 1 was a compound heterozygote that carried a reported pathogenic variant in trans, and 3 were compound heterozygotes that carried a reported pathogenic variant with unknown phase, which increases the likelihood that the p.Leu224Pro variant is pathogenic (VariationID: 2777; PMID: 8613547, 25665141, 23034915). This variant has also been reported in ClinVar (Variation ID#: 2778) and has been interpreted as likely pathogenic/pathogenic by Counsyl, Invitae, GeneReviews, and OMIM. In vitro functional studies provide some evidence that the p.Leu224Pro 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 GBE1-related disorders. ACMG/AMP Criteria applied: PP3, PS3_supporting, PM3_strong (Richards 2015).
OMIM RCV000002909 SCV000023067 pathogenic Glycogen storage disease IV, nonprogressive hepatic 1996-02-15 no assertion criteria provided literature only
GeneReviews RCV000056134 SCV000087213 pathologic Glycogen storage disease, type IV 2009-04-02 no assertion criteria provided curation Converted during submission to Pathogenic.
OMIM RCV000210781 SCV000266855 pathogenic Adult polyglucosan body neuropathy 1996-02-15 no assertion criteria provided literature only

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