# NM_003797.5(EED):c.266del (p.Lys89fs)

https://sugi.bio/variant/eed-p-lys89fs

## Summary

**EED p.Lys89fs (c.266del)** is classified **Uncertain significance** in EED (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-12-09). No gnomAD frequency available for this variant; Associated with Cohen-Gibson syndrome.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs2495764327 · 2 submitters · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the EED gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, and is linked to Cohen-Gibson syndrome.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0016235/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [EED](https://sugi.bio/atlas/gene/EED/) |
| Protein change (HGVS p.) | p.Lys89fs |
| Coding change (HGVS c.) | c.266del |
| MANE Select transcript | [NM_003797](https://www.ncbi.nlm.nih.gov/nuccore/NM_003797) |
| dbSNP | [rs2495764327](https://www.ncbi.nlm.nih.gov/snp/rs2495764327/) |
| Variant type | Deletion |
| Location | chr11:86250446-86250446 (GRCh38) |
| ClinVar | [VCV2701927](https://www.ncbi.nlm.nih.gov/clinvar/variation/2701927/) |

**All HGVS expressions:** `NC_000011.10:g.86250447del`, `NC_000011.9:g.85961489del`, `NG_029595.1:g.10684del`, `NG_029595.2:g.10696del`, `NM_001308007.2:c.266del`, `NM_001330334.2:c.266del`, `NM_003797.5:c.266del`

## 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 0.252, GERP 1.29, phastCons 0.976 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. the gene is **loss-of-function-intolerant** (LOEUF 0.41, pLI 0.99914), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 2 of 12**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion 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}

**EED** population constraint: LOEUF 0.41, pLI 0.99914, missense-Z 2.9266. *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):

- **Cohen-Gibson syndrome** — Moderate (AD)

## Protein context {#protein}

Residue **89** lies in the 'interaction with ezh2' region; a β-strand.

AlphaFold model confidence (whole protein): pLDDT 87.21, 80% of residues very-high.

**81 experimental structure(s)** (PDB): [3IIW](https://www.rcsb.org/structure/3IIW), [3IIY](https://www.rcsb.org/structure/3IIY), [3IJ0](https://www.rcsb.org/structure/3IJ0), [3IJ1](https://www.rcsb.org/structure/3IJ1), [3IJC](https://www.rcsb.org/structure/3IJC), [3JPX](https://www.rcsb.org/structure/3JPX) — incl. mutant structure 5IJ8.

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

*Describes the biological roles of EED (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:** EED's established molecular role includes transcription corepressor binding. p.Lys89fs falls in the interaction with ezh2 region. In Reactome, EED is annotated in disease pathway(s) including **Defective pyroptosis**, **HCMV Early Events**.

**Disease mechanism (Reactome):** EED loss or alteration is curated in [Defective pyroptosis](https://reactome.org/content/detail/R-HSA-9710421), [HCMV Early Events](https://reactome.org/content/detail/R-HSA-9609690).

### Pathways affected {#pathways}

EED participates in **10 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective pyroptosis](https://reactome.org/content/detail/R-HSA-9710421) | curated |
| ⚕ [HCMV Early Events](https://reactome.org/content/detail/R-HSA-9609690) | curated |
| [Negative Regulation of CDH1 Gene Transcription](https://reactome.org/content/detail/R-HSA-9764725) | curated |
| [Oxidative Stress Induced Senescence](https://reactome.org/content/detail/R-HSA-2559580) | curated |
| [PKMTs methylate histone lysines](https://reactome.org/content/detail/R-HSA-3214841) | curated |
| [PRC2 methylates histones and DNA](https://reactome.org/content/detail/R-HSA-212300) | curated |
| [Regulation of PD-L1(CD274) transcription](https://reactome.org/content/detail/R-HSA-9909649) | curated |
| [Transcriptional Regulation by E2F6](https://reactome.org/content/detail/R-HSA-8953750) | curated |
| [Activation of anterior HOX genes in hindbrain development during early embryogenesis](https://reactome.org/content/detail/R-HSA-5617472) | electronic |
| [Regulation of PTEN gene transcription](https://reactome.org/content/detail/R-HSA-8943724) | electronic |

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

**Molecular function:** transcription corepressor binding, enzyme activator activity, identical protein binding.

## Clinical significance {#significance}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2023-12-09.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2023); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-12-09 |
| Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-11-06 |

## Associated conditions {#conditions}

[Cohen-Gibson syndrome](https://sugi.bio/atlas/disease/cohen-gibson-syndrome/).

**Reported phenotype names (ClinVar):** Cohen-Gibson syndrome, EED-Related Overgrowth.

## Similar variants {#similar}

Related EED variant pages (same residue, condition, or type): [EED c.1199+8_1199+11del](/variant/eed-c-1199-plus-8-1199-plus-11del), [EED c.268-7_268-3del](/variant/eed-c-268-minus-7-268-minus-3del), [EED p.Asn194Ser](/variant/eed-p-asn194ser), [EED p.Asp237Gly](/variant/eed-p-asp237gly), [EED p.Ala17Val](/variant/eed-p-ala17val), [EED p.Arg4Met](/variant/eed-p-arg4met), [EED p.Lys83Ile](/variant/eed-p-lys83ile), [EED c.267+20C>G](/variant/eed-c-267-plus-20c-g).

### 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 2701927). 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.*