# NM_001123385.2(BCOR):c.1539dup (p.Pro514fs)

https://sugi.bio/variant/bcor-p-pro514fs

## Summary

**BCOR p.Pro514fs (c.1539dup)** is classified **Likely pathogenic** in BCOR (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-24). No gnomAD frequency available for this variant; Associated with Oculofaciocardiodental syndrome (OFCD).

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs2520018459 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the BCOR gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to Oculofaciocardiodental syndrome (OFCD).

*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 | [BCOR](https://sugi.bio/atlas/gene/BCOR/) |
| Protein change (HGVS p.) | p.Pro514fs |
| Coding change (HGVS c.) | c.1539dup |
| MANE Select transcript | [NM_001123385](https://www.ncbi.nlm.nih.gov/nuccore/NM_001123385) |
| dbSNP | [rs2520018459](https://www.ncbi.nlm.nih.gov/snp/rs2520018459/) |
| Variant type | Duplication |
| Location | chrX:40073806-40073807 (GRCh38) |
| ClinVar | [VCV3236708](https://www.ncbi.nlm.nih.gov/clinvar/variation/3236708/) |

**All HGVS expressions:** `LRG_627:g.108523dup`, `LRG_627t1:c.1539dup`, `LRG_627t2:c.1537dup`, `NC_000023.10:g.39933062dup`, `NC_000023.11:g.40073809dup`, `NG_008880.1:g.108523dup`, `NG_087735.1:g.169dup`, `NM_001123383.2:c.1537dup`, `NM_001123384.2:c.1539dup`, `NM_001123385.2:c.1539dup`, `NM_017745.6:c.1539dup`

## 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 11.906, GERP 1.58, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene, supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 4 of 15**, 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}

**BCOR** population constraint: ClinGen dosage — haploinsufficiency 3, triplosensitivity 0 (0–3 scale). *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):

- **microphthalmia, syndromic 2** — Definitive (XL)

## Protein context {#protein}

Residue **514** lies in the 'interaction with bcl6' region.

AlphaFold model confidence (whole protein): pLDDT 39.82, 7% of residues very-high.

**5 experimental structure(s)** (PDB): [2N1L](https://www.rcsb.org/structure/2N1L), [3BIM](https://www.rcsb.org/structure/3BIM), [4HPL](https://www.rcsb.org/structure/4HPL), [6B7G](https://www.rcsb.org/structure/6B7G), [8HCU](https://www.rcsb.org/structure/8HCU).

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

*Describes the biological roles of BCOR (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:** BCOR's established molecular role includes transcription cis-regulatory region binding. p.Pro514fs falls in the interaction with bcl6 region.


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

**Molecular function:** transcription cis-regulatory region binding, transcription corepressor activity, heat shock protein binding, histone deacetylase binding, DNA-binding transcription factor binding.

**Biological process:** negative regulation of transcription by RNA polymerase II, chromatin remodeling, heart development, negative regulation of bone mineralization, odontogenesis, negative regulation of DNA-templated transcription.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-05-24.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Centre for Inherited Metabolic Diseases, Karolinska University Hospital | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-05-24 |

## Associated conditions {#conditions}

[Oculofaciocardiodental syndrome (OFCD)](https://sugi.bio/atlas/disease/oculofaciocardiodental-syndrome-ofcd/).

**Reported phenotype names (ClinVar):** Oculofaciocardiodental syndrome (OFCD).

## Similar variants {#similar}

Related BCOR variant pages (same residue, condition, or type): [BCOR p.Leu1646fs](/variant/bcor-p-leu1646fs), [BCOR p.Asn87fs](/variant/bcor-p-asn87fs), [BCOR p.Arg1217Ter](/variant/bcor-p-arg1217ter), [BCOR p.Val797fs](/variant/bcor-p-val797fs), [BCOR p.Asp174Asn](/variant/bcor-p-asp174asn), [BCOR p.Ile730Leu](/variant/bcor-p-ile730leu), [BCOR c.4174-2A>G](/variant/bcor-c-4174-minus-2a-g), [BCOR p.Ala68fs](/variant/bcor-p-ala68fs).

### 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 3236708). 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.*