BCS1L

protein-coding

BCS1 homolog, ubiquinol-cytochrome c reductase complex chaperone, the group of Mitochondrial respiratory chain complex assembly factors|AAA ATPases

Gene summary

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. [provided by RefSeq, Jan 2016]

MANE transcript

NM_001079866.2

Inheritance

AR, AD

ClinVar variants

P:157U:142B:198

Top phenotype

Bjornstad syndrome; Mitochondrial complex III deficiency, nuclear type 1

gnomAD constraint

pLI —, LoF o/e 0.86

Max pathogenic AF

—

Genomic locus

chr2:218,658,764-218,663,443

External References & Databases

Ensembl (ENSG00000074582)

Transcript & Mutation Effects

hg38 • Region Span ~4.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Bjornstad syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009872

Submitter: Labcorp Genetics (formerly Invitae)

mitochondrial complex III deficiency nuclear type 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0007415

Submitter: Ambry Genetics

Bjornstad syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0009872

Submitter: Ambry Genetics

GRACILE syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011308

Submitter: Orphanet

Bjornstad syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009872

Submitter: Orphanet

mitochondrial complex III deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0015448

Submitter: Orphanet

renal tubulopathy-encephalopathy-liver failure syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0016811

Submitter: Orphanet

Bjornstad syndromeLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0009872

Submitter: G2P

mitochondrial diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *BCS1L* and *BCS1L*-related primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of September 19, 2024. The *BCS1L* gene encodes a complex III assembly factor presumed to facilitate insertion of Rieske Fe/S proteins. The *BCS1L* gene was first reported in relation to autosomal recessive *BCS1L*-related primary mitochondrial disease in 2002 (PMID: 12215968). *BCS1L* has been associated with three disease entities to date; Bjornstad syndrome (characterized by sensorineural hearing loss, pili torti, and hypotrichosis) [OMIM# 262000]; growth restriction, aminoaciduria, cholestasis, iron overload, lactic acidosis, and early death (GRACILE) syndrome [OMIM# 603358]; and mitochondrial complex III deficiency, nuclear type 1 [OMIM# 124000]. This is one disease entity according to the ClinGen Lumping and Splitting Framework, and has been renamed as *BCS1L*-related primary mitochondrial disease. Of note, *BCS1L* was first curated by this Expert Panel for its association with Leigh syndrome spectrum (LSS) on September 9, 2019 (SOP v7), with a final classification of Limited. This current curation for the association with *BCS1L*-related primary mitochondrial disease includes cases with LSS. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included 17 unique variants (12 missense, four premature truncation, one synonymous variant shown to impact splicing) identified in nine unrelated cases from eight publications (PMIDs: 17403714, 20472482, 25895478, 31435670, 35960161, 34650211, 28105683, 34662929), although more affected individuals have been reported to date (PMID: 34662929). While some reported individuals have features consistent with one of the three clinical syndromes reported to be associated with *BCS1L*, it is now known that these features occur on a spectrum and include LSS, developmental regression, seizures, exercise intolerance, growth restriction, short stature, failure to thrive, decreased liver function, cholestasis, optic atrophy, sensorineural hearing loss, pili torti, hypotrichosis, renal tubulopathy, and metabolic acidosis. Cerebral and cerebellar atrophy and thalamic and basal ganglia involvement can be seen on brain imaging. Ragged red fibers and complex III deficiency are seen in skeletal muscle. The mechanism of disease is loss of function. This gene-disease relationship is also supported by the known protein interaction with complex III subunits and assembly factors (PMIDs: 17314340, 30030361, 24466228), functional alteration studies in patient cells showing evidence of complex III deficiency (PMIDs: 17314340, 28427446), and model systems including fruit fly, mouse, and yeast (PMIDs: 34274978, 22829922, 21274865, 17314340). In summary, there is definitive evidence to support the relationship between *BCS1L* and autosomal recessive *BCS1L*-related primary mitochondrial disease. This relationship has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on September 19, 2024 (SOP Version 10).

mitochondrial complex III deficiency nuclear type 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0007415

Submitter: Natera

Leigh syndromeLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0009723

Submitter: ClinGen

The relationship between BCS1L and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of September 9, 2019. Variants in BCS1L were first reported in humans with Leigh syndrome spectrum in 2001 (PMID: 11528392). Several pathogenic variants have been reported in ClinVar, and loss of function is the mechanism of disease for this gene. Evidence supporting this gene-disease relationship includes case-level data and experimental data. One proband with BCS1L a homozygous pathogenic variant with Leigh syndrome spectrum has been reported in the 2001 publication (PMID: 11528392) to reach a case-level evidence score of 1.5. This gene-disease association is further supported by BCS1L protein interaction with other genes associated with Leigh syndrome spectrum, BCS1L expression in brain, mitochondrial alterations in patient cell lines, and a BCS1L mouse model exhibiting a neuropathological, biochemical, and developmental phenotype that recapitulates symptoms of Leigh syndrome spectrum reaching a experimental score of 5 pts. In summary, there is limited evidence to support the relationship between BCS1L and autosomal recessive Leigh syndrome spectrum. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on September 9, 2019 (SOP Version 7).

