BCS1L

Summary

BCS1L (BCS1 ubiquinol-cytochrome c reductase complex chaperone, HGNC:1020) is a protein-coding gene on chromosome 2q35, encoding Mitochondrial chaperone BCS1 (Q9Y276). Chaperone necessary for the incorporation of Rieske iron-sulfur protein UQCRFS1 into the mitochondrial respiratory chain complex III. It is a selective cancer dependency (DepMap: 34.8% of cell lines).

This gene encodes a homolog of the S. cerevisiae bcs1 protein which is involved in the assembly of complex III of the mitochondrial respiratory chain. The encoded protein does not contain a mitochondrial targeting sequence but experimental studies confirm that it is imported into mitochondria. Mutations in this gene are associated with mitochondrial complex III deficiency and the GRACILE syndrome. Several alternatively spliced transcripts encoding two different isoforms have been described.

Source: NCBI Gene 617 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial disease (Definitive, ClinGen) — +6 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 603 total — 38 pathogenic, 68 likely-pathogenic
• Phenotypes (HPO): 83
• Cancer dependency (DepMap): dependent in 34.8% of screened cell lines
• MANE Select transcript: NM_001079866

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1020
Approved symbol	BCS1L
Name	BCS1 ubiquinol-cytochrome c reductase complex chaperone
Location	2q35
Locus type	gene with protein product
Status	Approved
Aliases	Hs.6719, BCS, h-BCS, BJS
Ensembl gene	ENSG00000074582
Ensembl biotype	protein_coding
OMIM	603647
Entrez	617

Gene structure

Transcript identifiers

Ensembl transcripts: 62 — 56 protein_coding, 5 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000359273, ENST00000392109, ENST00000392110, ENST00000392111, ENST00000412366, ENST00000423377, ENST00000426649, ENST00000428880, ENST00000430322, ENST00000431802, ENST00000436603, ENST00000439945, ENST00000443791, ENST00000456050, ENST00000460579, ENST00000465706, ENST00000471576, ENST00000477422, ENST00000490188, ENST00000493376, ENST00000643945, ENST00000907075, ENST00000907076, ENST00000907077, ENST00000907078, ENST00000907079, ENST00000907080, ENST00000907081, ENST00000907082, ENST00000907083, ENST00000907084, ENST00000907085, ENST00000907086, ENST00000907087, ENST00000907088, ENST00000907089, ENST00000907090, ENST00000907091, ENST00000907092, ENST00000907093, ENST00000907094, ENST00000931811, ENST00000931812, ENST00000931813, ENST00000931814, ENST00000931815, ENST00000931816, ENST00000931817, ENST00000931818, ENST00000931819, ENST00000931820, ENST00000931821, ENST00000931822, ENST00000931823, ENST00000931824, ENST00000931825, ENST00000931826, ENST00000931827, ENST00000945766, ENST00000945767, ENST00000945768, ENST00000945769

RefSeq mRNA: 22 — MANE Select: NM_001079866 NM_001079866, NM_001257342, NM_001257343, NM_001257344, NM_001318836, NM_001320717, NM_001371443, NM_001371444, NM_001371446, NM_001371447, NM_001371448, NM_001371449, NM_001371450, NM_001371451, NM_001371452, NM_001371453, NM_001371454, NM_001371455, NM_001371456, NM_001374085, NM_001374086, NM_004328

CCDS: CCDS2419

Canonical transcript exons

ENST00000359273 — 8 exons

Exon	Start	End
ENSE00001039129	218660939	218661307
ENSE00001075099	218662510	218662679
ENSE00003504956	218661759	218661953
ENSE00003574936	218662197	218662260
ENSE00003615560	218661406	218661545
ENSE00003660120	218662883	218663000
ENSE00003902418	218659683	218659743
ENSE00003903671	218663134	218663443

Expression profiles

Bgee: expression breadth ubiquitous, 279 present calls, max score 97.07.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 8.7547 / max 71.7681, expressed in 1742 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
25363	8.5657	1741
25364	0.1890	66

