GeneBe

KCTD7

protein-coding

potassium channel tetramerization domain containing 7, the group of KCTD family

Gene summary

This gene encodes a member of the potassium channel tetramerization domain-containing protein family. Family members are identified on a structural basis and contain an amino-terminal domain similar to the T1 domain present in the voltage-gated potassium channel. Mutations in this gene have been associated with progressive myoclonic epilepsy-3. Alternative splicing results in multiple transcript variants.[provided by RefSeq, Jan 2011]

MANE transcript

NM_153033.5

Inheritance

AR

ClinVar variants

P:47U:157B:104

Top phenotype

Epilepsy, progressive myoclonic 3, with or without intracellular inclusions

gnomAD constraint

pLI —, LoF o/e 0.39

Max pathogenic AF

—

Genomic locus

chr7:66,628,881-66,649,067

External References & Databases

Ensembl (ENSG00000243335)NCBI Gene (154881)OMIM (611725)HGNC:21957GenCCUniProt (Q96MP8)AlphaFoldClinVar (KCTD7)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~20.2 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

progressive myoclonus epilepsyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0020074

Submitter: ClinGen

KCTD7 was first reported in relation to autosomal recessive progressive myoclonus epilepsy (PME) in 2007 (Van Bogaert et al., PMID: 17455289). The typical clinical presentation is characterized by onset of myoclonic seizures in infancy or early childhood followed by developmental regression and ataxia, sometimes also associated with cerebral or cerebellar atrophy and microcephaly (PMID: 34866617). Up to 25% of individuals with KCTD7 pathogenic variants have developmental delay and/or movement disorders such as ataxia, dyskinesia, dystonia, choreoathetosis, or tremors prior to the onset of seizures (PMIDs: 30295347, 31197948). The mechanism of pathogenicity is known to be loss of function (LOF). To date, approximately 55 missense, nonsense, frameshift, and splicing variants have been reported in more than 50 probands in the literature. Eight publications (PMIDs: 17455289, 22638565, 22693283, 27742667, 30295347, 30825425, 22748208, 25060828) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease association is also supported by experimental evidence from an animal model that exhibits spontaneous seizure activity in a knockout mouse (PMIDs: 35972048). In summary, KCTD7 is definitively associated with autosomal recessive progressive myoclonus epilepsy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.

progressive myoclonic epilepsy type 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012721

Submitter: PanelApp Australia

progressive myoclonic epilepsy type 3MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0012721

Submitter: Ambry Genetics

progressive myoclonic epilepsy type 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012721

Submitter: Labcorp Genetics (formerly Invitae)

progressive myoclonic epilepsy type 3SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012721

Submitter: Orphanet

progressive myoclonic epilepsy type 3DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012721

Submitter: G2P

progressive myoclonic epilepsy type 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012721

Submitter: Genomics England PanelApp

Clinical Genomic Database (CGD)

Epilepsy, progressive myoclonic 3, with or without intracellular inclusionsAR

Manifestation: Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision making, and avoidance of unnecessary testing

Comments: As with other conditions involving seizures, optimal seizure control is beneficial, and awareness of genetic causes may help with medication selection

Refs: 17455289; 22606975; 22638565; 22693283; 22748208Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to KCTD7 variants in ClinVar

11 Conditions Cataloged
Progressive myoclonic epilepsy type 3Total: 328
not providedTotal: 72
Inborn genetic diseasesTotal: 42
not specifiedTotal: 34
KCTD7-related disorderTotal: 9
Neuronal ceroid lipofuscinosisTotal: 7
Intellectual disabilityTotal: 4
Epileptic encephalopathyTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_153033.5. 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.

EffectPLPVUSLBBSum
synonymous
2
clinvar
3
clinvar
101
clinvar
2
clinvar
 108
missense
4
clinvar
21
clinvar
152
clinvar
1
clinvar
 178
nonsense
6
clinvar
2
clinvar
1
clinvar
 9
start loss
0
frameshift
6
clinvar
3
clinvar
 9
splice donor/acceptor (+/-2bp)
3
clinvar
1
clinvar
 4
Total16311571022308

Highest pathogenic variant AF is 0.000104728

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 19 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_153033.5RefSeqNP_694578.14MANE Select
ENST00000639828.2EnsemblENSP00000492240.14MANE Select
NM_001167961.2RefSeqNP_001161433.15Standard
ENST00000275532.8EnsemblENSP00000275532.44Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Post-translational protein modification
  • Metabolism of proteins
  • Immune System
  • Adaptive Immune System
  • Antigen processing: Ubiquitination & Proteasome degradation

Biological Process

  • cellular potassium ion homeostasis
  • positive regulation of transporter activity
  • post-translational protein modification
  • protein homooligomerization
  • membrane hyperpolarization

Molecular Function

  • protein binding

Cellular Component

  • cytoplasm
  • cytosol
  • plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000510829
Coding exons
8
Length
182579
Individuals with no LoFs
125736
Homozygous LoFs
0
Heterozygous LoFs
10
Defined
125746
p
0.0000398
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense1.472102790.7530.00001583274
Missense (PolyPhen)2064.9580.30789772
Synonymous0.754911010.9040.00000596875
Loss of Function2.901025.90.3850.00000149296

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American00.0absent
Ashkenazi Jewish0.0000990.000099rare
East Asian00.0absent
Finnish0.0000460.000046rare
European (Non-Finnish)0.0000720.000070rare
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: May be involved in the control of excitability of cortical neurons. {ECO:0000250}.;
Disease
DISEASE: Epilepsy, progressive myoclonic 3, with or without intracellular inclusions (EPM3) [MIM:611726]: An autosomal recessive, severe, progressive myoclonic epilepsy with early onset. Multifocal myoclonic seizures begin between 16 and 24 months of age after normal initial development. Neurodegeneration and regression occur with seizure onset. Other features include mental retardation, dysarthria, truncal ataxia, and loss of fine finger movements. EEG shows slow dysrhythmia, multifocal and occasionally generalized epileptiform discharges. In some patients, ultrastructural findings on skin biopsies identify intracellular accumulation of autofluorescent lipopigment storage material, consistent with neuronal ceroid lipofuscinosis. {ECO:0000269|PubMed:17455289, ECO:0000269|PubMed:22606975, ECO:0000269|PubMed:22612257, ECO:0000269|PubMed:22693283, ECO:0000269|PubMed:22748208}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=Defects in KCTD7 are a cause of opsoclonus-myoclonus ataxia-like syndrome. Opsoclonus myoclonus ataxia syndrome (OMS) is a rare pervasive and frequently permanent disorder that usually develops in previously healthy children with normal premorbid psychomotor development and characterized by association of abnormal eye movements (opsoclonus), severe dyskinesia (myoclonus), cerebellar ataxia, functional regression, and behavioral problems. The syndrome is considered to be an immune- mediated disorder and may be tumor-associated or idiopathic. OMS is one of a few steroid responsive disorders of childhood. KCTD7 mutations have been found in a patient with an atypical clinical presentation characterized by non-epileptic myoclonus and ataxia commencing in early infancy, abnormal opsoclonus-like eye movements, improvement of clinical symptoms under steroid treatment, and subsequent development of generalized epilepsy (PubMed:22638565). {ECO:0000269|PubMed:22638565}.;

Intolerance Scores

LoFtool
0.606
RVIS EVS
-0.65
RVIS percentile EVS
16.36

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.540

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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