MVK
protein-codingmevalonate kinase
Gene summary
This gene encodes the peroxisomal enzyme mevalonate kinase. Mevalonate is a key intermediate, and mevalonate kinase a key early enzyme, in isoprenoid and sterol synthesis. Mevalonate kinase deficiency caused by mutation of this gene results in mevalonic aciduria, a disease characterized psychomotor retardation, failure to thrive, hepatosplenomegaly, anemia and recurrent febrile crises. Defects in this gene also cause hyperimmunoglobulinaemia D and periodic fever syndrome, a disorder characterized by recurrent episodes of fever associated with lymphadenopathy, arthralgia, gastrointestinal dismay and skin rash. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~24.9 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0008293
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0012481
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0009849
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0019212
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0012481
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0012481
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0008293
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0012481
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0009849
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0017708
Submitter: ClinGen
MVK was first reported in relation to autosomal recessive Mevalonate Aciduria (MA) in 1997 in three families (Hinson et al., PMID: 9334262). In 1999 MVK variants were also implicated in a milder recessive condition, called Hyper-IgD Syndrome with periodic fever (HIDS) (Houten et al 1999). Collectively these conditions are known as Mevalonate Kinase Deficiency (MKD) and are characterized by episodes of recurrent fever lasting 3-6 days, which begin early in childhood. In addition to fevers, symptoms can include abdominal pain, hepatosplenomegaly, serositis, lymphadenopathy, skin lesions/rash, aphthous ulcers, arthralgia/arthritis. In more severe forms of MA there may also be growth delay, congenital anomalies (cataracts, shortened limbs and dysmorphic features), failure to thrive and neurological symptoms (PMID:27142780). Fetal ascites as well as oligohydramnios and polyhydramnios are other related prenatal phenotypes (PMID: 23146290, 27012807). There are many severe, neonatal-onset cases, which can be lethal (PMID: 14711867, PMID: 23146290) In both conditions there is decreased MVK enzyme activity which leads to the accumulation of mevalonic acid, defective prenylation, and ultimately constitutive activation of the pyrin inflammasome. This activation leads to excess production of IL-1 causing many of the inflammatory features of the disease. It is hypothesized that excess MA accumulation may lead to the ocular and neurologic symptoms which are seen in both forms of the disease, but more commonly in the more severe form of mevalonate aciduria (PMID:35685471). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism as both lead to varying levels of mevalonate kinase deficiency, and both follow the same inheritance pattern. Therefore, the following disease entities have been lumped into one disease entities, Hyper-IgD Syndrome (OMIM:260920) and Mevalonic Aciduria (OMIM:610377). The split curation for Porokeratosis, which is also caused by variants in MVK, but which is inherited in an autosomal dominant mechanism with localized post-zygotic mutation will be curated separately. 179 pathogenic or likely pathogenic variants have been reported in the Infevers database to date (https://infevers.umai-montpellier.fr/web/) and 132 have been reported in ClinVar. 19 probands in 2 publications (PMIDs: PMID:1036926 and PMID:11371670) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts) has been reached. The gene disease relationship is supported by experimental evidence. The mechanism of pathogenicity is reported to be loss of function. Several studies have shown decreased MVK activity in patient cells (PMIDs: 10369261, 11313769) and an upregulation of IL-1β and other cytokines (PMID:12384940, PMID:25173351). Mouse models with heterozygous MVK deletions (MVK +/-) have also shown decreased mevalonate kinase activity, immune dysfunction, and similar clinical features to individuals with HIDS included hepatosplenomegaly, abnormal thermoregulation and general malaise (PMID:18008182) In summary, there is definitive evidence supporting the relationship between MVK autosomal recessive Mevalonate Kinase Deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Autoinflammatory GCEP on the meeting date 05/15/2024 (SOP Version 10).
