ClinVar Genomic variation as it relates to human health

Identified in one affected individual from a genome-wide association study of hypertriglyceridemia, in one participant of the ClinSeq project who harbored another GCKR variant in cis with R540X, and in an unrelated individual with familial chylomicronemia syndrome (Johansen et al., 2010; Rees et al., 2012; D'Erasmo et al., 2019); Published cell-based expression assays showed undetectable protein expression (Rees et al., 2014); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene or region of a gene for which loss of function is not a well-established mechanism of disease; This variant is associated with the following publications: (PMID: 24879641, 31619059, 25525159, 20657596, 32041611, 34426522)

This sequence change creates a premature translational stop signal (p.Arg540*) in the GCKR gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in GCKR cause disease. This variant is present in population databases (rs146053779, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with hypertriglyceridemia (PMID: 20657596). ClinVar contains an entry for this variant (Variation ID: 1189882). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.