GRACILE syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011308

Submitter: G2P

Bjornstad syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009872

Submitter: ClinGen

The BCS1L gene has been associated with autosomal recessive Bjornstad syndrome using the ClinGen Clinical Validity Framework as of 12/13/16. This association was made using case-level data only. At least 12 missense, splice site, and frameshift variants have been reported in humans. BCS1L was first associated with this disease in humans as early as 2007 (Hinson et al.). Association is seen in at least 9 probands in 5 publications (17314340, 24172246, 25895478, 28322498, 28105683). Variants in this gene segregated with disease in 13 additional family members. This gene-disease association is supported by experimental evidence performed by Hinston et al. 2007. In summary, BCS1L is definitively associated with autosomal recessive Bjornstad syndrome. This classification was approved by the ClinGen Hearing Loss Working Group on 7/9/18.

mitochondrial complex III deficiency nuclear type 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0007415

Submitter: PanelApp Australia

Bjornstad syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009872

Submitter: PanelApp Australia

GRACILE syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011308

Submitter: PanelApp Australia

GRACILE syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011308

Submitter: Labcorp Genetics (formerly Invitae)

mitochondrial complex III deficiency nuclear type 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0007415

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Bjornstad syndrome; Mitochondrial complex III deficiency, nuclear type 1AR

Manifestation: Audiologic/Otolaryngologic; Biochemical; Dermatologic; Gastrointestinal; Genitourinary; Neurologic; Ophthalmologic; Renal

Intervention: Audiologic/Otolaryngologic; Biochemical

Rationale: In Bjornstad syndrome, early recognition and treatment of hearing impairment may improve outcomes, including speech and language development; It has been suggested that that stapes surgery should not be performed due to a high likelihood of complications (the use of cochlear implants has been reported as beneficial); In Mitochondrial complex III deficiency, nuclear, some treatment attempts (eg, with apotransferrin) have been reported, and treatment with mitochondrial cocktail type therapy may be beneficial

Refs: 9482441; 10654962; 7577396; 10654962; 11528392; 12215968; 12910490; 17314340; 17403714; 19162478; 19389488; 19508421; 20580947; 20518024; 20472482; 22277166; 22991165

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to BCS1L variants in ClinVar

21 Conditions Cataloged

not providedTotal: 441

GRACILE syndromeTotal: 191

Mitochondrial complex III deficiency nuclear type 1Total: 121

Pili torti-deafness syndromeTotal: 119

BCS1L-related disorderTotal: 73

not specifiedTotal: 42

Inborn genetic diseasesTotal: 39

Leigh syndromeTotal: 18

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001079866.2. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous		2 clinvar	5 clinvar	189 clinvar		196
missense	11 clinvar	33 clinvar	128 clinvar	8 clinvar	1 clinvar	181
nonsense	8 clinvar	29 clinvar				37
start loss	2 clinvar	1 clinvar				3
frameshift	21 clinvar	35 clinvar	1 clinvar			57
splice donor/acceptor (+/-2bp)	2 clinvar	13 clinvar	8 clinvar			23
Total	44	113	142	197	1	497

Highest pathogenic variant AF is 0.00026948866

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 130 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001079866.2	RefSeq	NP_001073335.1	7	MANE Select
ENST00000359273.8	Ensembl	ENSP00000352219.3	7	MANE Select
NM_001257342.2	RefSeq	NP_001244271.1	7	Standard
NM_001257343.2	RefSeq	NP_001244272.1	7	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Metabolism of proteins
Mitochondrial protein import

Biological Process

mitochondrion organization
mitochondrial respiratory chain complex I assembly
mitochondrial respiratory chain complex IV assembly
mitochondrial respiratory chain complex III assembly

Molecular Function

protein binding
ATP binding

Cellular Component

mitochondrion
mitochondrial respiratory chain complex III
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000431802
Coding exons: 7
Length: 4680
Individuals with no LoFs: 125614
Homozygous LoFs: 0
Heterozygous LoFs: 134
Defined: 125748
p: 0.000533

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.62	170	241	0.707	0.0000159	2705
Missense (PolyPhen)		62	106.85	0.58024		1144
Synonymous	-0.481	100	94.1	1.06	0.00000574	890
Loss of Function	0.647	21	24.5	0.859	0.00000199	201

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00049	0.00049	rare
Latino/Admixed American	0.00069	0.00069	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00038	0.00038	rare
Finnish	0.000092	0.000092	rare
European (Non-Finnish)	0.00068	0.00068	rare
South Asian	0.00052	0.00052	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Chaperone necessary for the assembly of 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. {ECO:0000269|PubMed:18628306}.;
Disease: DISEASE: Mitochondrial complex III deficiency, nuclear 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. {ECO:0000269|PubMed:11528392, ECO:0000269|PubMed:12910490, ECO:0000269|PubMed:17314340, ECO:0000269|PubMed:17403714, ECO:0000269|PubMed:18628306, ECO:0000269|PubMed:19162478, ECO:0000269|PubMed:22991165}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: 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. {ECO:0000269|PubMed:17314340, ECO:0000269|PubMed:24172246}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.654

Intolerance Scores

LoFtool: 0.170
RVIS EVS: -0.62
RVIS percentile EVS: 17.16

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.917

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium