BOLA3

Chr 2AR

bolA family member 3

Also known as: MMDS2

NCBI Gene: 388962ENSG00000163170UniProt: Q53S33

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]

Primary Disease Associations & Inheritance

Multiple mitochondrial dysfunctions syndrome 2 with hyperglycinemiaMIM #614299
AR
128
ClinVar variants
18
Pathogenic / LP
0.15
pLI score
0
Active trials
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
18 Pathogenic / Likely Pathogenic· 60 VUS of 128 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.55Z-score
OE missense 0.80 (0.64–1.02)
48 obs / 59.9 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.34 (0.14–1.06)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.80 (0.64–1.02)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.84
0≤1.21.6
LoF obs/exp: 2 / 5.9Missense obs/exp: 48 / 59.9Syn Z: 0.54

ClinVar Variant Classifications

128 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic11
Likely Pathogenic7
VUS60
Likely Benign29
Benign17
Conflicting4
11
Pathogenic
7
Likely Pathogenic
60
VUS
29
Likely Benign
17
Benign
4
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
1
0
10
0
11
Likely Pathogenic
1
3
3
0
7
VUS
1
47
9
3
60
Likely Benign
0
4
19
6
29
Benign
0
0
17
0
17
Conflicting
—4
Total354589128

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

View in ClinVar →

Protein Context — Lollipop Plot

BOLA3 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

BOLA3-related multiple mitochondrial dysfunctions syndrome

strong
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Multiple mitochondrial dysfunctions syndrome 2 with hyperglycinemia

MIM #614299

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — BOLA3
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Role of BOLA3 in the mitochondrial Fe-S cluster clarified by metabolomic analysis.
Iijima H et al.·Mol Genet Metab
2025
Lipoic acid biosynthesis defects.
Mayr JA et al.·J Inherit Metab Dis
2014Review
Engineered bacterial lipoate protein ligase A (lplA) restores lipoylation in cell models of lipoylation deficiency.
Bick NR et al.·J Biol Chem
2024Functional
Biochemical impact of a disease-causing Ile67Asn substitution on BOLA3 protein.
Sen S et al.·Metallomics
2021
Differential diagnosis of lipoic acid synthesis defects.
Tort F et al.·J Inherit Metab Dis
2016Review
Variant non ketotic hyperglycinemia is caused by mutations in LIAS, BOLA3 and the novel gene GLRX5.
Baker PR 2nd et al.·Brain
2014Case report
BOLA (BolA Family Member 3) Deficiency Controls Endothelial Metabolism and Glycine Homeostasis in Pulmonary Hypertension.
Yu Q et al.·Circulation
2019
Molecular Basis of Multiple Mitochondrial Dysfunctions Syndrome 2 Caused by CYS59TYR BOLA3 Mutation.
Saudino G et al.·Int J Mol Sci
2021
Novel IBA57 mutations in two chinese patients and literature review of multiple mitochondrial dysfunction syndrome.
Zhan F et al.·Metab Brain Dis
2022Review
Understanding the Molecular Basis of the Multiple Mitochondrial Dysfunctions Syndrome 2: The Disease-Causing His96Arg Mutation of BOLA3.
Bargagna B et al.·Int J Mol Sci
2023
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools