Submissions for variant NM_000293.3(PHKB):c.1969C>T (p.Gln657Ter)

dbSNP: rs34667348

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000014588	SCV000397083	likely pathogenic	Glycogen storage disease IXb	2019-04-08	criteria provided, single submitter	clinical testing	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000014588	SCV000829149	pathogenic	Glycogen storage disease IXb	2025-01-23	criteria provided, single submitter	clinical testing	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.
CeGaT Center for Human Genetics Tuebingen	RCV001171912	SCV001334813	pathogenic	not provided	2020-03-01	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000014588	SCV001367515	pathogenic	Glycogen storage disease IXb	2018-10-05	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2.
GeneDx	RCV001171912	SCV001790723	pathogenic	not provided	2025-02-05	criteria provided, single submitter	clinical testing	Reported (as Q656ter) in two individuals with glycogen storage disease type IX who also harbored a second variant in the PHKB gene (PMID: 9215682); 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; This variant is associated with the following publications: (PMID: 25525159, 9215682, 34426522, 31589614, 35854365, 35257483)
Revvity Omics, Revvity	RCV000014588	SCV002018780	pathogenic	Glycogen storage disease IXb	2019-12-05	criteria provided, single submitter	clinical testing
3billion, Medical Genetics	RCV000014588	SCV002520991	pathogenic	Glycogen storage disease IXb	2022-05-22	criteria provided, single submitter	clinical testing	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.
Fulgent Genetics, Fulgent Genetics	RCV000014588	SCV002793213	pathogenic	Glycogen storage disease IXb	2024-06-07	criteria provided, single submitter	clinical testing
OMIM	RCV000014588	SCV000034842	pathogenic	Glycogen storage disease IXb	1997-07-01	no assertion criteria provided	literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001171912	SCV001740137	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001171912	SCV001972541	pathogenic	not provided		no assertion criteria provided	clinical testing