OPA1

Chr 3ARAD

OPA1 mitochondrial dynamin like GTPase

Also known as: BERHS, MGM1, MTDPS14, MTDPS14A, MTDPS14B, NPG, NTG, largeG

NCBI Gene: 4976 ENSG00000198836 UniProt: O60313 OMIM: 605290

OPA1 encodes a dynamin-related GTPase that mediates fusion of mitochondrial inner membranes, regulates cristae morphology, and maintains respiratory chain function. Mutations cause autosomal dominant optic atrophy type 1 with progressive visual loss, as well as autosomal recessive conditions including Behr syndrome, optic atrophy plus syndrome, and mitochondrial DNA depletion syndromes affecting the heart, brain, and muscle. The gene is highly constrained against loss-of-function variants (pLI 0.99, LOEUF 0.29), reflecting its essential role in mitochondrial function.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is a nuclear-encoded mitochondrial protein with similarity to dynamin-related GTPases. The encoded protein localizes to the inner mitochondrial membrane and helps regulate mitochondrial stability and energy output. This protein also sequesters cytochrome c. Mutations in this gene have been associated with optic atrophy type 1, which is a dominantly inherited optic neuropathy resulting in progressive loss of visual acuity, leading in many cases to legal blindness. [provided by RefSeq, Aug 2017]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismAR/ADLOEUF 0.297 OMIM phenotypes

Clinical Summary— OPA1

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Gene-Disease Validity (ClinGen)

Leigh syndrome · ARModerate

Moderate evidence — consider for supplementary testing

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.99). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

399 unique Pathogenic / Likely Pathogenic· 657 VUS of 1824 total submissions

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Clinical Trials

3 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — OPA1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.29LOEUF

pLI 0.986

Z-score 6.33

OE 0.18 (0.12–0.29)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

1.97Z-score

OE missense 0.76 (0.70–0.83)

411 obs / 540.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.18 (0.12–0.29)

0≤0.351.4

Missense OE?0.76 (0.70–0.83)

0≤0.61.4

Synonymous OE?0.94

0≤1.21.6

LoF obs/exp: 13 / 70.3Missense obs/exp: 411 / 540.1Syn Z: 0.57

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveOPA1-related optic atrophy plus syndromeLOFAD

strongOPA1-related Behr syndromeLOFAR

definitiveOPA1-related optic atrophyOTHERAD

This gene — mechanism propensity

0.5279th %ile

GOF

0.4481th %ile

LOF

0.64top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF1 literature citation · 71% of P/LP variants are LoF · LOEUF 0.29

DN1 literature citation

Literature Evidence

DNThe majority of OPA1 mutations encodes truncated forms of the protein and causes DOA through haploinsufficiency, whereas missense OPA1 mutations are predicted to cause disease through deleterious dominant-negative mechanisms.1

LOFOur results emphasize the value of cDNA analysis in the characterization of OPA1 mutations and further strengthen the model of haploinsufficiency as a major pathomechanism in OPA1-associated adOA.2

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

ClinVar Variant Classifications

1824 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic271

Likely Pathogenic128

VUS657

Likely Benign533

Benign92

Conflicting111

271

Pathogenic

128

Likely Pathogenic

657

VUS

533

Likely Benign

Benign

111

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	213	28	27	3	271
Likely Pathogenic	69	46	12	1	128
VUS	16	523	107	11	657
Likely Benign	0	45	291	197	533
Benign	0	4	81	7	92
Conflicting	—				111
Total	298	646	518	219	1,792

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

View in ClinVar →

40 pathogenic / likely-pathogenic (of 48) ClinVar copy-number / structural variants overlap OPA1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →