# NM_001972.4(ELANE):c.566dup (p.Val190fs)

https://sugi.bio/variant/elane-p-val190fs

## Summary

**ELANE p.Val190fs (c.566dup)** is classified **Uncertain significance** in ELANE (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-04). No gnomAD frequency available for this variant; Associated with neutropenia, severe congenital, 1, autosomal dominant.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2512168637 · 1 submitter · 2 linked conditions · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the ELANE gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to neutropenia, severe congenital, 1, autosomal dominant.

*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 dominant |
| Age of onset (of this condition) | Infancy, Neonatal |
| Prevalence | <1 / 1 000 000 (Europe) |
| Diagnostic panels | ELANE is a diagnostic-grade gene on 8 Genomics England panels |

**Commonly reported features of Autosomal dominant severe congenital neutropenia** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Decreased total neutrophil count — Obligate (100%)
- Recurrent bacterial infections — Very frequent (99-80%)
- Recurrent viral infections — Very frequent (99-80%)
- Oral ulcer — Frequent (79-30%)
- Gingivitis — Frequent (79-30%)
- Periodontitis — Frequent (79-30%)
- Recurrent skin infections — Frequent (79-30%)
- Lymphopenia — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0025849/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ELANE](https://sugi.bio/atlas/gene/ELANE/) |
| Protein change (HGVS p.) | p.Val190fs |
| Coding change (HGVS c.) | c.566dup |
| MANE Select transcript | [NM_001972](https://www.ncbi.nlm.nih.gov/nuccore/NM_001972) |
| dbSNP | [rs2512168637](https://www.ncbi.nlm.nih.gov/snp/rs2512168637/) |
| Variant type | Duplication |
| Location | chr19:855762-855763 (GRCh38) |
| ClinVar | [VCV2921938](https://www.ncbi.nlm.nih.gov/clinvar/variation/2921938/) |

**All HGVS expressions:** `LRG_46:g.1099dup`, `LRG_57:g.8473dup`, `LRG_57t1:c.566dup`, `NC_000019.10:g.855763dup`, `NC_000019.9:g.855763dup`, `NG_007274.1:g.1099dup`, `NG_009627.1:g.8473dup`, `NM_001972.4:c.566dup`

## 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 -0.276, GERP -4.15 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.245, pLI 0.00041675. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **within the last 50 nt of the penultimate exon (4 of 5, 32 nt from its 3' end)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- 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}

**ELANE** population constraint: LOEUF 1.245, pLI 0.00041675, missense-Z -0.55026. *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):

- **neutropenia** — Definitive (AD)

## Protein context {#protein}

Residue **190** lies in a disulfide bond; the peptidase s1 domain; a UniProt-annotated variant site (in scn1 and ch).

AlphaFold model confidence (whole protein): pLDDT 88.42, 76% of residues very-high.

**38 experimental structure(s)** (PDB): [1B0F](https://www.rcsb.org/structure/1B0F), [1H1B](https://www.rcsb.org/structure/1H1B), [1HNE](https://www.rcsb.org/structure/1HNE), [1PPF](https://www.rcsb.org/structure/1PPF), [1PPG](https://www.rcsb.org/structure/1PPG), [2RG3](https://www.rcsb.org/structure/2RG3).

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

*Describes the biological roles of ELANE (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:** ELANE's established molecular role includes protease binding. p.Val190fs falls in the peptidase s1 domain.


### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Activation of Matrix Metalloproteinases](https://reactome.org/content/detail/R-HSA-1592389) | curated |
| [Antimicrobial peptides](https://reactome.org/content/detail/R-HSA-6803157) | curated |
| [Expression of NOTCH2NL genes](https://reactome.org/content/detail/R-HSA-9911233) | curated |
| [Neutrophil degranulation](https://reactome.org/content/detail/R-HSA-6798695) | curated |
| [Pyroptosis](https://reactome.org/content/detail/R-HSA-5620971) | curated |
| [Regulation of Complement cascade](https://reactome.org/content/detail/R-HSA-977606) | curated |
| [Collagen degradation](https://reactome.org/content/detail/R-HSA-1442490) | electronic |
| [Degradation of the extracellular matrix](https://reactome.org/content/detail/R-HSA-1474228) | electronic |

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

**Molecular function:** protease binding, transcription corepressor activity, endopeptidase activity, serine-type endopeptidase activity, heparin binding, peptidase activity.

**Biological process:** negative regulation of transcription by RNA polymerase II, biosynthetic process of antibacterial peptides active against Gram-negative bacteria, proteolysis, response to UV, negative regulation of heterochromatin formation, negative regulation of chemokine production.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-01-04.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-01-04 |

## Associated conditions {#conditions}

[neutropenia, severe congenital, 1, autosomal dominant](https://sugi.bio/atlas/disease/neutropenia-severe-congenital-1-autosomal-dominant/), [cyclic neutropenia](https://sugi.bio/atlas/disease/cyclic-neutropenia/).

**Reported phenotype names (ClinVar):** Neutropenia, severe congenital, 1, autosomal dominant, Cyclical neutropenia, Cyclic hematopoiesis, Cyclic Neutropenia.

## Same-residue context {#hotspot}

Residue **190** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [ELANE p.Val190=](/variant/elane-p-val190). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related ELANE variant pages (same residue, condition, or type): [ELANE p.Val190=](/variant/elane-p-val190), [ELANE p.Val190Gly](/variant/elane-p-val190gly), [ELANE p.Val190Leu](/variant/elane-p-val190leu), [ELANE p.Val190Met](/variant/elane-p-val190met), [ELANE p.Val101fs](/variant/elane-p-val101fs), [ELANE p.Ala100_Val101insGlnValPheAla](/variant/elane-p-ala100-val101insglnvalpheala), [ELANE p.Gly200fs](/variant/elane-p-gly200fs), [ELANE c.225-10_232dup](/variant/elane-c-225-minus-10-232dup).

### 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 2921938). 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.*