TMEM67
protein-codingtransmembrane protein 67, the group of MKS complex
Gene summary
The protein encoded by this gene localizes to the primary cilium and to the plasma membrane. The gene functions in centriole migration to the apical membrane and formation of the primary cilium. Multiple transcript variants encoding different isoforms have been found for this gene. Defects in this gene are a cause of Meckel syndrome type 3 (MKS3) and Joubert syndrome type 6 (JBTS6). [provided by RefSeq, Nov 2008]
- MKS3
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~64.4 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0013302
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0012539
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0005308
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0012539
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0008996
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0019394
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0018921
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0005308
Submitter: Natera
Inheritance Pattern: AR
Disease ID:MONDO:0011821
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0013302
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0013302
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0005308
Submitter: ClinGen
*TMEM67* (also found in the literature as MKS3) encodes the protein meckelin, located in the ciliary transition zone and plays an integral rile in ciliary structure and function. *TMEM67* has been associated with the following autosomal recessive disease entities: Meckel Syndrome Type 3 (MKS3, OMIM:607361); Joubert Syndrome 6 (JBTS6, OMIM:61088); COACH Syndrome 1 (OMIM:21630); Nephronophthisis 11 (NPHP11, OMIM:613550); and RHYNS Syndrome (OMIM:602152). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism AND/OR inheritance pattern. While these disease entities represent a wide range of clinical severity, the molecular mechanism is loss of function causing ciliopathy and the inheritance pattern is autosomal recessive. Therefore, the following disease entities have been lumped into one disease entity, ciliopathy (MONDO:0005308). Nomenclature for these disease entities is suggested to follow “Disease-Gene” system: MKS-*TMEM67*, JBTS-*TMEM67*, COACH-*TMEM67*, NPHP-*TMEM67*, RHYNS-*TMEM67*, and an overall proposed nomenclature is Ciliopathy-*TMEM67*. Summary of Case-Level Data: 12 points. Twenty-one unique variants (missense, frameshift, splice site) from 19 probands in 3 publications were curated (PMID:16415887, PMID:16415887, PMID:19058225). Homozygous variants were described as causative for MKS-*TMEM67* in four families with central nervous system, renal, hepatic, and polydactyly clinical features (PMID:16415887), and compound heterozygous variants in one family (PMID:17160906). One homozygous variant and two compound heterozygous variants were described in two families as causative for JBTS-*TMEM67* with hepatic, ocular, global developmental delay, and central nervous system clinical features (PMID:17160906). Seven families with COACH-*TMEM67* were described with twelve compound heterozygous variants, displaying central nervous system, hepatic, renal, growth delay, and ocular clinical features (PMID:19058225). More information is available in the literature but the maximum score for genetic evidence (12 points) has been reached. *TMEM67* variants have also been associated with RHYNS-*TMEM67* in one family (PMID:29891882) and four families with nephronophthisis and liver fibrosis, NPHP-*TMEM67* (PMID:19508969). The mechanism for disease is homozygous or compound heterozygous loss of function (PMID:16415887). Experimental Evidence: 6 points. This gene-disease association is supported by altered expression in patient liver tissue (PMID:16415887), characterization of the wpk rat model for Meckel Syndrome (PMID:16415887, PMID:19515853), mouse models (PMID:19211713, PMID:21725307), protein interactions between meckelin and filamen A, a transfection cell culture model system demonstrating a variant found in patients leads to loss of cilia formation and disrupts the meckelin-filamin A interatction, and a phenotype rescue in a mks3 zebrafish model displaying notochord, ocular, and renal abnormalities (PMID:22121117). In summary, there is definitive evidence to support the relationship between *TMEM67* and autosomal recessive ciliopathy-*TMEM67*. 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 Cystic and Ciliopathy Disorders GCEP on 7/14/21 (SOP Version 8).
Inheritance Pattern: AR
Disease ID:MONDO:0800103
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0018772
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0008996
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Audiologic/Otolaryngologic; Endocrine; Gastrointestinal; Musculoskeletal; Neurologic; Ophthalmologic; Renal
Intervention: Gastrointestinal
Rationale: In COACH syndrome, among other findings, individuals may have hepatic disease, and it has been suggested that identification of liver disease is critical as some patients may develop complications such as portal hypertension with fatal variceal bleeding
Comments: The condition may involve multi-systemic manifestations, including sequelae affecting the renal and hepatic systems, and surveillance and avoidance of certain medications (eg, nephrotoxic agents) may be beneficial; Variants may modify severity of BBS and related disorders due to variants in other BBS-associated genes; Renal transplant has been described in RHYNS syndrome
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to TMEM67 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_153704.6. 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 | 1 | 13 | 271 | 2 | 287 | |
| missense | 19 | 78 | 505 | 17 | 1 | 620 |
| nonsense | 27 | 17 | 3 | 47 | ||
| start loss | 1 | 2 | 3 | |||
| frameshift | 38 | 34 | 3 | 75 | ||
| splice donor/acceptor (+/-2bp) | 16 | 48 | 4 | 68 | ||
| Total | 100 | 179 | 530 | 288 | 3 | 1100 |
Highest pathogenic variant AF is 0.010984603
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_714915.3 | 28 | MANE Select | |
| Ensembl | ENSP00000389998.3 | 28 | MANE Select | |
| RefSeq | NP_001135773.1 | 27 | Standard | |
| Ensembl | ENSP00000314488.4 | 28 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| tmem67 | Danio rerio | Structure: head Quality: hydrocephalic abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Anchoring of the basal body to the plasma membrane
- Cilium Assembly
- Organelle biogenesis and maintenance
Biological Process
- negative regulation of centrosome duplication
- ubiquitin-dependent ERAD pathway
- cilium assembly
- ciliary basal body-plasma membrane docking
Molecular Function
- protein binding
- filamin binding
- unfolded protein binding
Cellular Component
- endoplasmic reticulum membrane
- centrosome
- integral component of membrane
- cytoplasmic vesicle membrane
- ciliary transition zone
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000453321
- Coding exons
- 28
- Length
- 64391
- Individuals with no LoFs
- 125589
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 159
- Defined
- 125748
- p
- 0.000632
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.492 | 483 | 514 | 0.939 | 0.0000244 | 6548 |
| Missense (PolyPhen) | 129 | 153.64 | 0.83961 | 2004 | ||
| Synonymous | 1.27 | 150 | 171 | 0.876 | 0.00000790 | 1847 |
| Loss of Function | 1.92 | 46 | 62.3 | 0.738 | 0.00000316 | 740 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00056 | 0.00055 | rare |
| Latino/Admixed American | 0.00041 | 0.00040 | rare |
| Ashkenazi Jewish | 0.0015 | 0.0015 | notable |
| East Asian | 0.00071 | 0.00071 | rare |
| Finnish | 0.00019 | 0.00018 | rare |
| European (Non-Finnish) | 0.00056 | 0.00054 | rare |
| South Asian | 0.0012 | 0.0012 | notable |
| Other | 0.00099 | 0.00098 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Required for ciliary structure and function. Part of the tectonic-like complex which is required for tissue-specific ciliogenesis and may regulate ciliary membrane composition (By similarity). Involved in centrosome migration to the apical cell surface during early ciliogenesis. Involved in the regulation of cilia length and appropriate number through the control of centrosome duplication. Required for cell branching morphology. Essential for endoplasmic reticulum-associated degradation (ERAD) of surfactant protein C (SFTPC). {ECO:0000250, ECO:0000269|PubMed:17185389, ECO:0000269|PubMed:19515853, ECO:0000269|PubMed:19596800, ECO:0000269|PubMed:19815549}.;
- Disease
- DISEASE: Meckel syndrome 3 (MKS3) [MIM:607361]: A disorder characterized by a combination of renal cysts and variably associated features including developmental anomalies of the central nervous system (typically encephalocele), hepatic ductal dysplasia and cysts, and polydactyly. {ECO:0000269|PubMed:16415887, ECO:0000269|PubMed:17185389, ECO:0000269|PubMed:19466712, ECO:0000269|PubMed:20232449}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Joubert syndrome 6 (JBTS6) [MIM:610688]: A disorder presenting with cerebellar ataxia, oculomotor apraxia, hypotonia, neonatal breathing abnormalities and psychomotor delay. Neuroradiologically, it is characterized by cerebellar vermian hypoplasia/aplasia, thickened and reoriented superior cerebellar peduncles, and an abnormally large interpeduncular fossa, giving the appearance of a molar tooth on transaxial slices (molar tooth sign). Additional variable features include retinal dystrophy and renal disease. {ECO:0000269|PubMed:17160906, ECO:0000269|PubMed:19508969, ECO:0000269|PubMed:19574260, ECO:0000269|PubMed:21633164, ECO:0000269|PubMed:26477546}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Bardet-Biedl syndrome 14 (BBS14) [MIM:615991]: A syndrome characterized by usually severe pigmentary retinopathy, early- onset obesity, polydactyly, hypogenitalism, renal malformation and mental retardation. Secondary features include diabetes mellitus, hypertension and congenital heart disease. Bardet-Biedl syndrome inheritance is autosomal recessive, but three mutated alleles (two at one locus, and a third at a second locus) may be required for clinical manifestation of some forms of the disease. {ECO:0000269|PubMed:18327255}. Note=The gene represented in this entry may act as a disease modifier. TMEM67 variations may influence the expression of Bardet-Biedl syndrome in patients who have causative mutations in other genes. Heterozygosity for a complex mutation in the TMEM67 gene coding for a protein with 2 in cis changes, and homozygosity for a truncating mutation of the CEP290 gene has been found in a patient with Bardet-Biedl syndrome 14.; DISEASE: COACH syndrome (COACHS) [MIM:216360]: A disorder characterized by mental retardation, ataxia due to cerebellar hypoplasia, and hepatic fibrosis. Patients present the molar tooth sign, a midbrain-hindbrain malformation pathognomonic for Joubert syndrome and related disorders. Other features, such as coloboma and renal cysts, may be variable. {ECO:0000269|PubMed:19058225, ECO:0000269|PubMed:19574260, ECO:0000269|PubMed:28860541}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Nephronophthisis 11 (NPHP11) [MIM:613550]: A disorder characterized by the association of nephronophthisis with hepatic fibrosis. Nephronophthisis is a progressive tubulo-interstitial kidney disorder histologically characterized by modifications of the tubules with thickening of the basement membrane, interstitial fibrosis and, in the advanced stages, medullary cysts. Typical clinical features are chronic renal failure, anemia, polyuria, polydipsia, isosthenuria, and growth retardation. Associations with extrarenal symptoms, especially ocular lesions, are frequent. {ECO:0000269|PubMed:19508969}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.191
Intolerance Scores
- LoFtool
- 0.0847
- RVIS EVS
- 0.31
- RVIS percentile EVS
- 72.75
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.329
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |