# NM_001005273.3(CHD3):c.1555del (p.Glu519fs)

https://sugi.bio/variant/chd3-p-glu519fs

## Summary

**CHD3 p.Glu519fs (c.1555del)** is classified **Likely pathogenic** in CHD3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-19). Associated with Snijders Blok-Campeau syndrome.

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

## For patients & families {#patients}

This is a change in the CHD3 gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to Snijders Blok-Campeau 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/0013806/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CHD3](https://sugi.bio/atlas/gene/CHD3/) |
| Protein change (HGVS p.) | p.Glu519fs |
| Coding change (HGVS c.) | c.1555del |
| MANE Select transcript | [NM_001005273](https://www.ncbi.nlm.nih.gov/nuccore/NM_001005273) |
| Variant type | Deletion |
| Location | chr17:7895385-7895385 (GRCh38) |
| ClinVar | [VCV3393102](https://www.ncbi.nlm.nih.gov/clinvar/variation/3393102/) |

**All HGVS expressions:** `NC_000017.10:g.7798708del`, `NC_000017.11:g.7895390del`, `NM_001005271.3:c.1732del`, `NM_001005273.3:c.1555del`, `NM_005852.4:c.1555del`

## 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 7.892, GERP 1.9, 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 0.257, 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 10 of 40**, 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.

*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}

**CHD3** population constraint: LOEUF 0.257, pLI 1, missense-Z 8.4269. *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):

- **Snijders Blok-Campeau syndrome** — Definitive (AD)

## Protein context {#protein}

Residue **519** lies in the chromo 1 domain; a UniProt-annotated variant site (in snibcps).

AlphaFold model confidence (whole protein): pLDDT 63.21, 15% of residues very-high.

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

*Describes the biological roles of CHD3 (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:** CHD3's established molecular role includes transcription cis-regulatory region binding. p.Glu519fs falls in the chromo 1 domain. In Reactome, CHD3 is annotated in disease pathway(s) including **Potential therapeutics for SARS**.

**Disease mechanism (Reactome):** CHD3 loss or alteration is curated in [Potential therapeutics for SARS](https://reactome.org/content/detail/R-HSA-9679191).

### Pathways affected {#pathways}

CHD3 participates in **13 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Potential therapeutics for SARS](https://reactome.org/content/detail/R-HSA-9679191) | curated |
| [HDACs deacetylate histones](https://reactome.org/content/detail/R-HSA-3214815) | curated |
| [Interaction of NuRD complexes with transcription factors](https://reactome.org/content/detail/R-HSA-9940951) | curated |
| [NuRD complex assembly](https://reactome.org/content/detail/R-HSA-9937850) | curated |
| [RNA Polymerase I Transcription Initiation](https://reactome.org/content/detail/R-HSA-73762) | curated |
| [Regulation of TP53 Activity through Acetylation](https://reactome.org/content/detail/R-HSA-6804758) | curated |
| [SUMOylation of chromatin organization proteins](https://reactome.org/content/detail/R-HSA-4551638) | curated |
| [Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)](https://reactome.org/content/detail/R-HSA-9976102) | electronic |
| [ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression](https://reactome.org/content/detail/R-HSA-427389) | electronic |
| [Regulation of PTEN gene transcription](https://reactome.org/content/detail/R-HSA-8943724) | electronic |
| [Regulation of endogenous retroelements by KRAB-ZFP proteins](https://reactome.org/content/detail/R-HSA-9843940) | electronic |
| [Regulation of endogenous retroelements by Piwi-interacting RNAs (piRNAs)](https://reactome.org/content/detail/R-HSA-9845323) | electronic |
| [Transcriptional regulation of brown and beige adipocyte differentiation by EBF2](https://reactome.org/content/detail/R-HSA-9844594) | electronic |

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

**Molecular function:** transcription cis-regulatory region binding, RNA binding, ATP hydrolysis activity, ATP-dependent chromatin remodeler activity.

**Biological process:** negative regulation of transcription by RNA polymerase II, chromatin remodeling, spindle organization, centrosome cycle.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-12-19.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-12-19 |

## Associated conditions {#conditions}

[Snijders Blok-Campeau syndrome](https://sugi.bio/atlas/disease/snijders-blok-campeau-syndrome/).

**Reported phenotype names (ClinVar):** Snijders Blok-Campeau syndrome, INTELLECTUAL DEVELOPMENTAL DISORDER WITH MACROCEPHALY, SPEECH DELAY, AND DYSMORPHIC FACIES.

## Similar variants {#similar}

Related CHD3 variant pages (same residue, condition, or type): [CHD3 p.Ala191fs](/variant/chd3-p-ala191fs), [CHD3 p.Arg1381fs](/variant/chd3-p-arg1381fs), [CHD3 p.Phe551fs](/variant/chd3-p-phe551fs), [CHD3 c.4357_4358+2del](/variant/chd3-c-4357-4358-plus-2del), [CHD3 p.Asp1671fs](/variant/chd3-p-asp1671fs), [CHD3 p.Glu519Lys](/variant/chd3-p-glu519lys), [CHD3 p.Ile20fs](/variant/chd3-p-ile20fs), [CHD3 p.Pro710fs](/variant/chd3-p-pro710fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); 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 2026-07-14); 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 3393102). 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.*