ClinVar Miner

Submissions for variant NM_000294.3(PHKG2):c.643G>A (p.Asp215Asn)

gnomAD frequency: 0.00001  dbSNP: rs767427889
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Centre for Human Genetics RCV001293806 SCV001482513 pathogenic Glycogen storage disease IXc 2020-08-27 criteria provided, single submitter clinical testing disease causing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001553756 SCV001774748 uncertain significance not specified 2021-07-22 criteria provided, single submitter clinical testing Variant summary: PHKG2 c.643G>A (p.Asp215Asn) results in a conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251486 control chromosomes (gnomAD). c.643G>A has been reported in the literature in individuals (both homozygous and compound heterozygous) affected with Glycogen Phosphorylase Kinase Deficiency (Burwinkel_2003, Roscher_2014). These data indicate that the variant may be associated with disease. Enzymatic activity from patient derived erythrocytes from homozygous patient show reduced activity (Burwinkel_2003). The variant was also reported in an animal model of PHKG2-mutatnt PhK deficiency (gsd rat) without providing further biochemical/functional details (Maichele_1996). One ClinVar submitter (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Invitae RCV001293806 SCV004297718 likely pathogenic Glycogen storage disease IXc 2023-12-18 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 215 of the PHKG2 protein (p.Asp215Asn). This variant is present in population databases (rs767427889, gnomAD 0.006%). This missense change has been observed in individuals with glycogen storage disease, (PMID: 12930917, 25266922, 35834487). ClinVar contains an entry for this variant (Variation ID: 998119). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PHKG2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PHKG2 function (PMID: 8896567). 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.

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