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) describes a 36-year old male who presented with, according to the authors, recurrent ?exertional myoglobinuria and muscle cramp without hemolytic anemia or CNS symptoms." Muscle and erythrocyte glycolytic enzyme activity revealed PGK-deficiency with 2.9% and 5.6% PGK activity, respectively. A 4-basepair deletion in exon 6 of the PGK1 gene was observed, resulting in a frameshift and truncated protein (c.716_719delGGCG). The variant was inherited from a phenotypically normal mother whose erythrocyte PGK enzyme activity was 62.5%.
16567715 Shirakawa et al (2006) describes a 33-year old male who presented with recurrent myoglobinuria and developmental delay. Muscle and erythrocyte glycolytic enzyme activity revealed PGK-deficiency with 8.9% and 13.6% PGK activity, respectively. An IVS7+5G>A substitution variant in the PGK1 gene was detected. This intron 7 substitution variant results in a 52-basepair insertion causing a frameshift and premature termination of the PGK1 protein product. The variant was inherited from a phenotypically normal mother whose erythrocyte PGK enzyme activity was 60.7%. The proband?s presumed unaffected brother was negative for the variant and had an erythrocyte PGK enzyme activity of 98.5%.
26883264 Coppens et al (2016) describes two male siblings age 14 and 16 who present with mild intellectual deficiency, exercise intolerance, muscle pain and weakness, rhabdomyolysis, seizures, and no hemolysis. Red blood cell PGK enzyme activity of both brothers was <15% of controls (34 U/g Hb and 35 U/g Hb). A c.756+3A>G substitution variant in the PGK1 gene was detected. This intron 7 variant results in four aberrantly spliced transcript variants. Three of the four aberrant transcript variants resulted in a frameshift and premature termination of the PGK1 protein product. The fourth aberrant transcript variant resulted in an 18 base pair deletion of exon 7. The variant was inherited from a phenotypically normal mother whose red blood cell PGK enzyme activity was 181 U/g Hb (reference range: 188-302 U/g Hb).
31658606 Garcia-Solaesa et al (2019) describes a 40 year old male who presented with mild psychomotor delay, mild intellectual disability, exercise intolerance, cramps and sporadic episodes of rhabdomyolysis, with not hematological features. Peripheral blood PGK enzyme activity was decreased, 39 U/g Hb (reference range: 197-343 U/g Hb). A c.1114G>A (p.G372S) substitution variant in the PGK1 gene was detected. This variant in exon 9 results in two aberrantly spliced transcript variants, both resulting in a frameshift and premature termination of the PGK1 protein product (p.G313Vfs*20 and p.G372Gfs*11). The variant was inherited from a phenotypically normal mother. However, PGK enzymatic activity was not assessed in the mother.

Haploinsufficiency phenotype comments:

Tsujino et al (1994; PMID: 8122886) describes a 12-year old male with myoglobinuria, mild developmental delay, and attention-deficit disorder. Muscle and erythrocyte glycolytic enzyme activity revealed PGK-deficiency with 2.0% and 2.7% PGK activity, respectively. A G>T substitution at the 5? end of intron 4 of the PGK1 gene was detected. Based on cDNA sequence analysis, the intronic G>T substitution results in aberrant splicing leading to an in-frame 30-basepair insertion between exon 4 and exon 5. This splice site variant does not cause frameshift or premature termination of the PGK1 protein product, but rather an insertion of 10 new amino acids between exon 4 and exon 5. Parents were not available for testing. Behlmann et al (2019; PMID 30570712) describes a 64-year old male who presented with childhood-onset metabolic myopathy. Muscle glycolytic enzyme activity revealed PGK-deficiency with 15% PGK activity. Congruent myopathic symptoms were noted in the proband?s maternal uncle, brother, and sister?s son. No history of, ?neurologic dysfunction? was noted in the proband or other affected family members. Array CGH identified an 886-kb deletion approximately 600-basepairs downstream of the translation termination site of the PGK1 gene (hg19, g.77,381,971-78,268,131). This deletion includes the 3?UTR of the PGK1 gene and five additional genes. The deletion was observed in the proband?s affected brother, no other family members were available for testing. Quantitative RNA analysis of both the proband and brother demonstrated a reduction (37-40%) in transcript levels of PGK1 when compared to that of sex-matched unaffected controls. 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 variants with documented reduced enzyme activity. See Beutler (2007) for review, PMID: 17222195. Most affected individuals are male and carrier females are unaffected; however, some affected females have been reported. Based on the specificity of the PGK enzymatic activity along with the available case study evidence haploinsufficiency of PGK1 is considered likely pathogenic.

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.