PCK2

Inheritance Pattern: AR

Disease ID:MONDO:0009864

Submitter: ClinGen

PCK2 encodes the mitochondrial phosphoenolpyruvate carboxykinase (PEPCK-M), a mitochondrial matrix enzyme that catalyzes the conversion of oxaloacetate to phosphoenolpyruvate. In contrast to the cytosolic isoform (PCK1), PCK2 primarily functions in cataplerosis, linking the tricarboxylic acid (TCA) cycle to glycolysis and multiple biosynthetic pathways rather than serving as the principal gluconeogenic enzyme. Although the mechanisms regulating PCK2 transcription remain incompletely understood, PCK2 has been shown to play an important role in cellular adaptation to metabolic stress, particularly in cancer cells, where it promotes survival during amino acid starvation and endoplasmic reticulum stress (PMID: 34020084). PCK deficiency was first described in 1974 by Fiser et al. (https://doi.org/10.1203/00006450-197404000-00552 PMID: unavailable), based on the clinical phenotype and markedly reduced hepatic phosphoenolpyruvate carboxykinase activity measured in liver biopsy specimens . A subsequent report by Hommes et al. (PMID: 176867) described a similar biochemical phenotype. However, these historical reports predated molecular genetic testing and therefore could not establish a relationship between *PCK2* and disease. A later publication reported a single individual with compound heterozygous variants in *PCK2*; however, both variants were classified as variants of uncertain significance, had benign in silico predictions, and lacked sufficient functional or segregation evidence to support pathogenicity. In addition, the clinical information was limited, and this case was not scored. More recently, two individuals with biallelic *PCK2 *variants were reported with peripheral neuropathy (Sondheimer et al., PMID: 36845668). Although *Pck2 *knockout mice demonstrated reduced sural nerve conduction velocities, occasional temporal dispersion, and increased variability in axon and myelin sheath diameters, consistent with a mild demyelinating peripheral neuropathy, the reported human evidence remains limited and has not been independently replicated. Consequently, this evidence was not scored for the present curation. Experimental studies have also implicated *PCK2* in skeletal development. Li et al. generated *Pck2* knockout mice that developed skeletal dysplasia and demonstrated partial rescue of the skeletal phenotype following metformin treatment (Li et al., PMID: 36376627). Because these studies were performed independently of the human genetic evidence supporting the disease association curated here, they were not scored. In summary, there is limited evidence supporting the relationship between *PCK2* and autosomal recessive PEPCK deficiency, mitochondrial. This classification was approved by the ClinGen IEM GCEP at the meeting on June 26, 2026 (SOP Version 12).

Inheritance Pattern: AR

Disease ID:MONDO:0005244

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0017320

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0009864

Submitter: Ambry Genetics