Submissions for variant NM_000158.4(GBE1):c.1570C>T (p.Arg524Ter)

gnomAD frequency: 0.00006  dbSNP: rs137852888

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000490013	SCV000577268	pathogenic	not provided	2021-11-26	criteria provided, single submitter	clinical testing	Nonsense 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; Published functional studies demonstrate GBE activity is inactivated (Bao Y et al., 1996); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 26166723, 15452297, 22305237, 29379554, 31589614, 30094188, 33332610, 8613547)
Invitae	RCV001052971	SCV001217211	pathogenic	Glycogen storage disease, type IV; Glycogen storage disease IV, classic hepatic	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg524*) 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 (rs137852888, gnomAD 0.007%). This premature translational stop signal has been observed in individuals with GBE1-related disease (PMID: 8613547, 15452297). ClinVar contains an entry for this variant (Variation ID: 2781). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000056093	SCV001520378	pathogenic	Glycogen storage disease, type IV	2024-03-29	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000490013	SCV002024210	pathogenic	not provided	2019-09-23	criteria provided, single submitter	clinical testing
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV000056093	SCV002053833	likely pathogenic	Glycogen storage disease, type IV		criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000056093	SCV002074257	pathogenic	Glycogen storage disease, type IV	2022-01-14	criteria provided, single submitter	clinical testing	Variant summary: GBE1 c.1570C>T (p.Arg524X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 3.7e-05 in 243478 control chromosomes. c.1570C>T has been reported in the literature in individuals affected with Glycogen Storage Disease, Type IV (example, Bao_1996, Bruno_2004, Bendroth-Asmussen_2016). At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (example, Bao_1996). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000056093	SCV002097091	pathogenic	Glycogen storage disease, type IV	2022-01-27	criteria provided, single submitter	curation	The p.Arg524Ter variant in GBE1 has been reported in 4 individuals with glycogen storage disease type IV (GSD IV) (PMID: 29379554, 15452297, 8613547, 26166723) and has been identified in 0.007% (8/111504) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs137852888). 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. Of the 4 affected individuals, 1 was a compound heterozygote that carried a reported pathogenic variant in trans, and 1 was a compound heterozygote that carried a variant of uncertain significance in trans, which increases the likelihood that the p.Arg524Ter variant is pathogenic (Variation ID#: 208584; PMID: 29379554, 26166723). This variant has also been reported in ClinVar (Variation ID#: 2781) and has been interpreted as pathogenic by OMIM, GeneDx, Baylor Genetics, Invitae, GeneReviews, and Natera. This nonsense variant leads to a premature termination codon at position 524, which is 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. The phenotype of individuals homozygous or compound heterozygous for this variant is highly specific for GSD IV based on strict biochemical investigations consistent with disease (PMID: 8613547). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive GSD IV. ACMG/AMP Criteria applied: PVS1, PM2_supporting, PM3, PP4 (Richards 2015).
Fulgent Genetics, Fulgent Genetics	RCV002490300	SCV002797622	pathogenic	Adult polyglucosan body disease; Glycogen storage disease, type IV	2022-03-07	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000490013	SCV005050937	pathogenic	not provided	2024-05-01	criteria provided, single submitter	clinical testing	GBE1: PVS1, PM2
OMIM	RCV000002913	SCV000023071	pathogenic	Glycogen storage disease IV, classic hepatic	2004-09-28	no assertion criteria provided	literature only
OMIM	RCV000002914	SCV000023072	pathogenic	Glycogen storage disease due to glycogen branching enzyme deficiency, childhood neuromuscular form	2004-09-28	no assertion criteria provided	literature only
GeneReviews	RCV000056093	SCV000087164	pathologic	Glycogen storage disease, type IV	2009-04-02	no assertion criteria provided	curation	Converted during submission to Pathogenic.
Natera, Inc.	RCV000056093	SCV001460445	pathogenic	Glycogen storage disease, type IV	2020-09-16	no assertion criteria provided	clinical testing