GK
protein-codingglycerol kinase, the group of Glycerol kinases
Gene summary
The protein encoded by this gene belongs to the FGGY kinase family. This protein is a key enzyme in the regulation of glycerol uptake and metabolism. It catalyzes the phosphorylation of glycerol by ATP, yielding ADP and glycerol-3-phosphate. Mutations in this gene are associated with glycerol kinase deficiency (GKD). Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2011]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~78.1 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0010613
Submitter: Ambry Genetics
Inheritance Pattern: XL
Disease ID:MONDO:0010613
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: XL
Disease ID:MONDO:0010613
Submitter: PanelApp Australia
Inheritance Pattern: XL
Disease ID:MONDO:0010613
Submitter: G2P
Inheritance Pattern: XL
Disease ID:MONDO:0010613
Submitter: ClinGen
The relationship between GK and glycerol kinase deficiency, an X-linked disorder of glycerol metabolism, was evaluated using the ClinGen Clinical Validity Framework as of December 8, 2020. Glycerol kinase (GK) catalyzes the phosphorylation of glycerol to glycerol-3-phosphate, which is required for the production of triglycerides. Deficiency of GK results in hyperglycerolemia and glyceroluria. Three distinct clinical phenotypes have been associated with GK deficiency. The complex infantile form results from a contiguous gene syndrome that includes GK in addition to the congenital adrenal hypoplasia gene, the Duchenne muscular dystrophy gene, or both. The juvenile and adult forms result from deleterious variants within the GK gene. The juvenile form is characterized by vomiting, metabolic acidosis, and coma in the first years of life. The adult form is usually benign and often comes to attention due hypertriglyceridemia that is refractory to treatment. Because the quantitation of glycerol is commonly used as an indirect means of determining triglyceride blood levels, GK-deficient patients appear to have elevated triglycerides. However, the finding is actually due to elevated glycerol, a finding termed pseudohypertriglyceridemia (Wu et al, 2015, PMID: 25300978 (review); Lamiquiz-Maneo et al, 2020, PMID: 33212314). The disease mechanism is loss of function. Hemizygous variants in GK were first reported in patients with glycerol kinase deficiency in 1996 (Walker et al, PMID: 8651297). Since then, over thirty GK variants have been associated with GK deficiency (https://databases.lovd.nl/shared/variants/GK/unique ). The relationship between GK and GK deficiency is supported by case-level and experimental evidence. Seventeen unique variants from seventeen probands in nine publications were curated (Walker al, 1996, PMID: 8651297; Gaudet et al, 2000, PMID: 10736265; Dipple et al, 2001, PMID: 11479736; Sjarif et al, 1998, PMID: 9719371; Zhang et al, 2000, PMID: 10737976; Sjarif et al, 2004, PMID: 15026783; Zhang et al, 2006, PMID: 16549535; Zhang et al, 2015, PMID: 26309814; Lamiquiz-Maneo et al, 2020, PMID: 33212314). Segregation evidence from two families was also included (Gaudet et al, 2000, PMID: 10736265; Lamiquiz-Maneo et al, 2020, PMID: 33212314). Further information is available in the literature but the maximum score for genetic evidence (12 points) has been reached. Note that only patients with isolated GK deficiency were included i.e. no patients with the contigious gene syndrome were included in this curation due to the involvement of other genes, which complicated the clinical picture and clinical validity assessment. Experimental evidence supporting this gene-disease relationship includes the biochemical function of glycerol kinase, which is consistent with the biochemical findings of hyperglycerolemia and glyerolurina in patients (McCabe et al, 1992, PMID: 6302392; Huq et al, 1996, PMID: 8884278), the biochemical and clinical features of a Gk knock out mouse (Huq et al, 1997, PMID: 9302256), and the impact of gene therapy in the Gk knock out mouse (Kuwada et al, 2005, PMID: 16105550). In summary, GK is definitively associated with glycerol kinase deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
Clinical Genomic Database (CGD)
Manifestation: Biochemical; Neurologic
Intervention: Biochemical
Rationale: Specific dietary measures (eg, fat/glycerol-restricted diet) can be beneficial
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to GK variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001205019.2. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 25 | 7 | 4 | 36 | ||
| missense | 3 | 2 | 80 | 6 | 91 | |
| nonsense | 3 | 6 | 4 | 13 | ||
| start loss | 0 | |||||
| frameshift | 2 | 2 | 4 | |||
| splice donor/acceptor (+/-2bp) | 3 | 5 | 54 | 62 | ||
| Total | 11 | 15 | 163 | 13 | 4 | 206 |
Highest pathogenic variant AF is 0.00035546644
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001191948.1 | 21 | MANE Select | |
| Ensembl | ENSP00000401720.2 | 21 | MANE Select | |
| RefSeq | NP_000158.1 | 19 | Standard | |
| RefSeq | NP_001121599.1 | 20 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Glycerolipid metabolism - Homo sapiens (human)
- PPAR signaling pathway - Homo sapiens (human)
- Familial lipoprotein lipase deficiency
- Glycerolipid Metabolism
- Glycerol Kinase Deficiency
Biological Process
- glycerol metabolic process
- triglyceride metabolic process
- phosphorylation
- triglyceride biosynthetic process
- glycerol catabolic process
Molecular Function
- glycerol kinase activity
- protein binding
- ATP binding
Cellular Component
- cytoplasm
- mitochondrion
- mitochondrial outer membrane
- cytosol
- extracellular exosome
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000378943
- Coding exons
- 20
- Length
- 77250
- Individuals with no LoFs
- 125687
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 3
- Defined
- 125690
- p
- 0.0000119
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 3.19 | 81 | 211 | 0.383 | 0.0000156 | 3616 |
| Missense (PolyPhen) | 13 | 75.463 | 0.17227 | 1380 | ||
| Synonymous | 0.776 | 64 | 72.4 | 0.884 | 0.00000565 | 1040 |
| Loss of Function | 4.27 | 3 | 26.9 | 0.112 | 0.00000199 | 445 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.000074 | 0.000058 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000013 | 0.0000088 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Key enzyme in the regulation of glycerol uptake and metabolism.;
Recessive Scores
- pRec
- 0.444
Intolerance Scores
- LoFtool
- 0.121
- RVIS EVS
- -0.27
- RVIS percentile EVS
- 33.97
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.151
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Low | Low |
| Primary Immunodeficiency | Medium | Low | Medium |
| Cancer | Medium | Medium | Medium |