ClinGen Dosage Sensitivity Curation Page

PGK1

  • Curation Status: Complete

Location Information

Select assembly: (NC_000023.10) (NC_000023.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
10720297 Hamano et al (2000) report a 36-year old male with PGK1-deficiency presenting with myopathy who had a 4-basepair deletion in exon 6 that results in a frameshift and truncated protein. This deletion was inherited from a phenotypically normal mother whose enzyme activity was at 62.5%. This patient was also found to carry a missense mutation in the PGK1 gene (published previously - PMID: 9512313).
16567715 Shirakawa et al (2006) report a 33-year old male with PGK1-deficiency presenting with myopathy and intellectual disability who had a substitution at IVS7 + 5 G>A which resulted in a 52-basepair insertion and premature protein truncation. Reduced enzyme levels were shown. The mutation was inherited from a normal mother.
8122886 Tsujino et al (1994) report a 12-year old boy with myopathy and intellectual disability who had a mutation of the consensus sequence at the 5' splice junction of intron 4 that led to an in-frame 30-basepair insertion. PGK enzyme activity was 2.7% of control value. Parental specimens were not available for testing.

Haploinsufficiency phenotype comments:

PGK1-deficiency, as measured by enzyme activity, can cause non-spherocytic hemolytic anemia, CNS involvement leading to intellectual disability, seizures, and other neurological symptoms, and myopathy. Most reported families have missense mutations with documented reduced enzyme activity (PMID: 19157875, 16412025). See Beutler (2007) for review, PMID: 17222195. Spanu et al report an affected father and daughter in whom a mutation was not identified but aberrant splicing is suspected. All affected individuals are shown to have reduced levels of PGK1 activity, consistent with a loss of function mechanism. Most affected individuals are male and carrier females are unaffected; however, some affected females have been reported.

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.