Top tissues by expression

295 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
body of pancreas	UBERON:0001150	97.07	gold quality
metanephros cortex	UBERON:0010533	96.62	gold quality
apex of heart	UBERON:0002098	96.35	gold quality
right uterine tube	UBERON:0001302	95.95	gold quality
right lobe of liver	UBERON:0001114	95.72	gold quality
lower esophagus mucosa	UBERON:0035834	95.68	gold quality
mucosa of transverse colon	UBERON:0004991	95.55	gold quality
right adrenal gland	UBERON:0001233	95.30	gold quality
right lobe of thyroid gland	UBERON:0001119	95.19	gold quality
right adrenal gland cortex	UBERON:0035827	95.19	gold quality
body of stomach	UBERON:0001161	94.96	gold quality
right ovary	UBERON:0002118	94.89	gold quality
left adrenal gland cortex	UBERON:0035825	94.71	gold quality
left adrenal gland	UBERON:0001234	94.62	gold quality
minor salivary gland	UBERON:0001830	94.62	gold quality
body of uterus	UBERON:0009853	94.59	gold quality
transverse colon	UBERON:0001157	94.56	gold quality
rectum	UBERON:0001052	94.55	gold quality
left lobe of thyroid gland	UBERON:0001120	94.47	gold quality
small intestine Peyer’s patch	UBERON:0003454	94.43	gold quality
left ovary	UBERON:0002119	94.41	gold quality
esophagus mucosa	UBERON:0002469	94.25	gold quality
tibial nerve	UBERON:0001323	94.13	gold quality
endocervix	UBERON:0000458	94.12	gold quality
adrenal cortex	UBERON:0001235	94.11	gold quality
granulocyte	CL:0000094	94.00	gold quality
lower esophagus	UBERON:0013473	94.00	gold quality
lower esophagus muscularis layer	UBERON:0035833	93.99	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	93.96	gold quality
esophagus	UBERON:0001043	93.92	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.51

Regulation

Is transcription factor: no

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 34.8% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 21)

• GRACILE syndrome, a lethal metabolic disorder with iron overload, is caused by a point mutation in BCS1L (PMID:12215968)
• a function of BCS1L is to promote the maturation of complex III and the incorporation of the Rieske iron-sulfur protein into the nascent complex. Defective BCS1L leads to the formation of a catalytically inactive, structurally unstable complex III. (PMID:17403714)
• assessed whether 232A–>G or other BCS1L mutations were present in infants (n = 21) of Finnish origin with severe, lethal disease compatible with mitochondrial disorder (PMID:18386115)
• BCS1L stimulates the assembly of the LETM1 complex. BCS1L knockdown caused disassembly of the respiratory chains as well as LETM1 downregulation and induced distinct changes in mitochondrial morphology. (PMID:18628306)
• The severity of the complex III enzyme defect correlated with decreased amounts of BCS1L and respiratory chain complex III. This supports a pathogenic role for the novel BCS1L mutation in a patient with a singular clinical phenotype. (PMID:19162478)
• The g.1181A>G mutation generated an alternative splicing site in the BCS1L transcript, causing a 19-nucleotides deletion in its 5’UTR region and Complex III deficiency. (PMID:19389488)
• mitochondrial complex III deficiency caused by mutations in the BCS1L gene (PMID:19508421)
• These results provide new insights into the role of pathogenic BCS1L mutations in mitochondrial function and dynamics. (PMID:20518024)
• A novel behavioral and psychiatric phenotype associated with a p.Gly129Arg BCS1L mutation. (PMID:22991165)
• This region encompasses the BCS1L gene. (PMID:24172246)
• Extensive statistical and cluster analyses revealed a protein profile characteristic for the BCS1L mutant fibroblasts that included alterations in energy metabolism, cell signaling and gene expression regulation, cytoskeleton formation and maintenance. (PMID:25239759)
• Exome sequencing revealed novel BCS1L mutations in two siblings with Bjornstad syndrome characterized by hearing loss and hypotrichosis. (PMID:25895478)
• * Description of a novel homozygous mutation in BCS1L with transient neonatal acidosis and persistent de Toni-Debre-Fanconi-type tubulopathy. * The long survival of patients with phenotypic presentation of severe complex III deficiency is uncommon. (PMID:26563427)
• We report the first Italian patients with Bjornstad syndrome, two siblings with pili torti and sensorineural hearing loss, in whom we detected two novel compound heterozygous mutations in BCS1L (PMID:28322498)
• The BCSIL gene mutation is responsible for GRACILE syndrome, Bjornstad syndrome and complex III deficiency. Bjomstad syndrome is characterized by sensorineural hearing loss and abnormal flat twisted hair shafts. The case is GRACILE syndrome with Bjomstad phenotype in neonatal period due to BCSL1 gene mutation. (PMID:30226971)
• We propose a change in nomenclature that unifies the intermediate phenotype under “BCS1L Mitopathies”. Patterns in genotype-phenotype correlations within these BCS1L Mitopathies are evident in the context of the tertiary and quaternary structure of BCS1L. (PMID:30582773)
• Data support the pathogenicity of the novel BCS1L variants identified in our patients. (PMID:31435670)
• Modelling of BCS1L-related human mitochondrial disease in Drosophila melanogaster. (PMID:34274978)
• BCS1L mutations produce Fanconi syndrome with developmental disability. (PMID:34650211)
• Expanding the phenotypic spectrum of BCS1L-related mitochondrial disease. (PMID:34662929)
• Conformations of Bcs1L undergoing ATP hydrolysis suggest a concerted translocation mechanism for folded iron-sulfur protein substrate. (PMID:38821922)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	bcs1l	ENSDARG00000012295
mus_musculus	Bcs1l	ENSMUSG00000026172
rattus_norvegicus	Bcs1l	ENSRNOG00000016754
drosophila_melanogaster	Bcs1	FBGN0032195
caenorhabditis_elegans		WBGENE00010042

