Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003398507 | SCV004122786 | pathogenic | Glycogen phosphorylase kinase deficiency | 2023-10-12 | criteria provided, single submitter | clinical testing | Variant summary: PHKB c.306-2A>G 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: Three predict the variant abolishes a 3 acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.2e-05 in 251128 control chromosomes (gnomAD). c.306-2A>G has been reported in the literature in one individual affected with Glycogen Phosphorylase Kinase Deficiency (Burwinkel_1997). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 17689125, 33858366, 9402963). No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. |
| Invitae | RCV000014589 | SCV004297721 | likely pathogenic | Glycogen storage disease IXb | 2023-12-02 | criteria provided, single submitter | clinical testing | This sequence change affects an acceptor splice site in intron 3 of the PHKB gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs797044442, gnomAD 0.006%). Disruption of this splice site has been observed in individual(s) with glycogen storage disease (PMID: 9402963). This variant is also known as IVS4 [–2A>G]. ClinVar contains an entry for this variant (Variation ID: 13619). Studies have shown that disruption of this splice site results in skipping of exon 4 and introduces a premature termination codon (PMID: 9402963). The resulting mRNA is expected to undergo nonsense-mediated decay. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
| OMIM | RCV000014589 | SCV000034843 | pathogenic | Glycogen storage disease IXb | 1997-12-01 | no assertion criteria provided | literature only |