Inheritance Pattern: AD
Disease ID:MONDO:0019141
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious; Dermatologic; Biochemical; Gastrointestinal; Neurologic; Ophthalmologic
Intervention: Allergy/Immunology/Infectious
Rationale: In Mevalonic aciduria, diagnosis can be challenging, and effective treatment is available with specific agents (eg, steroids, leukotriene receptor antagonists); In Hyper-IgD syndrome, accurate diagnosis may be beneficial in order to avoid unnecessary surgery for suspected appendicitis/acute abdomen; Medical treatment (eg, corticosteroids, leukotriene receptor inhibitors) during the acute phase can be effective, as well as medical treatment in the non-acute phase
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to MVK variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000431.4. 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 | 11 | 168 | 1 | 180 | ||
| missense | 11 | 40 | 237 | 4 | 1 | 293 |
| nonsense | 13 | 3 | 1 | 17 | ||
| start loss | 3 | 1 | 4 | |||
| frameshift | 24 | 12 | 6 | 42 | ||
| splice donor/acceptor (+/-2bp) | 2 | 11 | 9 | 22 | ||
| Total | 53 | 66 | 265 | 172 | 2 | 558 |
Highest pathogenic variant AF is 0.0020969014
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000422.1 | 10 | MANE Select | |
| Ensembl | ENSP00000228510.3 | 10 | MANE Select | |
| RefSeq | NP_001107657.1 | 10 | Standard | |
| RefSeq | NP_001288111.1 | 9 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Mevalonate pathway
- Peroxisome - Homo sapiens (human)
- Terpenoid backbone biosynthesis - Homo sapiens (human)
- Simvastatin Action Pathway
- Pravastatin Action Pathway
Biological Process
- cholesterol biosynthetic process
- isoprenoid biosynthetic process
- phosphorylation
- isopentenyl diphosphate biosynthetic process, mevalonate pathway
- regulation of cholesterol biosynthetic process
Molecular Function
- magnesium ion binding
- mevalonate kinase activity
- protein binding
- ATP binding
- identical protein binding
Cellular Component
- peroxisome
- cytosol
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000228510
- Coding exons
- 10
- Length
- 24008
- Individuals with no LoFs
- 125732
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 16
- Defined
- 125748
- p
- 0.0000636
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.941 | 183 | 222 | 0.823 | 0.0000142 | 2511 |
| Missense (PolyPhen) | 51 | 73.866 | 0.69044 | 845 | ||
| Synonymous | 0.883 | 91 | 102 | 0.889 | 0.00000721 | 859 |
| Loss of Function | 3.02 | 5 | 19.3 | 0.259 | 9.38e-7 | 227 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00025 | 0.00025 | rare |
| Latino/Admixed American | 0.000058 | 0.000058 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0.000092 | 0.000092 | rare |
| European (Non-Finnish) | 0.000045 | 0.000044 | rare |
| South Asian | 0.000098 | 0.000098 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Catalyzes the phosphorylation of mevalonate to mevalonate 5-phosphate, a key step in isoprenoid and cholesterol biosynthesis (PubMed:9325256, PubMed:18302342). {ECO:0000269|PubMed:18302342, ECO:0000269|PubMed:9325256}.;
- Disease
- DISEASE: Mevalonic aciduria (MEVA) [MIM:610377]: Accumulation of mevalonic acid which causes a variety of symptoms such as psychomotor retardation, dysmorphic features, cataracts, hepatosplenomegaly, lymphadenopathy, anemia, hypotonia, myopathy, and ataxia. {ECO:0000269|PubMed:10401001, ECO:0000269|PubMed:10417275, ECO:0000269|PubMed:11313768, ECO:0000269|PubMed:11313769, ECO:0000269|PubMed:1377680}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Hyperimmunoglobulinemia D and periodic fever syndrome (HIDS) [MIM:260920]: Autosomal recessive disease characterized by recurrent episodes of unexplained high fever associated with skin rash, diarrhea, adenopathy (swollen, tender lymph nodes), arthralgias and/or arthritis. Concentration of IgD, and often IgA, are above normal. {ECO:0000269|PubMed:10369261, ECO:0000269|PubMed:10369262, ECO:0000269|PubMed:11313768, ECO:0000269|PubMed:11313769, ECO:0000269|PubMed:15536479}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Porokeratosis 3, multiple types (POROK3) [MIM:175900]: A form of porokeratosis, a disorder of faulty keratinization characterized by one or more atrophic patches surrounded by a distinctive hyperkeratotic ridgelike border called the cornoid lamella. The keratotic lesions can progress to overt cutaneous neoplasms, typically squamous cell carcinomas. Multiple clinical variants of porokeratosis are recognized, including porokeratosis of Mibelli, linear porokeratosis, disseminated superficial actinic porokeratosis, palmoplantar porokeratosis, and punctate porokeratosis. Different clinical presentations can be observed among members of the same family. Individuals expressing more than one variant have also been reported. {ECO:0000269|PubMed:22983302, ECO:0000269|PubMed:24781643}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.318
Intolerance Scores
- LoFtool
- 0.0698
- RVIS EVS
- -0.2
- RVIS percentile EVS
- 38.98
Essentials
- Essential (CRISPR)
- E
- Essential (CRISPR2)
- E
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.997
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |