TMEM231

protein-coding

transmembrane protein 231, the group of MKS complex

Gene summary

This gene encodes a transmembrane protein, which is a component of the B9 complex involved in the formation of the diffusion barrier between the cilia and plasma membrane. Mutations in this gene cause Joubert syndrome (JBTS). Multiple alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jan 2013]

MANE transcript

NM_001077418.3

Inheritance

ClinVar variants

P:51U:193B:128

Top phenotype

Joubert syndrome 20; Meckel syndrome 11

gnomAD constraint

pLI —, LoF o/e 0.75

Max pathogenic AF

—

Genomic locus

chr16:75,536,741-75,556,289

External References & Databases

Ensembl (ENSG00000205084)

Transcript & Mutation Effects

hg38 • Region Span ~19.5 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Joubert syndrome 20STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013994

Submitter: Labcorp Genetics (formerly Invitae)

Joubert syndrome 20DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013994

Submitter: G2P

Meckel syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018921

Submitter: Orphanet

Joubert syndrome 20STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013994

Submitter: PanelApp Australia

ciliopathyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0005308

Submitter: Natera

Joubert syndrome with oculorenal defectSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009480

Submitter: Orphanet

Meckel syndrome, type 11STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014164

Submitter: PanelApp Australia

ciliopathyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0005308

Submitter: ClinGen

*TMEM231* was FIRST reported in relation to autosomal recessive Joubert syndrome in 2012 (Srour M et al., PMID: 23012439), autosomal recessive Meckel Gruber syndrome (Shaheen R et al., PMID: 23349226) in 2013, and autosomal recessive orofacial-digital syndrome type III (Roberson EC et al., PMID: 25869670) in 2015. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanisms, inheritance pattern and overlapping phenotypes. Therefore, the disease entities have been lumped into one disease entity, ciliopathy (MONDO:0005308). At least 16 distinct variants (missense, nonsense, splice site, and frameshift) have been reported in 20 probands in 7 publications (in addition to aforementioned publications: PMIDs: 34912761, 28289185, 32386258, 31663672). Genetic evidence supporting this gene-disease relationship includes segregation data and experimental data, such as biochemical functions, physical interaction studies, organ expression, rescue experiments, and three non-human model organisms (2x mouse, 1x C. elegans) published in 2011 (PMID: 22179047) and 2015 (PMID: 25869670). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. In summary, there is definitive evidence to support the relationship between *TMEM231* and autosomal recessive ciliopathy-*TMEM231*. 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 Working Group on 01/12/2022 (SOP Version 8).

Clinical Genomic Database (CGD)

Joubert syndrome 20; Meckel syndrome 11AR

Manifestation: Gastrointestinal; Musculoskeletal; Neurologic; Ophthalmologic; Renal

Intervention: General

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

Comments: Conditions 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;

Refs: 23012439; 23349226

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TMEM231 variants in ClinVar

12 Conditions Cataloged

Meckel syndrome, type 11Total: 402

Joubert syndrome 20Total: 402

not providedTotal: 109

not specifiedTotal: 78

Inborn genetic diseasesTotal: 74

TMEM231-related disorderTotal: 33

Joubert syndrome and related disordersTotal: 13

CiliopathyTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001077418.3. 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 clinvar		17 clinvar	99 clinvar	2 clinvar	119
missense	2 clinvar	9 clinvar	169 clinvar	24 clinvar	1 clinvar	205
nonsense	5 clinvar	7 clinvar	5 clinvar			17
start loss				1 clinvar		1
frameshift	6 clinvar	9 clinvar	1 clinvar			16
splice donor/acceptor (+/-2bp)	5 clinvar	7 clinvar	1 clinvar	1 clinvar		14
Total	19	32	193	125	3	372

Highest pathogenic variant AF is 0.00028606816

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 37 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001077418.3	RefSeq	NP_001070886.1	7	MANE Select
ENST00000258173.11	Ensembl	ENSP00000258173.5	7	MANE Select
NM_001077416.2	RefSeq	NP_001070884.2	6	Standard
ENST00000562410.5	Ensembl	ENSP00000454582.1	3	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

in utero embryonic development
vasculature development
smoothened signaling pathway
regulation of protein localization
embryonic digit morphogenesis

Molecular Function

protein binding

Cellular Component

integral component of membrane
ciliary transition zone
MKS complex
ciliary membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000568377
Coding exons: 6
Length: 18170
Individuals with no LoFs: 124611
Homozygous LoFs: 0
Heterozygous LoFs: 24
Defined: 124635
p: 0.0000963

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.411	201	185	1.08	0.0000102	2179
Missense (PolyPhen)		64	64.723	0.98883		824
Synonymous	-0.680	89	81.2	1.10	0.00000506	704
Loss of Function	0.933	12	16.0	0.748	0.00000105	149

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000065	0.000065	rare
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.00011	rare
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.000073	0.000071	rare
South Asian	0.00023	0.00023	rare
Other	0.00017	0.00017	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Transmembrane component of the tectonic-like complex, a complex localized at the transition zone of primary cilia and acting as a barrier that prevents diffusion of transmembrane proteins between the cilia and plasma membranes. Required for ciliogenesis and sonic hedgehog/SHH signaling (By similarity). {ECO:0000250}.;
Disease: DISEASE: Joubert syndrome 20 (JBTS20) [MIM:614970]: 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:23012439, ECO:0000269|PubMed:26477546}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Meckel syndrome 11 (MKS11) [MIM:615397]: 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:23349226}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.114

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium