PC

Inheritance Pattern: AR

Disease ID:MONDO:0009949

Submitter: ClinGen

*PC* was first reported in relation to autosomal recessive pyruvate carboxylase deficiency in 1987 (Yoshida Y et al., PMID: 5358431). Pyruvate carboxylase (PC) deficiency is a metabolic disorder typically presenting with poor growth, developmental delay, epilepsy, and metabolic acidosis, and is classified into three clinical forms of varying severity. Type A (infantile form) involves early-onset lactic acidosis, motor delay, intellectual disability, growth failure, and neurologic features such as hypotonia, ataxia, and seizures, with death often occurring in early childhood. Type B (severe neonatal form) is the most severe, presenting in the neonatal period with hypothermia, respiratory failure, profound lactic acidosis, hyperammonemia, and neurologic impairment, usually leading to death within the first eight months of life. Type C (intermittent/attenuated form) is milder, characterized by relatively normal or mildly delayed development, episodic metabolic acidosis, movement abnormalities, and rare seizures, with some individuals surviving into adulthood. Several variants (e.g., missense, splice site, frameshift) have been reported in multiple probands in three publications (PMID: 37207470, PMID: 24114256, PMID: 35782291) and are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts) has been reached. The mechanism of pathogenicity is reported to be loss of function. Disease severity in pyruvate carboxylase deficiency shows a loose genotype–phenotype correlation: missense and intronic variants are more commonly associated with the milder types A and C, while truncating or nonsense variants are typically linked to the more severe type B. However, it remains unclear whether additional disease-modifying factors influence outcomes for specific variants (Lasio MLD et al., PMID: 20301764). Of note, one specific variant has been identified as a founder mutation (c.1828G>A; p.A610T) in North American Indigenous populations (Ojibwa and Cree), where it is associated with type A pyruvate carboxylase deficiency characterized by infantile onset, profound developmental delay, and early childhood mortality (Lasio MLD et al., PMID: 20301764; Mhanni AA et al., PMID: 34485016). Functional studies of PC demonstrate its essential role in mitochondrial metabolism. In non-patient renal tubular epithelial cells (CL:0005010), loss of PC resulted in impaired mitochondrial function and an altered cellular metabolic state, consistent with disruption of its canonical enzymatic activity as a pyruvate carboxylase (GO:0004736) (Huang H et al., PMID: 39836535). In summary, there is definitive evidence supporting the relationship between *PC* and autosomal recessive pyruvate carboxylase deficiency. This has been repeatedly demonstrated in both research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen IEM GCEP at the meeting on April 10, 2026 (SOP Version 12).

Inheritance Pattern: AR

Disease ID:MONDO:0018141

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0018142

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0018143

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0009949

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0009949

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0009949

Submitter: Myriad Women's Health

Inheritance Pattern: AR

Disease ID:MONDO:0009949

Submitter: PanelApp Australia