# NM_000501.4(ELN):c.757del (p.Gln253fs)

https://sugi.bio/variant/eln-p-gln253fs

## Summary

**ELN p.Gln253fs (c.757del)** is classified **Pathogenic/Likely pathogenic** in ELN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-03). No gnomAD frequency available for this variant; Associated with supravalvular aortic stenosis.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs2131672289 · 2 submitters · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the ELN gene that is considered likely disease-causing, submitted by 2 submitters, and is linked to supravalvular aortic stenosis.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 3 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0000743/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ELN](https://sugi.bio/atlas/gene/ELN/) |
| Protein change (HGVS p.) | p.Gln253fs |
| Coding change (HGVS c.) | c.757del |
| MANE Select transcript | [NM_000501](https://www.ncbi.nlm.nih.gov/nuccore/NM_000501) |
| dbSNP | [rs2131672289](https://www.ncbi.nlm.nih.gov/snp/rs2131672289/) |
| Variant type | Deletion |
| Location | chr7:74048510-74048510 (GRCh38) |
| ClinVar | [VCV1678168](https://www.ncbi.nlm.nih.gov/clinvar/variation/1678168/) |

**All HGVS expressions:** `NC_000007.13:g.73462844del`, `NC_000007.14:g.74048514del`, `NG_009261.1:g.25418del`, `NM_000501.4:c.757del`, `NM_001081752.3:c.727del`, `NM_001081753.3:c.772del`, `NM_001081754.3:c.772del`, `NM_001081755.3:c.757del`, `NM_001278912.2:c.757del`, `NM_001278913.2:c.649del`, `NM_001278914.2:c.742del`, `NM_001278915.2:c.757del`, `NM_001278916.2:c.715del`, `NM_001278917.2:c.727del`, `NM_001278918.2:c.625del`, `NM_001278939.2:c.757del`

## 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 10.874, GERP 5.5, 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 15 of 33**, 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}

**ELN** population constraint: LOEUF 0.696, pLI 7.6169e-10, missense-Z 1.2583; 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):

- **cutis laxa, autosomal dominant 1** — Definitive (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 36.20, 0% of residues very-high.

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

*Describes the biological roles of ELN (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.*


### Pathways affected {#pathways}

ELN participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Degradation of the extracellular matrix](https://reactome.org/content/detail/R-HSA-1474228) | curated |
| [Elastic fibre formation](https://reactome.org/content/detail/R-HSA-1566948) | curated |
| [Molecules associated with elastic fibres](https://reactome.org/content/detail/R-HSA-2129379) | electronic |

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

**Biological process:** outflow tract morphogenesis.

## Clinical significance {#significance}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-07-03.

**Submitter consensus:** conflicting (1 Likely pathogenic, 1 Pathogenic).

**Submission history:** 2 submissions (2022–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| AiLife Diagnostics, AiLife Diagnostics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2022-02-23 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-07-03 |

## Associated conditions {#conditions}

[supravalvular aortic stenosis](https://sugi.bio/atlas/disease/supravalvular-aortic-stenosis/).

**Reported phenotype names (ClinVar):** Supravalvar aortic stenosis, not provided, none provided, Supravalvar aortic stenosis, Eisenberg type.

## Same-residue context {#hotspot}

Residue **253** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [ELN p.Gln253Ter](/variant/eln-p-gln253ter). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related ELN variant pages (same residue, condition, or type): [ELN p.Ala718fs](/variant/eln-p-ala718fs), [ELN p.Ala99fs](/variant/eln-p-ala99fs), [ELN p.Gly514fs](/variant/eln-p-gly514fs), [ELN p.Gly688fs](/variant/eln-p-gly688fs), [ELN p.Leu56fs](/variant/eln-p-leu56fs), [ELN p.Pro347fs](/variant/eln-p-pro347fs), [ELN p.Pro58fs](/variant/eln-p-pro58fs), [ELN p.Pro93fs](/variant/eln-p-pro93fs).

### 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 1678168). 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.*