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) 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.

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.