mitochondrial complex III deficiency nuclear type 1

Summary

mitochondrial complex III deficiency nuclear type 1 (MONDO:0007415) is a disease caused by BCS1L (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: BCS1L (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 131

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	mitochondrial complex III deficiency nuclear type 1
Mondo ID	MONDO:0007415
MeSH	C565128
OMIM	124000
DOID	DOID:0080111
UMLS	C3541471
MedGen	762097
GARD	0015056
Is cancer (heuristic)	no

Also known as: BCS1L mitochondrial complex III deficiency · Complex 3 mitochondrial respiratory chain deficiency · MC3DN1 · mitochondrial complex III deficiency · mitochondrial complex III deficiency caused by mutation in BCS1L · mitochondrial complex III deficiency, nuclear type 1

Data availability: 131 ClinVar variants · 3 GenCC gene-disease records.

Disease family

An umbrella term covering 1 Mondo subtype.

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 1

Related subtypes (10): mitochondrial complex III deficiency nuclear type 2, 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

Subtypes (1): renal tubulopathy-encephalopathy-liver failure syndrome

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

131 retrieved; paginated sample, class counts are floors:

47 uncertain significance, 24 pathogenic/likely pathogenic, 20 likely pathogenic, 19 conflicting classifications of pathogenicity, 12 pathogenic, 4 likely benign, 3 benign, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1028218	NM_001079866.2(BCS1L):c.696del (p.Gly233fs)	BCS1L	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1071417	NM_001079866.2(BCS1L):c.917G>A (p.Arg306His)	BCS1L	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1072216	NM_001079866.2(BCS1L):c.336G>A (p.Trp112Ter)	BCS1L	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1414470	NM_001079866.2(BCS1L):c.493A>T (p.Lys165Ter)	BCS1L	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1442140	NM_001079866.2(BCS1L):c.703G>C (p.Gly235Arg)	BCS1L	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1455942	NM_001079866.2(BCS1L):c.340C>T (p.Arg114Trp)	BCS1L	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1457638	NM_001079866.2(BCS1L):c.916C>T (p.Arg306Cys)	BCS1L	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1685568	NM_001079866.2(BCS1L):c.655+1G>C	BCS1L	Pathogenic	criteria provided, single submitter
214160	NM_001079866.2(BCS1L):c.205C>T (p.Arg69Cys)	BCS1L	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
214162	NM_001079866.2(BCS1L):c.871C>T (p.Arg291Ter)	BCS1L	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
214166	NM_001079866.2(BCS1L):c.325C>T (p.Arg109Trp)	BCS1L	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2680155	NM_001079866.2(BCS1L):c.950_953del (p.Asp317fs)	BCS1L	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3065324	NM_001079866.2(BCS1L):c.25G>A (p.Ala9Thr)	BCS1L	Pathogenic	criteria provided, single submitter
370128	NM_001079866.2(BCS1L):c.607dup (p.Arg203fs)	BCS1L	Pathogenic	criteria provided, multiple submitters, no conflicts
370247	NM_001079866.2(BCS1L):c.889+1G>T	BCS1L	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
371015	NM_001079866.2(BCS1L):c.245C>A (p.Ser82Ter)	BCS1L	Pathogenic	criteria provided, multiple submitters, no conflicts
374395	NM_001079866.2(BCS1L):c.598C>T (p.Arg200Ter)	BCS1L	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
381524	NM_001079866.2(BCS1L):c.385G>A (p.Gly129Arg)	BCS1L	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
553134	NM_001079866.2(BCS1L):c.-50+405A>G	BCS1L	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
554756	NM_001079866.2(BCS1L):c.772del (p.Asp258fs)	BCS1L	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
557160	NM_001079866.2(BCS1L):c.372dup (p.Asp125fs)	BCS1L	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
6163	NM_001079866.2(BCS1L):c.830G>A (p.Ser277Asn)	BCS1L	Pathogenic	no assertion criteria provided
6164	NM_001079866.2(BCS1L):c.296C>T (p.Pro99Leu)	BCS1L	Pathogenic	criteria provided, multiple submitters, no conflicts
6165	NM_001079866.2(BCS1L):c.464G>C (p.Arg155Pro)	BCS1L	Pathogenic	no assertion criteria provided
6167	NM_001079866.2(BCS1L):c.232A>G (p.Ser78Gly)	BCS1L	Pathogenic	criteria provided, multiple submitters, no conflicts
6168	NM_001079866.2(BCS1L):c.133C>T (p.Arg45Cys)	BCS1L	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
6169	NM_001079866.2(BCS1L):c.166C>T (p.Arg56Ter)	BCS1L	Pathogenic	criteria provided, multiple submitters, no conflicts
6170	NM_001079866.2(BCS1L):c.548G>A (p.Arg183His)	BCS1L	Pathogenic	criteria provided, multiple submitters, no conflicts
6171	NM_001079866.2(BCS1L):c.550C>T (p.Arg184Cys)	BCS1L	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
6173	NM_001079866.2(BCS1L):c.148A>G (p.Thr50Ala)	BCS1L	Pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 16 · Orphanet: 5 · 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
BCS1L	Strong	Autosomal recessive	mitochondrial complex III deficiency nuclear type 1	16

