Submissions for variant NM_000158.4(GBE1):c.1909C>T (p.Arg637Ter)

gnomAD frequency: 0.00001  dbSNP: rs766935302

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000303766	SCV000446284	likely pathogenic	GBE1-Related Disorders	2017-04-28	criteria provided, single submitter	clinical testing	The GBE1 c.1909C>T (p.Arg637Ter) variant is a stop-gained variant that has been reported in three studies, in which it is found in a total of three individuals with the most severe form of glycogen storage disorder type IV, including in one in a homozygous state and in two in a compound heterozygous state (Bruno et al. 2004; Janecke et al. 2004; Jimenez-Mallebrera et al. 2009). The p.Arg637Ter variant was absent from 120 control chromosomes but reported at a frequency of 0.00005 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies in both individual fibroblasts and muscle tissue demonstrated that the variant resulted in less than five percent of glycogen branching enzyme activity compared to wild type (Bruno et al. 2004; Jimenez-Mallebrera et al. 2009). Due to the potential impact of stop-gained variants and the supporting evidence, the p.Arg637Ter variant is considered to be pathogenic for GBE1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae	RCV000808547	SCV000948657	pathogenic	Glycogen storage disease, type IV; Glycogen storage disease IV, classic hepatic	2024-01-27	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg637*) 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 (rs766935302, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with glycogen storage disease (PMID: 15452297, 15520786, 17915577). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 346785). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001275347	SCV002097077	pathogenic	Glycogen storage disease, type IV	2022-01-27	criteria provided, single submitter	curation	The p.Arg637Ter variant in GBE1 has been reported in 4 individuals with glycogen storage disease type IV (GSD IV) (PMID: 15452297, 15520786, 19438752, 31747834) and has been identified in 0.007% (1/15366) of African/African-American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs766935302). 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 of those was a homozygote and 1 was a compound heterozygote that carried a reported variant of uncertain significance in trans, which increases the likelihood that the p.Arg637Ter variant is pathogenic (PMID: 19438752, 31747834). This variant has also been reported in ClinVar (Variation ID#: 346785) and has been interpreted as likely pathogenic or pathogenic by Illumina Clinical Services Laboratory, Invitae and Natera. This nonsense variant leads to a premature termination codon at position 637, 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: 15452297, 19438752). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive GSD IV. ACMG/AMP Criteria applied: PVS1, PM2_supporting, PM3_supporting, PP4 (Richards 2015).
Baylor Genetics	RCV001275347	SCV004198696	pathogenic	Glycogen storage disease, type IV	2023-07-24	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001275347	SCV001460441	pathogenic	Glycogen storage disease, type IV	2020-09-16	no assertion criteria provided	clinical testing