Submission Details

The relationship between PGM1 and PGM1-Congenital Disorder of Glycosylation (Congenital disorder of glycosylation, type It included), an autosomal recessive disorder, was evaluated using the ClinGen Clinical Validity Framework as of June, 2023. PGM1 encodes phosphoglucomutase 1, the predominant PGM isoform in most cell types, contributing to 90% of total PGM activity, except red blood cells, wherein PGM2 is the major isoform, and the brain. Redundancy of PGM1 activity in the brain correlates well with the absence of neurological phenotypes in patients with PGM1 deficiency. The primary role of phosphoglucomutase 1 is to catalyze the interconversion of glucose 1-phosphate and glucose 6-phosphate, and it is involved in several crucial metabolic pathways including glycolysis, glycogenolysis, glycogenesis and N-linked glycosylation (PMID: 24499211, 28794993). The clinical manifestations of PGM1-congenital disorder of glycosylation (PGM1-CDG) include bifid uvula, myopathy, hepatopathy, short stature, hypoglycemia and dilated cardiomyopathy.

PGM1 was first reported in relation to autosomal recessive PGM1-CDG in 2009 (Stojkovic et al, 2009; PMID: 19625727). More than 30 nonsense, splice site, frameshift, deletion/duplication and missense variants have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data.

Summary of Case Level Data (12 points): Variants in this gene have been reported in at least 8 probands in 2 publication (PMID: 19625727, 24499211). More evidence is available in the literature, but the maximum score for genetic evidence was reached.

The mechanism for disease is biallelic loss of function.

Summary of experimental data (6 points): This gene-disease relationship is supported by in vitro functional studies, model organisms and rescue evidence. The function of PGM1 is well understood and the onset of symptoms is associated with defects in glycosylation, which can be rescued to an extent by supplementing with galactose (PMID: 24499211, 28794993). Constitutive knock-out of Pgm2, the mouse ortholog of human PGM1, leads to embryonic lethality (PMID: 31077402). Cardiomyocyte-specific conditional knock-out of Pgm2 in mice recapitulates the human dilated cardiomyopathy phenotype seen in some patients with PGM1-CDG (PMID: 36709920). The defect in cKO mice is rescued when AAV-mediated WT Pgm2 is introduced into the affected animals (PMID: 36709920).

In summary, PGM1 is definitively associated with autosomal recessive PGM1-CDG. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the Congenital Disorders of Glycosylation GCEP on August 2nd, 2023.