Lissencephaly 8

Summary

Lissencephaly 8 (MONDO:0014992) is a disease caused by TMTC3 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: TMTC3 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 25

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	lissencephaly 8
Mondo ID	MONDO:0014992
OMIM	617255
DOID	DOID:0112233
UMLS	C4310646
MedGen	934613
GARD	0025044
Is cancer (heuristic)	no

Also known as: LIS8 · lissencephaly (disease) caused by mutation in TMTC3 · lissencephaly 8 · lissencephaly 8; LIS8 · lissencephaly type 8 · TMTC3 lissencephaly (disease)

Data availability: 25 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › lissencephaly spectrum disorders › lissencephaly 8

Related subtypes (14): craniotelencephalic dysplasia, X-linked lissencephaly with abnormal genitalia, lissencephaly 7 with cerebellar hypoplasia, classic lissencephaly, lissencephaly type 3, microlissencephaly, Warburg micro syndrome, Baraitser-Winter cerebrofrontofacial syndrome, cobblestone lissencephaly, lissencephaly with cerebellar hypoplasia, lissencephaly 10, cortical dysplasia, complex, with other brain malformations 9, massa casaer ceulemans syndrome, lissencephaly spectrum disorder with complex brainstem malformation

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

25 retrieved; paginated sample, class counts are floors:

10 uncertain significance, 7 likely pathogenic, 5 pathogenic, 2 pathogenic/likely pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1339495	NM_181783.4(TMTC3):c.1554del (p.Lys518fs)	TMTC3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1456984	NM_181783.4(TMTC3):c.1966C>T (p.Arg656Ter)	TMTC3	Pathogenic	criteria provided, multiple submitters, no conflicts
372273	NM_181783.4(TMTC3):c.1462del (p.Arg488fs)	TMTC3	Pathogenic	no assertion criteria provided
372274	NM_181783.4(TMTC3):c.2617C>T (p.Gln873Ter)	TMTC3	Pathogenic	no assertion criteria provided
372275	NM_181783.4(TMTC3):c.1959_1960insTT (p.Arg654fs)	TMTC3	Pathogenic	no assertion criteria provided
372277	NM_181783.4(TMTC3):c.3G>A (p.Met1Ile)	TMTC3	Pathogenic	no assertion criteria provided
488948	NM_181783.4(TMTC3):c.955C>T (p.Arg319Ter)	TMTC3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2690766	NM_181783.4(TMTC3):c.795dup (p.Arg266fs)	TMTC3	Likely pathogenic	criteria provided, single submitter
2882124	NM_181783.4(TMTC3):c.950A>G (p.Asp317Gly)	TMTC3	Likely pathogenic	criteria provided, single submitter
3064748	NM_181783.4(TMTC3):c.838C>T (p.Gln280Ter)	TMTC3	Likely pathogenic	criteria provided, single submitter
372276	NM_181783.4(TMTC3):c.199C>G (p.His67Asp)	TMTC3	Likely pathogenic	criteria provided, single submitter
3780722	NM_181783.4(TMTC3):c.1432+1G>A	TMTC3	Likely pathogenic	criteria provided, single submitter
4846952	NM_181783.4(TMTC3):c.1230_1233del (p.Ser411fs)	TMTC3	Likely pathogenic	criteria provided, single submitter
4848517	NM_181783.4(TMTC3):c.2338_2341del (p.Val780fs)	TMTC3	Likely pathogenic	criteria provided, single submitter
1033238	NM_181783.4(TMTC3):c.10A>G (p.Ile4Val)	TMTC3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1033240	NM_181783.4(TMTC3):c.816T>A (p.Ala272=)	TMTC3	Uncertain significance	criteria provided, single submitter
1443385	NM_181783.4(TMTC3):c.1681G>A (p.Asp561Asn)	TMTC3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1494499	NM_181783.4(TMTC3):c.59A>G (p.Tyr20Cys)	TMTC3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1925664	NM_181783.4(TMTC3):c.1388A>C (p.Glu463Ala)	TMTC3	Uncertain significance	criteria provided, multiple submitters, no conflicts
2437124	NM_181783.4(TMTC3):c.1357G>T (p.Gly453Cys)	TMTC3	Uncertain significance	criteria provided, single submitter
3234073	NM_181783.4(TMTC3):c.2176GAG[1] (p.Glu727del)	TMTC3	Uncertain significance	criteria provided, single submitter
3376481	NM_181783.4(TMTC3):c.1313C>T (p.Ala438Val)	TMTC3	Uncertain significance	criteria provided, single submitter
4086128	NM_181783.4(TMTC3):c.332G>A (p.Cys111Tyr)	TMTC3	Uncertain significance	criteria provided, single submitter
4846951	NM_181783.4(TMTC3):c.*814G>A	TMTC3	Uncertain significance	criteria provided, single submitter
4759447	NM_181783.4(TMTC3):c.2233A>G (p.Ile745Val)	TMTC3	Likely benign	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 2 · 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
TMTC3	Strong	Autosomal recessive	lissencephaly 8	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TMTC3	Orphanet:352682	Cobblestone lissencephaly without muscular or ocular involvement
TMTC3	Orphanet:98892	Periventricular nodular heterotopia

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TMTC3	HGNC:26899	ENSG00000139324	Q6ZXV5	Protein O-mannosyl-transferase TMTC3	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TMTC3	Protein O-mannosyl-transferase TMTC3	Transfers mannosyl residues to the hydroxyl group of serine or threonine residues.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TMTC3	Other/Unknown	no		TPR-like_helical_dom_sf, TMTC_DUF1736, TPR_rpt

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
Brodmann (1909) area 23	1
endothelial cell	1
gingival epithelium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TMTC3	256	ubiquitous	marker	endothelial cell, Brodmann (1909) area 23, gingival epithelium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TMTC3	2,090

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TMTC3	Q6ZXV5	87.83

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of proteasomal protein catabolic process	1	991.3×	0.002	TMTC3
protein O-linked glycosylation via mannose	1	936.2×	0.002	TMTC3
response to endoplasmic reticulum stress	1	166.8×	0.006	TMTC3

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TMTC3	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
TMTC3	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	1	TMTC3

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TMTC3	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.