Protein

Protein identifiers

Mitochondrial chaperone BCS1 — Q9Y276 (reviewed: Q9Y276)

Alternative names: BCS1-like protein

All UniProt accessions (9): Q9Y276, A0A024R445, A0A2R8Y7T3, C9J1S9, C9J4Q9, C9J8G3, C9JAS4, H7BZF6, H7C492

UniProt curated annotations — full annotation on UniProt →

Function. Chaperone necessary for the incorporation of Rieske iron-sulfur protein UQCRFS1 into the mitochondrial respiratory chain complex III. Plays an important role in the maintenance of mitochondrial tubular networks, respiratory chain assembly and formation of the LETM1 complex.

Subunit / interactions. Interacts with LETM1.

Subcellular location. Mitochondrion inner membrane.

Tissue specificity. Ubiquitous.

Disease relevance. GRACILE syndrome (GRACILE) [MIM:603358] GRACILE stands for ‘growth retardation, aminoaciduria, cholestasis, iron overload, lactic acidosis, and early death’. It is a recessively inherited lethal disease characterized by fetal growth retardation, lactic acidosis, aminoaciduria, cholestasis, and abnormalities in iron metabolism. The disease is caused by variants affecting the gene represented in this entry. Mitochondrial complex III deficiency, nuclear type 1 (MC3DN1) [MIM:124000] A disorder of the mitochondrial respiratory chain resulting in a highly variable phenotype depending on which tissues are affected. Clinical features include mitochondrial encephalopathy, psychomotor retardation, ataxia, severe failure to thrive, liver dysfunction, renal tubulopathy, muscle weakness and exercise intolerance. The disease is caused by variants affecting the gene represented in this entry. Bjoernstad syndrome (BJS) [MIM:262000] An autosomal recessive disease characterized by congenital sensorineural hearing loss and twisted hairs (pili torti). Pili torti is a condition in which the hair shafts are flattened at irregular intervals and twisted 180 degrees from the normal axis, making the hair extremely brittle. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the AAA ATPase family. BCS1 subfamily.

RefSeq proteins (22): NP_001073335, NP_001244271, NP_001244272, NP_001244273, NP_001305765, NP_001307646, NP_001358372, NP_001358373, NP_001358375, NP_001358376, NP_001358377, NP_001358378, NP_001358379, NP_001358380, NP_001358381, NP_001358382, NP_001358383, NP_001358384, NP_001358385, NP_001361014, NP_001361015, NP_004319 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003593	AAA+_ATPase	Domain
IPR003959	ATPase_AAA_core	Domain
IPR003960	ATPase_AAA_CS	Conserved_site
IPR014851	BCS1_N	Domain
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR050747	Mitochondrial_chaperone_BCS1	Family
IPR057495	AAA_lid_BCS1	Domain

Pfam: PF00004, PF08740, PF25426

Catalyzed reactions (Rhea), 1 shown:

• ATP + H2O = ADP + phosphate + H(+) (RHEA:13065)

UniProt features (28 total): sequence variant 20, topological domain 2, initiator methionine 1, chain 1, sequence conflict 1, transmembrane region 1, binding site 1, modified residue 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y276-F1	87.10	0.53

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (1): 230–237

Post-translational modifications (1): 181

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-1268020	Mitochondrial protein import
R-HSA-9865881	Complex III assembly
R-HSA-1428517	Aerobic respiration and respiratory electron transport
R-HSA-1430728	Metabolism
R-HSA-611105	Respiratory electron transport
R-HSA-9609507	Protein localization

