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

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]

Primary Disease Associations & Inheritance

?Mitochondrial DNA depletion syndrome 14B (cardioencephalomyopathic type)MIM #616896

{Glaucoma, normal tension, susceptibility to}MIM #606657

Behr syndromeMIM #210000

Mitochondrial DNA depletion syndrome 14A (encephalomyopathic type)MIM #621481

Optic atrophy 1MIM #165500

Optic atrophy plus syndromeMIM #125250

Optic atrophy 1MIM #165500

472

ClinVar variants

Pathogenic / LP

0.99

pLI score· haploinsufficient

Active trials

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

99 Pathogenic / Likely Pathogenic· 217 VUS of 472 total submissions

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Clinical Trials

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

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

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.

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?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.

1.97Z-score

OE missense 0.76 (0.70–0.83)

411 obs / 540.1 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.0.18 (0.12–0.29)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.76 (0.70–0.83)

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.0.94

0≤1.21.6

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

ClinVar Variant Classifications

472 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic69

Likely Pathogenic30

VUS217

Likely Benign149

Benign4

Conflicting3

Pathogenic

Likely Pathogenic

217

VUS

149

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	41	7	21	0	69
Likely Pathogenic	16	11	3	0	30
VUS	4	176	34	3	217
Likely Benign	0	11	84	54	149
Benign	0	0	4	0	4
Conflicting	—				3
Total	61	205	146	57	472

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

View in ClinVar →

Protein Context — Lollipop Plot

OPA1 · protein map & ClinVar variants

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

Gene2Phenotype Curations

OPA1-related optic atrophy plus syndrome

definitive

ADLoss Of FunctionAbsent Gene Product, Altered Gene Product Structure

Eye

G2P ↗

missense variantinframe deletioninframe insertion

OPA1-related Behr syndrome

strong

ARLoss Of FunctionAbsent Gene Product

Eye

G2P ↗

OPA1-related optic atrophy

definitive

ADUndeterminedUncertain

Eye

G2P ↗

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

OMIM — Genotype-Phenotype Relationships

2 OMIM entries

OMIM

OPA1 MITOCHONDRIAL DYNAMIN-LIKE GTPase; OPA1

MIM #605290 · *

?Mitochondrial DNA depletion syndrome 14B (cardioencephalomyopathic type)

MIM #616896