ClinVar Genomic variation as it relates to human health

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; Reported (as Q656ter) in two individuals with glycogen storage disease type IX who also harbored a second variant in the PHKB gene (Burwinkel et al., 1997); This variant is associated with the following publications: (PMID: 25525159, 9215682, 34426522, 31589614)

This sequence change creates a premature translational stop signal (p.Gln657*) in the PHKB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PHKB are known to be pathogenic (PMID: 9215682, 9326319). This variant is present in population databases (rs34667348, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with glycogen storage disease (PMID: 9215682). ClinVar contains an entry for this variant (Variation ID: 13618). 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.

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2.

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.010%). Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000013618). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

The PHKB c.1969C>T (p.Gln657Ter) variant is a stop-gained variant predicted to result in premature termination of the protein. The p.Gln657Ter variant has been reported in a single study in which it was identified in a compound heterozygous state with a null variant on the second allele in two patients with glycogen storage disease due to phosphorylase kinase deficiency, one in combination with a frameshift variant and one with another stop-gained variant (Burwinkel et al. 1997). The p.Gln657Ter variant was reported in a heterozygous state in one of the unaffected parents. Control data are unavailable for this variant, which is reported at a frequency of 0.00021 in the European (non-Finnish) population of the Exome Aggregation Consortium. Analysis of PhK activity in patient erythrocytes demonstrated that each had 12-13% residual PhK activity compared to wild-type, with the heterozygous parent having 56% of normal activity (Burwinkel et al. 1997). Based on the evidence and the potential impact of stop-gained variants, the p.Gln657Ter variant is classified as likely pathogenic for phosphorylase kinase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.The PHKB c.1969C>T (p.Gln657Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. The p.Gln657Ter variant has been reported in a single study in which it is found in a compound heterozygous state in two patients with glycogen storage disease due to phosphorylase kinase deficiency, one in combination with a frameshift variant and one with another stop-gained variant (Burwinkel et al. 1997). The p.Gln657Ter variant was reported in a heterozygous state in one of the unaffected parents. Control data are unavailable for this variant, which is reported at a frequency of 0.00021 in the European (Non-Finnish) population of the Exome Aggregation Consortium. Analysis of PhK activity in patient erythrocytes demonstrated that each had 12-13% residual PhK activity compared to wild type, with the heterozygous parent having 56% of normal activity (Burwinkel et al. 1997). Based on the evidence and the potential impact of stop-gained variants, the p.Gln657Ter variant is classified as likely pathogenic for phosphorylase kinase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.