Submissions for variant NM_000158.4(GBE1):c.1468del (p.Leu490fs)

gnomAD frequency: 0.00002  dbSNP: rs774465102

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000523375	SCV000617539	pathogenic	not provided	2022-10-06	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 15019703, 30311141)
Invitae	RCV001203493	SCV001374661	pathogenic	Glycogen storage disease, type IV; Glycogen storage disease IV, classic hepatic	2023-12-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu490Trpfs*5) in the GBE1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GBE1 are known to be pathogenic (PMID: 15452297, 20058079). This variant is present in population databases (rs774465102, gnomAD 0.07%). This premature translational stop signal has been observed in individuals with glycogen storage disease IV (PMID: 15019703, 15520786, 30311141). ClinVar contains an entry for this variant (Variation ID: 449406). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000523375	SCV002024213	pathogenic	not provided	2023-11-17	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001275350	SCV002097097	likely pathogenic	Glycogen storage disease, type IV	2022-01-27	criteria provided, single submitter	curation	The p.Leu490fs variant in GBE1 has been reported in 3 individuals with glycogen storage disease type IV (GSD IV) and has been identified in 0.08% (26/32980) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs774465102). 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#: 449406) and has been interpreted as pathogenic by Invitae, GeneDx, and Natera. Of the 3 affected individuals, 2 were compound heterozygotes that carried reported pathogenic/likely pathogenic variants in trans and with unknown phase, which increases the likelihood that the p.Leu490fs variant is pathogenic (VariationID: 452861, 346785; PMID: 30311141, 15520786). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 490 and leads to a premature termination codon 5 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the GBE1 gene is an established disease mechanism in autosomal recessive GSD IV. 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: PVS1, PM3 (Richards 2015).
Baylor Genetics	RCV001275350	SCV004198689	pathogenic	Glycogen storage disease, type IV	2023-08-10	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001275350	SCV001460448	pathogenic	Glycogen storage disease, type IV	2020-09-16	no assertion criteria provided	clinical testing