# NM_130837.3(OPA1):c.3013_3019dup (p.Phe1007Ter)

https://sugi.bio/variant/opa1-p-phe1007ter

## Summary

**OPA1 p.Phe1007Ter (c.3013_3019dup)** is classified **Conflicting classifications of pathogenicity** in OPA1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2023-06-06). No gnomAD frequency available for this variant; Associated with OPA1-related disorder.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs1553797598 · 3 submitters · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the OPA1 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 3 submitters, and is linked to OPA1-related disorder.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [OPA1](https://sugi.bio/atlas/gene/OPA1/) |
| Protein change (HGVS p.) | p.Phe1007Ter |
| Coding change (HGVS c.) | c.3013_3019dup |
| MANE Select transcript | [NM_130837](https://www.ncbi.nlm.nih.gov/nuccore/NM_130837) |
| dbSNP | [rs1553797598](https://www.ncbi.nlm.nih.gov/snp/rs1553797598/) |
| Variant type | Duplication |
| Location | chr3:193692088-193692089 (GRCh38) |
| ClinVar | [VCV447903](https://www.ncbi.nlm.nih.gov/clinvar/variation/447903/) |

**All HGVS expressions:** `LRG_337:g.103949_103955dup`, `LRG_337t1:c.2848_2854dup`, `NC_000003.11:g.193409881_193409887dup`, `NC_000003.12:g.193692092_193692098dup`, `NG_011605.1:g.103949_103955dup`, `NM_001354663.2:c.2479_2485dup`, `NM_001354664.2:c.2476_2482dup`, `NM_015560.3:c.2848_2854dup`, `NM_130831.3:c.2740_2746dup`, `NM_130832.3:c.2794_2800dup`, `NM_130833.3:c.2851_2857dup`, `NM_130834.3:c.2902_2908dup`, `NM_130835.3:c.2905_2911dup`, `NM_130836.3:c.2959_2965dup`, `NM_130837.3:c.3013_3019dup`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 3.555, GERP 0.862, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **nonsense (stop-gain)** — a predicted loss-of-function variant. the gene is **loss-of-function-intolerant** (LOEUF 0.503, pLI 0.92269), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **within the last 50 nt of the penultimate exon (30 of 31, 44 nt from its 3' end)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**OPA1** population constraint: LOEUF 0.503, pLI 0.92269, missense-Z 2.7012. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **Leigh syndrome** — Moderate (AR)
- **OPA1-related optic atrophy with or without extraocular features** — Definitive (SD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 74.02, 23% of residues very-high.

**11 experimental structure(s)** (PDB): [6JTG](https://www.rcsb.org/structure/6JTG), [8CT1](https://www.rcsb.org/structure/8CT1), [8CT9](https://www.rcsb.org/structure/8CT9), [8EEW](https://www.rcsb.org/structure/8EEW), [8EF7](https://www.rcsb.org/structure/8EF7), [8EFF](https://www.rcsb.org/structure/8EFF).

## What this gene does {#gene-function}

*Describes the biological roles of OPA1 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** OPA1's established molecular role includes GTPase activity.


### Pathways affected {#pathways}

OPA1 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Regulation of Apoptosis](https://reactome.org/content/detail/R-HSA-169911) | curated |
| [Mitochondrial protein degradation](https://reactome.org/content/detail/R-HSA-9837999) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** GTPase activity, phosphatidic acid binding, GTPase-dependent fusogenic activity, membrane bending activity, cardiolipin binding.

**Biological process:** mitochondrion organization, inner mitochondrial membrane organization, visual perception, mitochondrial fusion, cristae formation, negative regulation of apoptotic process.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2023-06-06.

**Submitter consensus:** conflicting (1 Pathogenic, 1 Uncertain significance, 1 Likely pathogenic).

**Submission history:** 3 submissions (2022–2023); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Athena Diagnostics | Pathogenic | criteria provided, single submitter | clinical testing | 2023-06-06 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-03-03 |
| Blueprint Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2022-01-29 |

## Associated conditions {#conditions}

[OPA1-related disorder](https://sugi.bio/atlas/disease/opa1-related-disorder/).

**Reported phenotype names (ClinVar):** OPA1-related disorder, not provided, OPA1-related condition, OPA1-related disorders, none provided.

## Similar variants {#similar}

Related OPA1 variant pages (same residue, condition, or type): [OPA1 p.Asp170Ter](/variant/opa1-p-asp170ter), [OPA1 p.Gly464fs](/variant/opa1-p-gly464fs), [OPA1 p.Ser387fs](/variant/opa1-p-ser387fs), [OPA1 p.Asn636Ter](/variant/opa1-p-asn636ter), [OPA1 p.Asp525fs](/variant/opa1-p-asp525fs), [OPA1 p.Gln1001fs](/variant/opa1-p-gln1001fs), [OPA1 p.His513fs](/variant/opa1-p-his513fs), [OPA1 p.Ile818fs](/variant/opa1-p-ile818fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 447903). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*