# NM_000501.4(ELN):c.259T>C (p.Phe87Leu)

https://sugi.bio/variant/eln-p-phe87leu

## Summary

**ELN p.Phe87Leu (c.259T>C)** is classified **Benign/Likely benign** in ELN (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-03-27). AlphaMissense: likely pathogenic (0.834); Ultra-rare (popmax 0.0384%, sas); Associated with cutis laxa, autosomal dominant 1.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs140411170 · 6 submitters · 2 linked conditions · AlphaMissense likely pathogenic · ultra-rare (popmax 0.0384%, sas)

## For patients & families {#patients}

This is a change in the ELN gene that is classified as benign/likely benign — not considered disease-causing, submitted by 6 submitters, and is linked to cutis laxa, autosomal dominant 1.

*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 |
| Diagnostic panels | ELN is a diagnostic-grade gene on 8 Genomics England panels |

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

- Cutis laxa — Very frequent (99-80%)
- Hyperextensible skin — Very frequent (99-80%)
- Redundant skin — Very frequent (99-80%)
- Increased number of skin folds — Very frequent (99-80%)
- Fragmented elastic fibers in the dermis — Very frequent (99-80%)
- Premature skin wrinkling — Very frequent (99-80%)
- Joint hypermobility — Frequent (79-30%)
- Inguinal hernia — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015055/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.Phe87Leu |
| Coding change (HGVS c.) | c.259T>C |
| MANE Select transcript | [NM_000501](https://www.ncbi.nlm.nih.gov/nuccore/NM_000501) |
| dbSNP | [rs140411170](https://www.ncbi.nlm.nih.gov/snp/rs140411170/) |
| Variant type | single nucleotide variant |
| Location | chr7:74042640-74042640 (GRCh38) |
| ClinVar | [VCV360635](https://www.ncbi.nlm.nih.gov/clinvar/variation/360635/) |

**All HGVS expressions:** `NC_000007.13:g.73456970T>C`, `NC_000007.14:g.74042640T>C`, `NG_009261.1:g.19544T>C`, `NM_000501.4:c.259T>C`, `NM_001081752.3:c.229T>C`, `NM_001081753.3:c.259T>C`, `NM_001081754.3:c.259T>C`, `NM_001081755.3:c.259T>C`, `NM_001278912.2:c.259T>C`, `NM_001278913.2:c.223T>C`, `NM_001278914.2:c.229T>C`, `NM_001278915.2:c.259T>C`, `NM_001278916.2:c.259T>C`, `NM_001278917.2:c.229T>C`, `NM_001278918.2:c.229T>C`, `NM_001278939.2:c.259T>C`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely pathogenic** (0.834)
- REVEL 0.125 (moderately benign-leaning) — differs from AlphaMissense
- SaProt LLR -5.156 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense calls this damaging; REVEL and SaProt do not
- Conservation: phyloP 7.345, GERP 4.32, phastCons 0.991 — highly conserved (agrees)
- CADD: **PHRED 20.7**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Regional missense constraint: **o/e 0.91** across the covering region of the MANE Select transcript (74,028,188–74,068,697), spanning 40,509 bp. Chi-square p 0.005. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.0384%** (sas) · FAF95 0.0283% · FAF99 0.0249% · 35/91,078 in the highest group · 951/1,613,662 alleles overall — ultra-rare (popmax 0.0384%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 0.731% | 137 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.182% | 548 |
| Remaining individuals (not grpmax-eligible) | 0.102% | 976 |
| South Asian (grpmax) | 0.0384% | 2,602 |
| European (non-Finnish) | 0.0275% | 3,642 |
| East Asian | 0.0201% | 4,985 |

Finnish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-03-27.

**Submitter consensus:** conflicting (4 Likely benign, 3 Benign).

**Submission history:** 7 submissions (2018–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Illumina Laboratory Services, Illumina | Likely benign | criteria provided, single submitter | clinical testing | 2018-01-13 |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2020-11-12 |
| Breakthrough Genomics, Breakthrough Genomics | Likely benign | criteria provided, single submitter | not provided |  |
| Blueprint Genetics | Benign | criteria provided, single submitter | clinical testing | 2024-10-04 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2025-12-30 |
| Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | Likely benign | criteria provided, single submitter | clinical testing | 2026-03-27 |

## Associated conditions {#conditions}

[cutis laxa, autosomal dominant 1](https://sugi.bio/atlas/disease/cutis-laxa-autosomal-dominant-1/), [supravalvular aortic stenosis](https://sugi.bio/atlas/disease/supravalvular-aortic-stenosis/).

**Reported phenotype names (ClinVar):** Cutis laxa, autosomal dominant 1, Supravalvar aortic stenosis, not provided, not specified, AllHighlyPenetrant, ELN-Related Cutis Laxa, none provided, Supravalvar aortic stenosis, Eisenberg type.

## Similar variants {#similar}

Related ELN variant pages (same residue, condition, or type): [ELN c.377-2A>G](/variant/eln-c-377-minus-2a-g), [ELN c.643+1G>C](/variant/eln-c-643-plus-1g-c), [ELN c.686-2A>G](/variant/eln-c-686-minus-2a-g), [ELN c.800-1G>A](/variant/eln-c-800-minus-1g-a), [ELN c.800-2A>G](/variant/eln-c-800-minus-2a-g), [ELN c.800-3C>G](/variant/eln-c-800-minus-3c-g), [ELN c.82+1G>A](/variant/eln-c-82-plus-1g-a), [ELN c.889+1G>A](/variant/eln-c-889-plus-1g-a).

### 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 360635). 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.*