BCS1L

Chr 2AR

BCS1 ubiquinol-cytochrome c reductase complex chaperone

Also known as: BCS, BCS1, BJS, FLNMS, GRACILE, Hs.6719, MC3DN1, PTD

NCBI Gene: 617 ENSG00000074582 UniProt: Q9Y276 OMIM: 603647

The protein is essential for assembly of mitochondrial respiratory chain complex III. Autosomal recessive mutations cause mitochondrial complex III deficiency, GRACILE syndrome (growth restriction, aminoaciduria, cholestasis, iron overload, lactic acidosis, and early death), and Bjornstad syndrome. The pathogenic mechanism involves loss of function leading to defective complex III assembly and impaired cellular respiration.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

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]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 1.243 OMIM phenotypes

Clinical Summary— BCS1L

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Gene-Disease Validity (ClinGen)

Leigh syndrome · ARLimited

Limited evidence — not for standalone diagnostic reporting

3 total gene-disease associations curated

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

143 unique Pathogenic / Likely Pathogenic· 146 VUS of 607 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — BCS1L

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.24LOEUF

pLI 0.000

Z-score 0.65

OE 0.86 (0.61–1.24)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

1.62Z-score

OE missense 0.71 (0.62–0.80)

170 obs / 240.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.86 (0.61–1.24)

0≤0.351.4

Missense OE?0.71 (0.62–0.80)

0≤0.61.4

Synonymous OE?1.06

0≤1.21.6

LoF obs/exp: 21 / 24.5Missense obs/exp: 170 / 240.5Syn Z: -0.48

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

limitedBCS1L-related Bjornstad syndromeOTHERAD

definitiveBCS1L-related Gracile syndromeLOFAR

This gene — mechanism propensity

0.7035th %ile

GOF

0.4776th %ile

LOF

0.3647th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

607 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic38

Likely Pathogenic105

VUS146

Likely Benign266

Benign11

Conflicting32

Pathogenic

105

Likely Pathogenic

146

VUS

266

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	24	11	3	0	38
Likely Pathogenic	75	26	2	2	105
VUS	6	124	11	5	146
Likely Benign	0	5	83	178	266
Benign	1	0	8	2	11
Conflicting	—				32
Total	106	166	107	187	598

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

28 pathogenic / likely-pathogenic (of 31) ClinVar copy-number / structural variants overlap BCS1L — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →