# NM_134261.3(RORA):c.867_876dup (p.Glu293fs)

https://sugi.bio/variant/rora-p-glu293fs

## Summary

**RORA p.Glu293fs (c.867_876dup)** is classified **Pathogenic** in RORA (ClinVar, Single submitter, 1 submitter; last evaluated 2019-10-02). No gnomAD frequency available for this variant; Associated with intellectual developmental disorder with or without epilepsy or cerebellar ataxia.

**At a glance:** Pathogenic · review: Single submitter · rsID rs1595874842 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the RORA gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to intellectual developmental disorder with or without epilepsy or cerebellar ataxia.

*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 | [RORA](https://sugi.bio/atlas/gene/RORA/) |
| Protein change (HGVS p.) | p.Glu293fs |
| Coding change (HGVS c.) | c.867_876dup |
| MANE Select transcript | [NM_134261](https://www.ncbi.nlm.nih.gov/nuccore/NM_134261) |
| dbSNP | [rs1595874842](https://www.ncbi.nlm.nih.gov/snp/rs1595874842/) |
| Variant type | Duplication |
| Location | chr15:60505573-60505574 (GRCh38) |
| ClinVar | [VCV807672](https://www.ncbi.nlm.nih.gov/clinvar/variation/807672/) |

**All HGVS expressions:** `NC_000015.10:g.60505575_60505584dup`, `NC_000015.9:g.60797774_60797783dup`, `NG_029246.1:g.728721_728730dup`, `NM_002943.4:c.942_951dup`, `NM_134260.3:c.966_975dup`, `NM_134261.3:c.867_876dup`, `NM_134262.3:c.702_711dup`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 7.711, GERP 7.31, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. the gene is **loss-of-function-intolerant** (LOEUF 0.207, pLI 1), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 6 of 11**, 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.
- 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}

**RORA** population constraint: LOEUF 0.207, pLI 1, missense-Z 2.3246. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **293** lies in the nr lbd domain; an α-helix.

AlphaFold model confidence (whole protein): pLDDT 76.40, 57% of residues very-high.

**3 experimental structure(s)** (PDB): [1N83](https://www.rcsb.org/structure/1N83), [1S0X](https://www.rcsb.org/structure/1S0X), [4S15](https://www.rcsb.org/structure/4S15).

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

*Describes the biological roles of RORA (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:** RORA's established molecular role includes RNA polymerase II transcription regulatory region sequence-specific DNA binding. p.Glu293fs falls in the nr lbd domain.


### Pathways affected {#pathways}

RORA participates in **8 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Interleukin-4 and Interleukin-13 signaling](https://reactome.org/content/detail/R-HSA-6785807) | curated |
| [Nuclear Receptor transcription pathway](https://reactome.org/content/detail/R-HSA-383280) | curated |
| [SUMOylation of intracellular receptors](https://reactome.org/content/detail/R-HSA-4090294) | curated |
| [Expression of BMAL (ARNTL), CLOCK, and NPAS2](https://reactome.org/content/detail/R-HSA-9931509) | electronic |
| [Heme signaling](https://reactome.org/content/detail/R-HSA-9707616) | electronic |
| [PPARA activates gene expression](https://reactome.org/content/detail/R-HSA-1989781) | electronic |
| [Phosphorylated BMAL1:CLOCK (ARNTL:CLOCK) activates expression of core clock genes](https://reactome.org/content/detail/R-HSA-9931510) | electronic |
| [RORA,B,C and NR1D1 (REV-ERBA) regulate gene expression](https://reactome.org/content/detail/R-HSA-9933387) | electronic |

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

**Molecular function:** RNA polymerase II transcription regulatory region sequence-specific DNA binding, RNA polymerase II cis-regulatory region sequence-specific DNA binding, transcription coregulator binding, transcription corepressor binding, transcription coactivator binding, DNA binding.

**Biological process:** angiogenesis, regulation of DNA-templated transcription, positive regulation of vascular endothelial growth factor production, intracellular receptor signaling pathway, cellular response to sterol, muscle cell differentiation.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2019-10-02.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Institute of Human Genetics Munich, TUM University Hospital | Pathogenic | criteria provided, single submitter | clinical testing | 2019-10-02 |

## Associated conditions {#conditions}

[intellectual developmental disorder with or without epilepsy or cerebellar ataxia](https://sugi.bio/atlas/disease/intellectual-developmental-disorder-with-or-without-epilepsy-or-cerebellar-ataxia/).

**Reported phenotype names (ClinVar):** Intellectual developmental disorder with or without epilepsy or cerebellar ataxia.

## Similar variants {#similar}

Related RORA variant pages (same residue, condition, or type): [RORA p.Cys245fs](/variant/rora-p-cys245fs), [RORA p.Lys240_Pro241insSerTer](/variant/rora-p-lys240-pro241insserter), [RORA p.Ala11Val](/variant/rora-p-ala11val), [RORA p.Ala7Ser](/variant/rora-p-ala7ser), [RORA p.Arg170His](/variant/rora-p-arg170his), [RORA p.Arg462Gln](/variant/rora-p-arg462gln), [RORA p.Arg47Thr](/variant/rora-p-arg47thr), [RORA p.Glu14Lys](/variant/rora-p-glu14lys).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 807672). 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.*