ClinVar Genomic variation as it relates to human health

The G6PC c.379_380dupTA (p.Tyr128ThrfsTer3) variant, also referred to as c.376_377insTA, causes a frameshift and is predicted to truncate the protein. The p.Tyr128ThrfsTer3 variant was first identified by Lei et al. (1993) in a homozygous state in an individual whose liver biopsy contained no detectable G6Pase activity. Since then, the variant has been identified in several affected Hispanic individuals in both the homozygous and compound heterozygous state, and is a known common variant in individuals with glycogen storage disease (GSD) type Ia, accounting for approximately 50% of disease alleles in Hispanic populations (Lei et al. 1995; Rake et al. 2000; Matern et al. 2002; Koeberl et al. 2009; Wang et al. 2013). The variant was also shown to segregate with disease (Lei et al. 1995). Control data are not reported for this variant in these studies, but the variant is reported at a frequency of 0.00115 in the Latino population of the Exome Aggregation Consortium. Transient expression analysis of the p.Tyr128ThrfsTer3 variant showed the variant abolished G6Pase activity (Rake et al. 2000). Based on the collective evidence, the p.Tyr128ThrfsTer3 variant is classified as pathogenic for glycogen storage disease type I. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

Variant summary: G6PC c.379_380dupTA (p.Tyr128ThrfsX3) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 0.00011 in 251208 control chromosomes. c.379_380dupTA has been reported in the literature in multiple individuals affected with Glycogen Storage Disease Type Ia (example, Lei_1993, Wang_2013, Peeks_2017). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Lei_1993). The most pronounced variant effect results in no detectable G6Pase activity in liver biopsy specimens from an affected patient. Seven 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.

PP4, PM2, PM3, PS4_moderate, PVS1

This sequence change creates a premature translational stop signal (p.Tyr128Thrfs*3) in the G6PC gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in G6PC are known to be pathogenic (PMID: 8182131). This variant is present in population databases (rs756356652, gnomAD 0.07%). This premature translational stop signal has been observed in individuals with glycogen storage disease type Ia (PMID: 8211187, 22899091, 28397058). ClinVar contains an entry for this variant (Variation ID: 11997). For these reasons, this variant has been classified as Pathogenic.

NM_000151.3(G6PC):c.379_380dupTA(Y128Tfs*3) is classified as pathogenic in the context of glycogen storage disease type Ia. Sources cited for classification include the following: PMID 8211187, 22899091, 12373566 and 7573034. Classification of NM_000151.3(G6PC):c.379_380dupTA(Y128Tfs*3) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.

Published functional studies demonstrate a damaging effect, abolishing G6pase catalytic activity completely (PMID: 7814621); 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: 8211187, 31589614, 34258141, 28397058, 7814621)