mitochondrial complex III deficiency nuclear type 2

Summary

mitochondrial complex III deficiency nuclear type 2 (MONDO:0014063) is a disease caused by TTC19 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: TTC19 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 101

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	mitochondrial complex III deficiency nuclear type 2
Mondo ID	MONDO:0014063
OMIM	615157
DOID	DOID:0060351
UMLS	C3554605
MedGen	767519
GARD	0015910
Is cancer (heuristic)	no

Also known as: MC3DN2 · mitochondrial complex III deficiency caused by mutation in TTC19 · mitochondrial complex III deficiency nuclear type 2 · mitochondrial complex III deficiency, nuclear type 2 · TTC19 mitochondrial complex III deficiency

Data availability: 101 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › developmental anomaly of metabolic origin › inborn mitochondrial metabolism disorder › mitochondrial oxidative phosphorylation disorder › mitochondrial respiratory chain complex deficiency › mitochondrial complex III deficiency › mitochondrial complex III deficiency, nuclear type › mitochondrial complex III deficiency nuclear type 2

Related subtypes (10): mitochondrial complex III deficiency nuclear type 1, mitochondrial complex III deficiency nuclear type 3, mitochondrial complex III deficiency nuclear type 4, mitochondrial complex III deficiency nuclear type 5, mitochondrial complex III deficiency nuclear type 6, mitochondrial complex III deficiency nuclear type 7, mitochondrial complex III deficiency nuclear type 8, mitochondrial complex III deficiency nuclear type 9, mitochondrial complex III deficiency, nuclear type 10, mitochondrial complex III deficiency, nuclear type 11

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

101 retrieved; paginated sample, class counts are floors:

46 uncertain significance, 22 conflicting classifications of pathogenicity, 11 pathogenic, 8 benign, 6 likely pathogenic, 5 likely benign, 2 pathogenic/likely pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
3896255	NM_017775.4(TTC19):c.72C>A (p.Cys24Ter)	LOC130060311	Pathogenic	criteria provided, single submitter
102437	NM_017775.4(TTC19):c.601_604del (p.Gly201fs)	TTC19	Pathogenic	criteria provided, multiple submitters, no conflicts
102438	TTC19, TRP186TER	TTC19	Pathogenic	no assertion criteria provided
102439	TTC19, 4-BP DEL, 964GGCT	TTC19	Pathogenic	no assertion criteria provided
102440	NM_017775.4(TTC19):c.829C>T (p.Gln277Ter)	TTC19	Pathogenic	no assertion criteria provided
1323720	NM_017775.4(TTC19):c.581+1G>A	TTC19	Pathogenic	criteria provided, single submitter
2579225	GRCh38/hg38 17p12(chr17:16018139-16028011)x0	TTC19	Pathogenic	criteria provided, single submitter
31073	NM_017775.4(TTC19):c.656T>G (p.Leu219Ter)	TTC19	Pathogenic	criteria provided, multiple submitters, no conflicts
31074	NM_017775.4(TTC19):c.517C>T (p.Gln173Ter)	TTC19	Pathogenic	no assertion criteria provided
3252023	NM_017775.4(TTC19):c.718_719insA (p.Leu240fs)	TTC19	Pathogenic	no assertion criteria provided
437076	NM_017775.4(TTC19):c.817G>T (p.Glu273Ter)	TTC19	Pathogenic	criteria provided, single submitter
437427	NM_017775.4(TTC19):c.554T>C (p.Leu185Pro)	TTC19	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
982298	NM_017775.4(TTC19):c.583C>T (p.Gln195Ter)	TTC19	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2441843	NM_017775.4(TTC19):c.903dup (p.Met302fs)	TTC19	Likely pathogenic	criteria provided, single submitter
2683759	NM_017775.4(TTC19):c.519+2T>A	TTC19	Likely pathogenic	criteria provided, single submitter
2690770	NM_017775.4(TTC19):c.463-1G>C	TTC19	Likely pathogenic	criteria provided, single submitter
3065645	NM_017775.4(TTC19):c.184+1G>A	TTC19	Likely pathogenic	criteria provided, single submitter
3393129	NM_017775.4(TTC19):c.93dup (p.Leu32fs)	TTC19	Likely pathogenic	criteria provided, single submitter
873487	NM_017775.4(TTC19):c.581+1_581+5del	TTC19	Likely pathogenic	criteria provided, single submitter
321941	NM_017775.4(TTC19):c.146C>T (p.Pro49Leu)	LOC130060311	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
137766	NM_017775.4(TTC19):c.1041A>G (p.Gln347=)	TTC19	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
137773	NM_017775.4(TTC19):c.-1C>T	TTC19	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2054602	NM_017775.4(TTC19):c.906G>A (p.Met302Ile)	TTC19	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
215297	NM_017775.4(TTC19):c.1004C>T (p.Thr335Ile)	TTC19	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
215303	NM_017775.4(TTC19):c.7C>T (p.Arg3Trp)	TTC19	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
215304	NM_017775.4(TTC19):c.820A>G (p.Arg274Gly)	TTC19	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
215305	NM_017775.4(TTC19):c.997C>T (p.Arg333Ter)	TTC19	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
215307	NM_017775.4(TTC19):c.612C>G (p.Phe204Leu)	TTC19	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
321940	NM_017775.4(TTC19):c.25C>T (p.Leu9=)	TTC19	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
321947	NM_017775.4(TTC19):c.758C>T (p.Pro253Leu)	TTC19	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 1 · 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
TTC19	Definitive	Autosomal recessive	mitochondrial complex III deficiency nuclear type 2	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TTC19	Orphanet:1460	Isolated complex III deficiency

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
TTC19	HGNC:26006	ENSG00000011295	Q6DKK2	Tetratricopeptide repeat protein 19, mitochondrial	gencc,clinvar
NCOR1	HGNC:7672	ENSG00000141027	O75376	Nuclear receptor corepressor 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TTC19	Tetratricopeptide repeat protein 19, mitochondrial	Required for the preservation of the structural and functional integrity of mitochondrial respiratory complex III by allowing the physiological turnover of the Rieske protein UQCRFS1.
NCOR1	Nuclear receptor corepressor 1	Mediates transcriptional repression by certain nuclear receptors.

Protein-family classification

Druggable: 0 · Difficult: 1 · 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
Transcription factor	1	4.1×	0.455
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TTC19	Other/Unknown	no		TPR-like_helical_dom_sf, TPR_rpt, TTC19
NCOR1	Transcription factor	no		SANT/Myb, Homeodomain-like_sf, SANT_dom

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
ileal mucosa	1
jejunal mucosa	1
upper leg skin	1
calcaneal tendon	1
colonic epithelium	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TTC19	291	ubiquitous	marker	jejunal mucosa, ileal mucosa, upper leg skin
NCOR1	290	ubiquitous	marker	sural nerve, colonic epithelium, calcaneal tendon

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NCOR1	5,169
TTC19	2,381

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NCOR1	O75376	27

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TTC19	Q6DKK2	80.28

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 69. 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
R-HSA-1368071	1	5710.0×	0.012	NCOR1
Loss of MECP2 binding ability to the NCoR/SMRT complex	1	815.7×	0.014	NCOR1
Loss of function of MECP2 in Rett syndrome	1	713.8×	0.014	NCOR1
Pervasive developmental disorders	1	713.8×	0.014	NCOR1
NR1H2 & NR1H3 regulate gene expression to control bile acid homeostasis	1	713.8×	0.014	NCOR1
Disorders of Developmental Biology	1	713.8×	0.014	NCOR1
Disorders of Nervous System Development	1	713.8×	0.014	NCOR1
Activation of HOX genes during differentiation	1	219.6×	0.019	NCOR1
Complex III assembly	1	219.6×	0.019	TTC19
Signaling by NOTCH1 PEST Domain Mutants in Cancer	1	203.9×	0.019	NCOR1
Signaling by NOTCH1 in Cancer	1	203.9×	0.019	NCOR1
Signaling by NOTCH1 HD+PEST Domain Mutants in Cancer	1	203.9×	0.019	NCOR1
Notch-HLH transcription pathway	1	203.9×	0.019	NCOR1
RORA,B,C and NR1D1 (REV-ERBA) regulate gene expression	1	203.9×	0.019	NCOR1
NR1H2 and NR1H3-mediated signaling	1	196.9×	0.019	NCOR1
Transcriptional activity of SMAD2/SMAD3:SMAD4 heterotrimer	1	184.2×	0.019	NCOR1
Downregulation of SMAD2/3:SMAD4 transcriptional activity	1	184.2×	0.019	NCOR1
Regulation of MECP2 expression and activity	1	184.2×	0.019	NCOR1
Signaling by NOTCH1	1	178.4×	0.019	NCOR1
Nuclear signaling by ERBB4	1	173.0×	0.019	NCOR1
R-HSA-400253	1	173.0×	0.019	NCOR1
HCMV Infection	1	163.1×	0.019	NCOR1
Transcriptional Regulation by MECP2	1	158.6×	0.019	NCOR1
NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux	1	154.3×	0.019	NCOR1
Expression of BMAL (ARNTL), CLOCK, and NPAS2	1	146.4×	0.019	NCOR1
Signaling by ERBB4	1	135.9×	0.019	NCOR1
NOTCH1 Intracellular Domain Regulates Transcription	1	119.0×	0.020	NCOR1
Heme signaling	1	107.7×	0.020	NCOR1
Epigenetic regulation of adipogenesis genes by MLL3 and MLL4 complexes	1	107.7×	0.020	NCOR1
Transcriptional activation of mitochondrial biogenesis	1	102.0×	0.020	NCOR1

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
negative regulation of fatty acid metabolic process	1	2106.5×	0.005	NCOR1
mitochondrial respiratory chain complex III assembly	1	601.9×	0.005	TTC19
locomotor rhythm	1	526.6×	0.005	NCOR1
negative regulation of glycolytic process	1	526.6×	0.005	NCOR1
negative regulation of androgen receptor signaling pathway	1	468.1×	0.005	NCOR1
negative regulation of miRNA transcription	1	312.1×	0.006	NCOR1
negative regulation of JNK cascade	1	280.9×	0.006	NCOR1
spindle assembly	1	221.7×	0.007	NCOR1
mitotic cytokinesis	1	129.6×	0.010	TTC19
chromatin organization	1	49.6×	0.024	NCOR1
negative regulation of DNA-templated transcription	1	15.8×	0.068	NCOR1
negative regulation of transcription by RNA polymerase II	1	8.9×	0.110	NCOR1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
NCOR1	ROMIDEPSIN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NCOR1	4	4
TTC19	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ROMIDEPSIN	4	NCOR1
VORINOSTAT	4	NCOR1
MOCETINOSTAT	2	NCOR1
TRICHOSTATIN	1	NCOR1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
NCOR1	31	Binding:31

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

4 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.

Compound	Max phase	Cohort target (bioactivity)
ROMIDEPSIN	4	NCOR1
VORINOSTAT	4	NCOR1
MOCETINOSTAT	2	NCOR1
TRICHOSTATIN	1	NCOR1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	NCOR1
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	TTC19

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)
TTC19	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.