MSigDB gene sets: 305 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_DN, GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_UP, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, GOBP_RESPIRATORY_CHAIN_COMPLEX_IV_ASSEMBLY, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_MITOCHONDRIAL_RESPIRATORY_CHAIN_COMPLEX_ASSEMBLY, GAUSSMANN_MLL_AF4_FUSION_TARGETS_C_DN, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_ORGANELLE, GOBP_CYTOCHROME_COMPLEX_ASSEMBLY, CREIGHTON_ENDOCRINE_THERAPY_RESISTANCE_1, GOBP_INNER_MITOCHONDRIAL_MEMBRANE_ORGANIZATION, WCTCNATGGY_UNKNOWN, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_MEMBRANE, GOCC_MITOCHONDRIAL_ENVELOPE

GO Biological Process (5): mitochondrion organization (GO:0007005), protein insertion into mitochondrial inner membrane from matrix (GO:0032979), mitochondrial respiratory chain complex I assembly (GO:0032981), mitochondrial respiratory chain complex IV assembly (GO:0033617), mitochondrial respiratory chain complex III assembly (GO:0034551)

GO Molecular Function (5): ATP binding (GO:0005524), ATP hydrolysis activity (GO:0016887), nucleotide binding (GO:0000166), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (5): mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), respiratory chain complex III (GO:0045275), membrane (GO:0016020), mitochondrial membrane (GO:0031966)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Protein localization	1
Respiratory electron transport	1
Metabolism	1
Aerobic respiration and respiratory electron transport	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
mitochondrial respiratory chain complex assembly	3
mitochondrion	3
organelle organization	1
inner mitochondrial membrane organization	1
protein insertion into mitochondrial membrane	1
NADH dehydrogenase complex assembly	1
respiratory chain complex IV assembly	1
respiratory chain complex III assembly	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
ribonucleoside triphosphate phosphatase activity	1
ATP-dependent activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
catalytic activity	1
cytoplasm	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
mitochondrial membrane	1
cytochrome complex	1
respiratory chain complex	1
transmembrane transporter complex	1
oxidoreductase complex	1
cellular anatomical structure	1
mitochondrial envelope	1
organelle membrane	1

Protein interactions and networks

STRING

3569 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
BCS1L	UQCRQ	O14949	935
BCS1L	UQCRB	P14927	897
BCS1L	SDHA	P31040	816
BCS1L	COX10	Q12887	797
BCS1L	SURF1	Q15526	791
BCS1L	COX15	Q7KZN9	789
BCS1L	TTC19	Q6DKK2	772
BCS1L	LYRM7	Q5U5X0	759
BCS1L	UQCRFS1	P47985	757
BCS1L	NDUFV1	P49821	747
BCS1L	TACO1	Q9BSH4	721
BCS1L	NDUFS4	O43181	715
BCS1L	MT-ATP6	P00846	701
BCS1L	NDUFAF6	Q330K2	701
BCS1L	NDUFS7	O75251	697

IntAct

70 interactions, top by confidence:

A	B	Type	Score
NRP1	CSNK2A2	psi-mi:“MI:0914”(association)	0.790
NDUFS7	NDUFS8	psi-mi:“MI:0914”(association)	0.640
MX1	BCS1L	psi-mi:“MI:0915”(physical association)	0.590
LETM1	BCS1L	psi-mi:“MI:0915”(physical association)	0.560
SLC2A12	METTL15	psi-mi:“MI:0914”(association)	0.530
	UBXN8	psi-mi:“MI:0914”(association)	0.530
IMPDH1	BCAT2	psi-mi:“MI:0914”(association)	0.530
DNAJC30	NDUFS8	psi-mi:“MI:0914”(association)	0.530
GPS1	PXDNL	psi-mi:“MI:0914”(association)	0.530
STX3	NBAS	psi-mi:“MI:0914”(association)	0.530
EMB	BCS1L	psi-mi:“MI:0915”(physical association)	0.500
BCS1L	DNAJA1	psi-mi:“MI:0915”(physical association)	0.370
Rbm8a	GOSR1	psi-mi:“MI:0914”(association)	0.350
Myh9	GOSR1	psi-mi:“MI:0914”(association)	0.350
VPS26A	LCMT2	psi-mi:“MI:0914”(association)	0.350
HSCB	RBP5	psi-mi:“MI:0914”(association)	0.350
RBFOX2	PRMT5	psi-mi:“MI:0914”(association)	0.350
IMPDH1	LCMT2	psi-mi:“MI:0914”(association)	0.350
NDUFS7		psi-mi:“MI:0914”(association)	0.350
LITAF	SDCBP	psi-mi:“MI:0914”(association)	0.350
	PLSCR1	psi-mi:“MI:0914”(association)	0.350
VCAM1	APOA1	psi-mi:“MI:0914”(association)	0.350
TMEFF1	FGF2	psi-mi:“MI:0914”(association)	0.350
MATN4	MATN1	psi-mi:“MI:0914”(association)	0.350