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
BCS1L	Orphanet:123	Björnstad syndrome
BCS1L	Orphanet:1460	Isolated complex III deficiency
BCS1L	Orphanet:254902	Renal tubulopathy-encephalopathy-liver failure syndrome
BCS1L	Orphanet:53693	GRACILE syndrome
LYRM7	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
BCS1L	HGNC:1020	ENSG00000074582	Q9Y276	Mitochondrial chaperone BCS1	gencc,clinvar
LYRM7	HGNC:28072	ENSG00000186687	Q5U5X0	Complex III assembly factor LYRM7	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
BCS1L	Mitochondrial chaperone BCS1	Chaperone necessary for the incorporation of Rieske iron-sulfur protein UQCRFS1 into the mitochondrial respiratory chain complex III.
LYRM7	Complex III assembly factor LYRM7	Assembly factor required for Rieske Fe-S protein UQCRFS1 incorporation into the cytochrome b-c1 (CIII) complex.

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)
BCS1L	Other/Unknown	no		AAA+_ATPase, ATPase_AAA_core, ATPase_AAA_CS
LYRM7	Other/Unknown	no		Complex1_LYR_dom, Complex1_LYR_LYRM7, MZM1/LYRM7

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
apex of heart	1
body of pancreas	1
metanephros cortex	1
deltoid	1
left ventricle myocardium	1
vastus lateralis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
BCS1L	279	ubiquitous	marker	body of pancreas, metanephros cortex, apex of heart
LYRM7	254	ubiquitous	marker	left ventricle myocardium, vastus lateralis, deltoid

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
BCS1L	3,789
LYRM7	1,740

Intra-cohort edges

A	B	Sources
BCS1L	LYRM7	string_interaction

Structural data

PDB: 0 · AlphaFold-only: 2 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
LYRM7	Q5U5X0	91.70
BCS1L	Q9Y276	87.10

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. 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
Complex III assembly	2	439.2×	3e-05	BCS1L, LYRM7
Respiratory electron transport	2	95.2×	3e-04	BCS1L, LYRM7
Aerobic respiration and respiratory electron transport	2	88.5×	3e-04	BCS1L, LYRM7
Metabolism	2	11.6×	0.011	BCS1L, LYRM7
Protein localization	1	95.2×	0.012	BCS1L
Mitochondrial protein import	1	84.0×	0.012	BCS1L

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
mitochondrial respiratory chain complex III assembly	2	1203.7×	4e-06	BCS1L, LYRM7
protein insertion into mitochondrial inner membrane from matrix	1	1685.2×	0.002	BCS1L
mitochondrial respiratory chain complex IV assembly	1	312.1×	0.006	BCS1L
cellular respiration	1	216.1×	0.006	LYRM7
mitochondrial respiratory chain complex I assembly	1	205.5×	0.006	BCS1L
mitochondrion organization	1	75.9×	0.013	BCS1L

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
BCS1L	0	0
LYRM7	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	BCS1L, LYRM7

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)
BCS1L	0	—
LYRM7	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.