Submissions for variant NM_000158.4(GBE1):c.1336-1G>A

dbSNP: rs375253942

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001381386	SCV001579758	pathogenic	Glycogen storage disease, type IV; Glycogen storage disease IV, classic hepatic	2023-10-22	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 10 of the GBE1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in GBE1 are known to be pathogenic (PMID: 15452297, 20058079). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. Disruption of this splice site has been observed in individual(s) with GBE1-related conditions (PMID: 16874838). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1069503). 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	RCV001826157	SCV002097099	uncertain significance	Glycogen storage disease, type IV	2022-01-27	criteria provided, single submitter	curation	The c.1336-1G>A variant in GBE1 has been reported in 1 individual, in the homozygous state, with glycogen storage disease type IV (GSD IV) (PMID: 16874838), segregated with disease in 1 affected relative from the same family, and has been identified in 0.001% (1/100886) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs375253942). 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#: 1069503) and has been interpreted as pathogenic by Invitae. This variant is located in the 5' splice region. Computational tools predict a splicing impact, though this information is not predictive enough to determine pathogenicity. This variant is adjacent to an in-frame exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. Loss of function of the GBE1 gene is an established disease mechanism in autosomal recessive GSD IV. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PVS1_moderate, PM2_supporting, PM3_supporting (Richards 2015).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001826157	SCV003928815	likely pathogenic	Glycogen storage disease, type IV	2023-04-28	criteria provided, single submitter	clinical testing	Variant summary: GBE1 c.1336-1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 3' acceptor site and three predict the variant also creates a new 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4.7e-06 in 212152 control chromosomes (gnomAD). c.1336-1G>A has been reported in the literature in at least one homozygous individual affected with Glycogen Storage Disease, Type IV (e.g. Akman_2006). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 16874838). Three submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and classified it as either pathogenic (n=2) or VUS (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics	RCV001826157	SCV004198706	pathogenic	Glycogen storage disease, type IV	2023-07-03	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001826157	SCV002082383	pathogenic	Glycogen storage disease, type IV	2020-12-24	no assertion criteria provided	clinical testing