# NM_000274.4(OAT):c.890dup (p.Tyr299fs)

https://sugi.bio/variant/oat-p-tyr299fs

## Summary

**OAT p.Tyr299fs (c.890dup)** is classified **Likely pathogenic** in OAT (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-03). Associated with ornithine aminotransferase deficiency.

**At a glance:** Likely pathogenic · review: Single submitter · 1 submitter · 1 linked condition

## For patients & families {#patients}

This is a change in the OAT gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to ornithine aminotransferase deficiency.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Childhood |
| Prevalence | 1-9 / 100 000 (Finland) |
| Clinical trials | 5 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | OAT is a diagnostic-grade gene on 8 Genomics England panels |

**Commonly reported features of Gyrate atrophy of choroid and retina** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Progressive visual loss — Very frequent (99-80%)
- Chorioretinal atrophy — Very frequent (99-80%)
- Myopia — Very frequent (99-80%)
- Hyperornithinemia — Very frequent (99-80%)
- Chorioretinal degeneration — Very frequent (99-80%)
- Cataract — Frequent (79-30%)
- Subcapsular cataract — Frequent (79-30%)
- Blindness — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0006556/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [OAT](https://sugi.bio/atlas/gene/OAT/) |
| Protein change (HGVS p.) | p.Tyr299fs |
| Coding change (HGVS c.) | c.890dup |
| MANE Select transcript | [NM_000274](https://www.ncbi.nlm.nih.gov/nuccore/NM_000274) |
| Variant type | Duplication |
| Location | chr10:124402936-124402937 (GRCh38) |
| ClinVar | [VCV4818084](https://www.ncbi.nlm.nih.gov/clinvar/variation/4818084/) |

**All HGVS expressions:** `LRG_685:g.21014dup`, `LRG_685t1:c.886dup`, `NC_000010.10:g.126091510dup`, `NC_000010.11:g.124402941dup`, `NG_008861.1:g.21014dup`, `NM_000274.3:c.890dup`, `NM_000274.4:c.890dup`, `NM_001171814.2:c.476dup`, `NM_001322965.2:c.890dup`, `NM_001322966.2:c.890dup`, `NM_001322967.2:c.890dup`, `NM_001322968.2:c.890dup`, `NM_001322969.2:c.890dup`, `NM_001322970.2:c.890dup`, `NM_001322971.2:c.569dup`, `NM_001322974.2:c.290dup`

## 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 0.853, GERP -1.12, phastCons 0.913 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.968, pLI 2.2793e-07. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 7 of 10**, so the transcript is predicted to undergo NMD.
- 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.

*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}

**OAT** population constraint: LOEUF 0.968, pLI 2.2793e-07, missense-Z 1.6632. *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):

- **ornithine aminotransferase deficiency** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 94.29, 92% of residues very-high.

**35 experimental structure(s)** (PDB): [10LW](https://www.rcsb.org/structure/10LW), [10LX](https://www.rcsb.org/structure/10LX), [12AL](https://www.rcsb.org/structure/12AL), [12AV](https://www.rcsb.org/structure/12AV), [12AX](https://www.rcsb.org/structure/12AX), [12AY](https://www.rcsb.org/structure/12AY) — incl. mutant structure 2BYJ.

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

*Describes the biological roles of OAT (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:** OAT's established molecular role includes L-ornithine transaminase activity.


### Pathways affected {#pathways}

OAT participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Glutamate and glutamine metabolism](https://reactome.org/content/detail/R-HSA-8964539) | curated |

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

**Molecular function:** L-ornithine transaminase activity, identical protein binding.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-11-03.

**Submitter consensus:** unanimous (1/1 Likely pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Natera, Inc. | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-11-03 |

## Associated conditions {#conditions}

[ornithine aminotransferase deficiency](https://sugi.bio/atlas/disease/ornithine-aminotransferase-deficiency/).

**Reported phenotype names (ClinVar):** Ornithine aminotransferase deficiency, HYPERORNITHINEMIA WITH GYRATE ATROPHY OF CHOROID AND RETINA, OAT DEFICIENCY, OKT DEFICIENCY, Ornithine ketoacid aminotransferase deficiency, Gyrate atrophy, Gyrate atrophy of choroid and retina, Girate atrophy of the retina.

## Same-residue context {#hotspot}

Residue **299** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [OAT p.Tyr299Ter](/variant/oat-p-tyr299ter). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related OAT variant pages (same residue, condition, or type): [OAT p.Tyr299Ter](/variant/oat-p-tyr299ter), [OAT p.Tyr299=](/variant/oat-p-tyr299), [OAT p.Arg372fs](/variant/oat-p-arg372fs), [OAT c.199+11_199+16dup](/variant/oat-c-199-plus-11-199-plus-16dup), [OAT p.Ala335fs](/variant/oat-p-ala335fs), [OAT p.Arg331fs](/variant/oat-p-arg331fs), [OAT p.Asn117fs](/variant/oat-p-asn117fs), [OAT p.Lys421delinsTrpTer](/variant/oat-p-lys421delinstrpter).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 4818084). 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.*