ClinGen Dosage Sensitivity Curation Page

PGK1

Curation Status: Complete

Gene Information

Location Information

Evidence for Loss Phenotypes

Evidence for loss of function 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.

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.

Evidence for Triplosenstive Phenotype

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.

NOTE:The loss of function score should be used to evaluate deletions, and the triplosensitivity score should be used to evaluated duplications. CNVs encompassing more than one gene must be evaluated in their totality (e.g. overall size, gain vs. loss, presence of other genes, etc). The rating of a single gene within the CNV should not necessarily be the only criteria by which one defines a clinical interpretation. Individual interpretations must take into account the phenotype described for the patient as well as issues of penetrance and expressivity of the disorder. ACMG has published guidelines for the characterization of postnatal CNVs, and these recommendations should be utilized (Genet Med (2011)13: 680-685). Exceptions to these interpretive correlations will occur, and clinical judgment should always be exercised.