ClinGen Dosage Sensitivity Curation Page

GK

Curation Status: Complete

Gene Information

Location Information

Evidence for Loss Phenotypes

Evidence for loss of function phenotype
PubMed ID Description
8651297 Walker et al. (1996) report mutations in GK in 3 families with isolated GK deficiency. Pt 1 had no GK activity, but was in good health. A splice site mutation resulting in a premature stop codon was identified. Pts 2 & 3 were brothers with a deletion of exon 17. Pt 2 had a more severe phenotype, including growth and psychomotor retardation delay, bone dysplasia, and seizures, while Pt 3 had normal development. Pt 4 had ID and a missense mutation was identified (D440V).
9719371 Sjarif et al. (1998) report mutations in GK in 3 families with isolated GK deficiency. The phenotypes varied greatly among the probands, though all had GK deficiency. The reported mutations included a 20 kb deletion near the 3' end of the gene, a nonsense mutation (R413X), and a missense change (W503R).
10851254 Sargent et al. (2000) report 5 mutations in GK in patients with isolated GK deficiency, including two nonsense changes (R310X and Q403X).

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.