BioGRID (150): BCS1L (Affinity Capture-MS), BCS1L (Affinity Capture-MS), BCS1L (Affinity Capture-MS), AIFM1 (Co-fractionation), BCS1L (Co-fractionation), VAPA (Co-fractionation), BCS1L (Affinity Capture-MS), BCS1L (Affinity Capture-MS), BCS1L (Affinity Capture-MS), BCS1L (Affinity Capture-MS), BCS1L (Affinity Capture-MS), BCS1L (Affinity Capture-MS), BCS1L (Affinity Capture-MS), BCS1L (Affinity Capture-MS), BCS1L (Affinity Capture-MS)

ESM2 similar proteins: A1CJ34, A1CRW7, A1D4S4, A1D8E4, A2Q8L1, A2QY22, A4R1J7, A6QLJ0, A8MPP1, E7F8F4, F1R345, F4JWP9, O08811, O62621, P06839, P0CR38, P0CR39, P11498, P18074, P24785, P26659, P45437, Q01320, Q0CUU1, Q0US25, Q1DY01, Q1E5T3, Q295E6, Q29RK2, Q2HB00, Q2U587, Q2URM9, Q4WK80, Q55G81, Q5BGR9, Q5E9H5, Q60452, Q6E6J3, Q6Z9U7, Q8K224

Diamond homologs: A3CV35, A4G0S4, A6UQT3, A6VHR1, A8ZNZ4, A9A916, B1ZMG6, B2UE66, B3DY14, B6YXR2, B8GGN4, B8J992, C3MRF1, C3MY47, C3MZI6, C3N7K8, C3NFW6, C4KIR6, C5A6P8, D0MGU8, D1C4U5, D2QZ34, D4GUJ7, F4IJ77, F4IQG2, F4J0B7, F4J0C0, F4JPK8, F4KFX5, F4KID5, O04019, O05209, O16368, O17071, O26824, O28972, O32617, O59824, O74445, P32839

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
BCS1L	“up-regulates activity”	LETM1	binding
BCS1L	up-regulates	Mitochondrial_biogenesis

Disease & clinical

Clinical variants and AI predictions

ClinVar

603 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	38
Likely pathogenic	68
Uncertain significance	141
Likely benign	263
Benign	11

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1075999	NM_001079866.2(BCS1L):c.610_611del (p.Asp204fs)	Pathogenic
126497	NM_001079866.2(BCS1L):c.901T>A (p.Tyr301Asn)	Pathogenic
1350357	NM_001079866.2(BCS1L):c.1A>G (p.Met1Val)	Pathogenic
1453418	NM_001079866.2(BCS1L):c.253C>T (p.Gln85Ter)	Pathogenic
1455266	NM_001079866.2(BCS1L):c.238G>T (p.Glu80Ter)	Pathogenic
1458352	NM_001079866.2(BCS1L):c.320+1G>A	Pathogenic
1685568	NM_001079866.2(BCS1L):c.655+1G>C	Pathogenic
1698536	NC_000002.11:g.(?219524378)(219528167_?)del	Pathogenic
2004262	NM_001079866.2(BCS1L):c.217del (p.Arg73fs)	Pathogenic
2023779	NM_001079866.2(BCS1L):c.429_432dup (p.Lys145fs)	Pathogenic
2130564	NM_001079866.2(BCS1L):c.695del (p.Pro232fs)	Pathogenic
214164	NM_001079866.2(BCS1L):c.625_626del (p.Ile209fs)	Pathogenic
2709655	NM_001079866.2(BCS1L):c.434dup (p.Val146fs)	Pathogenic
2710671	NM_001079866.2(BCS1L):c.826C>T (p.Gln276Ter)	Pathogenic
2728494	NM_001079866.2(BCS1L):c.67dup (p.Val23fs)	Pathogenic
3065324	NM_001079866.2(BCS1L):c.25G>A (p.Ala9Thr)	Pathogenic
3247519	NC_000002.11:g.(?219521986)(219527996_?)del	Pathogenic
3247520	NC_000002.11:g.(?219524871)(219679753_?)del	Pathogenic
3247521	NC_000002.11:g.(?219527335)(219528514_?)del	Pathogenic
3623355	NM_001079866.2(BCS1L):c.1105_1108dup (p.Pro370fs)	Pathogenic
370128	NM_001079866.2(BCS1L):c.607dup (p.Arg203fs)	Pathogenic
371015	NM_001079866.2(BCS1L):c.245C>A (p.Ser82Ter)	Pathogenic
371250	NM_001079866.2(BCS1L):c.556C>T (p.Arg186Ter)	Pathogenic
3764570	NM_001079866.2(BCS1L):c.899del (p.Lys300fs)	Pathogenic
4687344	NM_001079866.2(BCS1L):c.694_695dup (p.Gly233fs)	Pathogenic
4733111	NM_001079866.2(BCS1L):c.3G>A (p.Met1Ile)	Pathogenic
520622	NM_001079866.2(BCS1L):c.785_786del (p.Leu261_Ser262insTer)	Pathogenic
555982	NM_001079866.2(BCS1L):c.821del (p.Pro274fs)	Pathogenic
6163	NM_001079866.2(BCS1L):c.830G>A (p.Ser277Asn)	Pathogenic
6164	NM_001079866.2(BCS1L):c.296C>T (p.Pro99Leu)	Pathogenic

