BOLA3

Chr 2AR

bolA family member 3

Also known as: MMDS2

NCBI Gene: 388962 ENSG00000163170 UniProt: Q53S33 OMIM: 613183

The protein is essential for iron-sulfur cluster production required for maturation of lipoate-containing 2-oxoacid dehydrogenases and assembly of mitochondrial respiratory chain complexes. Mutations cause multiple mitochondrial dysfunctions syndrome 2 with hyperglycinemia, inherited in an autosomal recessive pattern. The pathogenic mechanism involves dominant-negative effects disrupting normal mitochondrial function.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a protein that plays an essential role in the production of iron-sulfur (Fe-S) clusters for the normal maturation of lipoate-containing 2-oxoacid dehydrogenases, and for the assembly of the mitochondrial respiratory chain complexes. Mutation in this gene has been associated with multiple mitochondrial dysfunctions syndrome-2. Two alternatively spliced transcript variants encoding different isoforms with distinct subcellular localization have been reported for this gene (PMID:21944046). [provided by RefSeq, Dec 2011]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 1.061 OMIM phenotype

Clinical Summary— BOLA3

🧬

Gene-Disease Validity (ClinGen)

mitochondrial disease · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡

Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.34) despite low pLI — interpret in context.

📋

ClinVar Variants

8 unique Pathogenic / Likely Pathogenic· 59 VUS of 117 total submissions

Explore recent and relevant literature in Research Assistant →

📖

GeneReview available — BOLA3

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?

1.06LOEUF

pLI 0.149

Z-score 1.50

OE 0.34 (0.14–1.06)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.55Z-score

OE missense 0.80 (0.64–1.02)

48 obs / 59.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.34 (0.14–1.06)

0≤0.351.4

Missense OE?0.80 (0.64–1.02)

0≤0.61.4

Synonymous OE?0.84

0≤1.21.6

LoF obs/exp: 2 / 5.9Missense obs/exp: 48 / 59.9Syn Z: 0.54

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongBOLA3-related multiple mitochondrial dysfunctions syndromeLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.6937th %ile

GOF

0.5464th %ile

LOF

0.3647th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

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

ClinVar Variant Classifications

117 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic2

Likely Pathogenic6

VUS59

Likely Benign29

Benign16

Conflicting4

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	2	0	0	0	2
Likely Pathogenic	2	4	0	0	6
VUS	2	48	6	3	59
Likely Benign	0	4	19	6	29
Benign	0	0	16	0	16
Conflicting	—				4
Total	6	56	41	9	116

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

View in ClinVar →

11 pathogenic / likely-pathogenic (of 15) ClinVar copy-number / structural variants overlap BOLA3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →