Meckel syndrome, type 3

Summary

Meckel syndrome, type 3 (MONDO:0011821) is a disease caused by TMEM67 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: TMEM67 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 303

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Meckel syndrome, type 3
Mondo ID	MONDO:0011821
MeSH	C536132
OMIM	607361
DOID	DOID:0070117
UMLS	C1846357
MedGen	335402
GARD	0008744
Is cancer (heuristic)	no

Also known as: Meckel syndrome caused by mutation in TMEM67 · Meckel syndrome type 3 · Meckel syndrome, type 3 · Meckel-Gruber syndrome, type 3 · MKS3 · TMEM67 Meckel syndrome

Data availability: 303 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › Meckel syndrome › Meckel syndrome, type 3

Related subtypes (13): Meckel syndrome, type 1, NPHP3-related Meckel-like syndrome, Meckel syndrome, type 2, Meckel syndrome, type 4, Meckel syndrome, type 5, Meckel syndrome, type 6, Meckel syndrome, type 8, Meckel syndrome, type 10, Meckel syndrome, type 9, Meckel syndrome, type 11, lethal fetal cerebrorenogenitourinary agenesis/hypoplasia syndrome, meckel syndrome 14, Meckel syndrome 13

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

303 retrieved; paginated sample, class counts are floors:

142 uncertain significance, 45 conflicting classifications of pathogenicity, 37 pathogenic/likely pathogenic, 27 likely pathogenic, 22 pathogenic, 17 likely benign, 10 benign/likely benign, 3 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
156377	NM_025114.4(CEP290):c.1711+1G>A	CEP290	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2431201	NM_025114.4(CEP290):c.2632dup (p.Ile878fs)	CEP290	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
982526	NM_025114.4(CEP290):c.3847C>T (p.Gln1283Ter)	CEP290	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1072098	NM_153704.6(TMEM67):c.1975C>T (p.Arg659Ter)	TMEM67	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1074275	NM_153704.6(TMEM67):c.1338_1350del (p.Ala447fs)	TMEM67	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1252092	NM_153704.6(TMEM67):c.2306del (p.Leu769fs)	TMEM67	Pathogenic	no assertion criteria provided
1252093	NM_153704.6(TMEM67):c.2439G>A (p.Ala813=)	TMEM67	Pathogenic	criteria provided, multiple submitters, no conflicts
1252094	NM_153704.6(TMEM67):c.2326T>A (p.Ser776Thr)	TMEM67	Pathogenic	no assertion criteria provided
126306	NM_153704.6(TMEM67):c.748G>A (p.Gly250Arg)	TMEM67	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1365	NM_153704.6(TMEM67):c.383_384del (p.His128fs)	TMEM67	Pathogenic/Likely pathogenic	no assertion criteria provided
1366	NM_153704.6(TMEM67):c.648del (p.Val217fs)	TMEM67	Pathogenic/Likely pathogenic	no assertion criteria provided
1367	NM_153704.6(TMEM67):c.870-2A>G	TMEM67	Pathogenic/Likely pathogenic	no assertion criteria provided
1369	NM_153704.6(TMEM67):c.1127A>C (p.Gln376Pro)	TMEM67	Pathogenic	no assertion criteria provided
1370	NM_153704.6(TMEM67):c.1575+1G>A	TMEM67	Pathogenic/Likely pathogenic	no assertion criteria provided
1371	NM_153704.6(TMEM67):c.1538A>G (p.Tyr513Cys)	TMEM67	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1376	NM_153704.6(TMEM67):c.622A>T (p.Arg208Ter)	TMEM67	Pathogenic	criteria provided, multiple submitters, no conflicts
1378	NM_153704.6(TMEM67):c.2498T>C (p.Ile833Thr)	TMEM67	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1380	NM_153704.6(TMEM67):c.312+5G>A	TMEM67	Pathogenic	criteria provided, multiple submitters, no conflicts
1381	NM_153704.6(TMEM67):c.1769T>C (p.Phe590Ser)	TMEM67	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1383	NM_153704.6(TMEM67):c.1843T>C (p.Cys615Arg)	TMEM67	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1387	NM_153704.6(TMEM67):c.755T>C (p.Met252Thr)	TMEM67	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1411457	NM_153704.6(TMEM67):c.1387C>T (p.Arg463Ter)	TMEM67	Pathogenic	criteria provided, multiple submitters, no conflicts
1454299	NM_153704.6(TMEM67):c.1927C>T (p.Arg643Ter)	TMEM67	Pathogenic	criteria provided, multiple submitters, no conflicts
1691287	NM_153704.6(TMEM67):c.479_480del (p.Phe160fs)	TMEM67	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
191259	NM_153704.6(TMEM67):c.1413-2A>G	TMEM67	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
216826	NM_153704.6(TMEM67):c.725A>G (p.Asn242Ser)	TMEM67	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
217710	NM_153704.6(TMEM67):c.769A>G (p.Met257Val)	TMEM67	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
217712	NM_153704.6(TMEM67):c.300C>A (p.Cys100Ter)	TMEM67	Pathogenic	criteria provided, multiple submitters, no conflicts
217717	NM_153704.6(TMEM67):c.2290C>T (p.Arg764Ter)	TMEM67	Pathogenic	criteria provided, multiple submitters, no conflicts
217724	NM_153704.6(TMEM67):c.1351C>T (p.Arg451Ter)	TMEM67	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 13 · Orphanet: 10 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
TMEM67	Definitive	Autosomal recessive	Meckel syndrome, type 3	13

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TMEM67	Orphanet:140976	RHYNS syndrome
TMEM67	Orphanet:1454	Joubert syndrome with hepatic defect
TMEM67	Orphanet:475	Isolated Joubert syndrome
TMEM67	Orphanet:564	Meckel syndrome
TMEM67	Orphanet:84081	Senior-Boichis syndrome
CEP290	Orphanet:110	Bardet-Biedl syndrome
CEP290	Orphanet:2318	Joubert syndrome with oculorenal defect
CEP290	Orphanet:3156	Senior-Loken syndrome
CEP290	Orphanet:564	Meckel syndrome
CEP290	Orphanet:65	Leber congenital amaurosis

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TMEM67	HGNC:28396	ENSG00000164953	Q5HYA8	Meckelin	gencc,clinvar
CEP290	HGNC:29021	ENSG00000198707	O15078	Centrosomal protein of 290 kDa	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TMEM67	Meckelin	Required for ciliary structure and function.
CEP290	Centrosomal protein of 290 kDa	Involved in early and late steps in cilia formation.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TMEM67	Other/Unknown	no		Growth_fac_rcpt_cys_sf, Meckelin
CEP290	Other/Unknown	no		Cep290, Cep209_CC5

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right uterine tube	2
buccal mucosa cell	1
calcaneal tendon	1
male germ line stem cell (sensu Vertebrata) in testis	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TMEM67	203	ubiquitous	marker	buccal mucosa cell, right uterine tube, calcaneal tendon
CEP290	278	ubiquitous	marker	right uterine tube, male germ line stem cell (sensu Vertebrata) in testis, ventricular zone

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CEP290	2,778
TMEM67	1,194

Intra-cohort edges

A	B	Sources
CEP290	TMEM67	string_interaction

Structural data

PDB: 1 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TMEM67	Q5HYA8	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CEP290	O15078	60.90

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 19. Enrichment computed across 2 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Anchoring of the basal body to the plasma membrane	2	113.1×	8e-04	TMEM67, CEP290
Cilium Assembly	2	108.8×	8e-04	TMEM67, CEP290
Organelle biogenesis and maintenance	2	66.0×	0.001	TMEM67, CEP290
Centrosome maturation	1	126.9×	0.027	CEP290
Loss of Nlp from mitotic centrosomes	1	79.3×	0.027	CEP290
Loss of proteins required for interphase microtubule organization from the centrosome	1	79.3×	0.027	CEP290
AURKA Activation by TPX2	1	76.1×	0.027	CEP290
Recruitment of mitotic centrosome proteins and complexes	1	68.0×	0.027	CEP290
Regulation of PLK1 Activity at G2/M Transition	1	63.4×	0.027	CEP290
Mitotic G2-G2/M phases	1	63.4×	0.027	CEP290
G2/M Transition	1	63.4×	0.027	CEP290
Recruitment of NuMA to mitotic centrosomes	1	58.3×	0.027	CEP290
Mitotic Prometaphase	1	34.6×	0.041	CEP290
M Phase	1	33.0×	0.041	CEP290
Cell Cycle, Mitotic	1	24.1×	0.052	CEP290
Cell Cycle	1	18.0×	0.065	CEP290
Innate Immune System	1	12.8×	0.086	CEP290
Neutrophil degranulation	1	11.5×	0.090	CEP290
Immune System	1	6.5×	0.148	CEP290

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
obsolete ciliary basal body-plasma membrane docking	1	4213.0×	0.002	CEP290
ciliary transition zone assembly	1	2808.7×	0.002	CEP290
cilium assembly	2	73.6×	0.002	TMEM67, CEP290
negative regulation of centrosome duplication	1	1685.2×	0.002	TMEM67
pronephros development	1	1203.7×	0.002	CEP290
regulation of establishment of protein localization	1	1203.7×	0.002	CEP290
otic vesicle formation	1	1053.2×	0.002	CEP290
hindbrain development	1	561.7×	0.004	CEP290
eye photoreceptor cell development	1	421.3×	0.004	CEP290
positive regulation of intracellular protein transport	1	337.0×	0.005	CEP290
non-canonical Wnt signaling pathway	1	290.6×	0.005	TMEM67
camera-type eye development	1	179.3×	0.008	CEP290
non-motile cilium assembly	1	145.3×	0.009	CEP290
ERAD pathway	1	90.6×	0.013	TMEM67
kidney development	1	70.2×	0.016	CEP290
protein transport	1	21.9×	0.048	CEP290
positive regulation of DNA-templated transcription	1	14.0×	0.070	CEP290

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TMEM67	0	0
CEP290	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	TMEM67, CEP290

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
TMEM67	0	—
CEP290	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.