SpliceAI

1575 predictions. Top by Δscore:

Variant	Effect	Δscore
2:218659366:CAC:C	donor_loss	1.0000
2:218659367:A:C	donor_loss	1.0000
2:218659368:C:CA	donor_loss	1.0000
2:218659751:GGC:G	donor_gain	1.0000
2:218659752:GC:G	donor_gain	1.0000
2:218659753:C:G	donor_gain	1.0000
2:218660164:G:T	donor_gain	1.0000
2:218661542:G:GT	donor_gain	1.0000
2:218661543:A:T	donor_gain	1.0000
2:218661755:CCAGC:C	acceptor_loss	1.0000
2:218661757:A:AG	acceptor_gain	1.0000
2:218661757:A:T	acceptor_loss	1.0000
2:218661757:AGCTC:A	acceptor_gain	1.0000
2:218661758:G:GA	acceptor_gain	1.0000
2:218661758:GC:G	acceptor_gain	1.0000
2:218661758:GCT:G	acceptor_gain	1.0000
2:218661758:GCTC:G	acceptor_gain	1.0000
2:218661758:GCTCG:G	acceptor_gain	1.0000
2:218661939:G:GA	donor_gain	1.0000
2:218661951:GAG:G	donor_gain	1.0000
2:218661952:AGG:A	donor_loss	1.0000
2:218661954:G:GG	donor_gain	1.0000
2:218661954:GTGAG:G	donor_loss	1.0000
2:218662508:A:AG	acceptor_gain	1.0000
2:218662509:G:GG	acceptor_gain	1.0000
2:218662637:G:GT	donor_gain	1.0000
2:218662675:GGAGA:G	donor_gain	1.0000
2:218662676:GAGA:G	donor_gain	1.0000
2:218662676:GAGAG:G	donor_gain	1.0000
2:218662677:A:T	donor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000259331 (2:218662588 C>G), RS1000352446 (2:218659981 G>A), RS1000522183 (2:218657555 A>C), RS1000629747 (2:218662887 A>C,G), RS1000761034 (2:218657827 C>G), RS1001355643 (2:218661677 C>G,T), RS1003378777 (2:218658297 T>TG), RS1004216953 (2:218656924 T>C), RS1004254276 (2:218663152 A>G), RS1004656165 (2:218657065 G>A,C), RS1004879625 (2:218661897 G>A,C), RS1005321294 (2:218658212 T>A,C), RS1006209817 (2:218659195 C>G), RS1006666790 (2:218659778 T>C), RS1006907254 (2:218660131 C>G)

Disease associations

OMIM: gene MIM:603647 | disease phenotypes: MIM:124000, MIM:262000, MIM:603358, MIM:256000

GenCC curated gene-disease

Disease	Classification	Inheritance
Bjornstad syndrome	Definitive	Autosomal recessive
GRACILE syndrome	Definitive	Autosomal recessive
mitochondrial complex III deficiency nuclear type 1	Strong	Autosomal recessive
mitochondrial complex III deficiency	Supportive	Autosomal recessive
renal tubulopathy-encephalopathy-liver failure syndrome	Supportive	Autosomal recessive
Leigh syndrome	Limited	Autosomal recessive

ClinGen Gene-Disease Validity (3)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
mitochondrial disease	Definitive	AR
Leigh syndrome	Limited	AR
Bjornstad syndrome	Definitive	AR

Mondo (10): mitochondrial complex III deficiency nuclear type 1 (MONDO:0007415), Bjornstad syndrome (MONDO:0009872), GRACILE syndrome (MONDO:0011308), Leigh syndrome (MONDO:0009723), neuromuscular disease (MONDO:0019056), intellectual disability (MONDO:0001071), microcephaly (MONDO:0001149), movement disorder (MONDO:0005395), mitochondrial complex III deficiency (MONDO:0015448), renal tubulopathy-encephalopathy-liver failure syndrome (MONDO:0016811)

Orphanet (6): Björnstad syndrome (Orphanet:123), Renal tubulopathy-encephalopathy-liver failure syndrome (Orphanet:254902), GRACILE syndrome (Orphanet:53693), Leigh syndrome (Orphanet:506), Neuromuscular disease (Orphanet:68381), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

83 total (30 of 83 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000035	Abnormal testis morphology
HP:0000135	Hypogonadism
HP:0000365	Hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000478	Abnormality of the eye
HP:0000508	Ptosis
HP:0000510	Rod-cone dystrophy
HP:0000518	Cataract
HP:0000712	Emotional lability
HP:0000716	Depression
HP:0000738	Hallucinations
HP:0000970	Anhidrosis
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001272	Cerebellar atrophy
HP:0001290	Generalized hypotonia
HP:0001319	Neonatal hypotonia
HP:0001324	Muscle weakness
HP:0001347	Hyperreflexia
HP:0001394	Cirrhosis
HP:0001396	Cholestasis
HP:0001397	Hepatic steatosis
HP:0001405	Periportal fibrosis
HP:0001410	Decreased liver function
HP:0001414	Microvesicular hepatic steatosis

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST006661_114	Male-pattern baldness	2.000000e-16

MeSH disease descriptors (8)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D007888	Leigh Disease	C10.228.140.163.100.412; C16.320.565.189.412; C16.320.565.202.810.444; C18.452.132.100.412; C18.452.648.189.412; C18.452.648.202.810.444; C18.452.660.520
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
D009069	Movement Disorders	C10.228.662
D009468	Neuromuscular Diseases	C10.668
C537633	Bjornstad syndrome (supp.)
C537934	Finnish lethal neonatal metabolic syndrome (supp.)
C565128	Mitochondrial Complex III Deficiency (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

20 total (human), top 20 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Tretinoin	decreases expression	2
sodium arsenate	increases expression	1
arsenite	affects binding, increases reaction	1
sodium arsenite	decreases expression	1
astragaloside A	decreases expression, decreases reaction	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
ICG 001	increases expression	1
Temozolomide	increases expression	1
Sunitinib	decreases expression	1
Acetaminophen	affects response to substance	1
Atrazine	increases expression	1
Coumestrol	increases expression	1
Silicon Dioxide	increases expression	1
Thiram	decreases expression	1
Tunicamycin	increases expression	1
1-Methyl-4-phenylpyridinium	decreases expression, decreases reaction	1
Aflatoxin B1	increases methylation	1
Cadmium Chloride	decreases expression	1
Copper Sulfate	decreases expression	1

Clinical trials (associated diseases)

212 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00331656	PHASE4	UNKNOWN	Comparative Study of Non-Invasive Mask Ventilation vs Cuirass Ventilation in Patients With Acute Respiratory Failure.
NCT00994552	PHASE4	UNKNOWN	Comparison of Pressure Support and Pressure Control Ventilation in Chronic Respiratory Failure
NCT00839033	PHASE3	TERMINATED	Evaluation of a Mechanical Device During Acute Respiratory Failure in Patients With Neuromuscular Disorders
NCT00942227	PHASE3	COMPLETED	The Value of Traction in Treatment of Lumbar Radiculopathy
NCT00979108	PHASE3	COMPLETED	The Value of Traction in the Treatment of Cervical Radiculopathy
NCT01826487	PHASE3	COMPLETED	Phase 3 Study of Ataluren in Participants With Nonsense Mutation Duchenne Muscular Dystrophy (nmDMD)
NCT02090959	PHASE3	TERMINATED	An Extension Study of Ataluren (PTC124) in Participants With Nonsense Mutation Dystrophinopathy
NCT02436096	PHASE3	COMPLETED	A Study to Evaluate eFFIcacy and Safety of Sublingual TNX-102 SL Tablet Taken at Bedtime in Patients With fibRoMyalgia
NCT02829814	PHASE3	TERMINATED	Repeat of: A Study to Evaluate Efficacy and Safety of Sublingual TNX-102 SL Tablet Taken at Bedtime in Patients With Fibromyalgia
NCT03179631	PHASE3	COMPLETED	Long-Term Outcomes of Ataluren in Duchenne Muscular Dystrophy
NCT05126758	PHASE3	ACTIVE_NOT_RECRUITING	A Study of Deramiocel (CAP-1002) in Ambulatory and Non-Ambulatory Patients With Duchenne Muscular Dystrophy
NCT05156320	PHASE3	COMPLETED	Efficacy and Safety of Apitegromab in Patients With Later-Onset Spinal Muscular Atrophy Treated With Nusinersen or Risdiplam
NCT05337553	PHASE3	ACTIVE_NOT_RECRUITING	A Study to Evaluate the Efficacy and Safety of Taldefgrobep Alfa in Participants With Spinal Muscular Atrophy
NCT05626855	PHASE3	ACTIVE_NOT_RECRUITING	Long-Term Safety & Efficacy of Apitegromab in Patients With SMA Who Completed Previous Trials of Apitegromab
NCT06672237	PHASE3	RECRUITING	A Phase 3 Study of NTLA-2001 in ATTRv-PN
NCT01721733	PHASE2	COMPLETED	Safety and Efficacy Study of EPI-743 in Children With Leigh Syndrome
NCT02352896	PHASE2	COMPLETED	Long-Term Safety and Efficacy Evaluation of EPI-743 in Children With Leigh Syndrome
NCT03747328	PHASE2	WITHDRAWN	ABI-009 (Nab-sirolimus) in Patients With Genetically-confirmed Leigh or Leigh-like Syndrome
NCT06843811	PHASE2	ENROLLING_BY_INVITATION	Sirolimus for Leigh Syndrome
NCT06990984	PHASE2	NOT_YET_RECRUITING	A Dose-ranging Study of TTI-0102 in Adults and Children With Leigh Syndrome Spectrum (LSS)
NCT01074359	PHASE2	TERMINATED	Safety and Efficacy Study of A0001 in Patients With the A3243G Mitochondrial DNA Point Mutation
NCT01371149	PHASE2	COMPLETED	Patient -Ventilator Interaction in Chronic Respiratory Failure
NCT02022072	PHASE2	TERMINATED	Evaluation of Vital Capacity
NCT03127514	PHASE2	COMPLETED	AMX0035 in Patients With Amyotrophic Lateral Sclerosis (ALS)
NCT03406780	PHASE2	COMPLETED	A Study of CAP-1002 in Ambulatory and Non-Ambulatory Patients With Duchenne Muscular Dystrophy
NCT03921528	PHASE2	COMPLETED	An Active Treatment Study of SRK-015 in Patients With Type 2 or Type 3 Spinal Muscular Atrophy
NCT05479981	PHASE2	COMPLETED	Extension of AOC 1001-CS1 (MARINA) Study in Adult Myotonic Dystrophy Type 1 (DM1) Patients
NCT06339580	PHASE2	RECRUITING	Assessment of Volume-targeted Ventilation in Patients With Neuromuscular Disease
NCT07071935	PHASE2	NOT_YET_RECRUITING	A Clinical Trial of Early Ventilation in Amyotrophic Lateral Sclerosis (EVENT ALS)
NCT07287189	PHASE2	RECRUITING	Phase 2 Study of SAT-3247 in Pediatric Ambulatory Patients
NCT02544217	PHASE1	COMPLETED	A Dose-escalating Clinical Trial With KH176
NCT00252252	PHASE1	COMPLETED	AutoVPAP Versus VPAP; Assessment of Sleep and Ventilation
NCT01560741	PHASE1	UNKNOWN	Telemedicine and Ventilator Titration in Chronic Respiratory Patients Initiating Non-invasive Ventilation
NCT01621984	PHASE1	COMPLETED	Therapeutic Riding and Neuromuscular Disease
NCT01758510	PHASE1	COMPLETED	Safety Study of HLA-haplo Matched Allogenic Bone Marrow Derived Stem Cell Treatment in Amyotrophic Lateral Sclerosis
NCT03440034	PHASE1	COMPLETED	Study of Pioglitazone in Sporadic Inclusion Body Myositis
NCT05730842	PHASE1	COMPLETED	Absorption, Metabolism, Excretion and Absolute Bioavailability of EDG-5506 in Healthy Volunteers
NCT04378075	PHASE2/PHASE3	TERMINATED	A Study to Evaluate Efficacy and Safety of Vatiquinone for Treating Mitochondrial Disease in Participants With Refractory Epilepsy
NCT01780168	Not specified	RECRUITING	The NIH MINI Study: Metabolism, Infection, and Immunity in Inborn Errors of Metabolism
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford