# NM_003640.5(ELP1):c.620_621del (p.Phe207fs)

https://sugi.bio/variant/elp1-p-phe207fs

## Summary

**ELP1 p.Phe207fs (c.620_621del)** is classified **Pathogenic** in ELP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-17). Associated with Riley-Day syndrome.

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

## For patients & families {#patients}

This is a change in the ELP1 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to Riley-Day 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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Childhood, Infancy, Neonatal |
| Prevalence | <1 / 1 000 000 (Europe) |
| Clinical trials | 12 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | ELP1 is a diagnostic-grade gene on 7 Genomics England panels |

**Commonly reported features of Familial dysautonomia** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Alacrima — Very frequent (99-80%)
- Abnormal pupil morphology — Very frequent (99-80%)
- Hypohidrosis — Very frequent (99-80%)
- Hyperhidrosis — Very frequent (99-80%)
- Hyporeflexia — Very frequent (99-80%)
- Orthostatic hypotension — Very frequent (99-80%)
- Growth delay — Very frequent (99-80%)
- Malignant hyperthermia — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0007581/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ELP1](https://sugi.bio/atlas/gene/ELP1/) |
| Protein change (HGVS p.) | p.Phe207fs |
| Coding change (HGVS c.) | c.620_621del |
| MANE Select transcript | [NM_003640](https://www.ncbi.nlm.nih.gov/nuccore/NM_003640) |
| Variant type | Deletion |
| Location | chr9:108919281-108919282 (GRCh38) |
| ClinVar | [VCV3385235](https://www.ncbi.nlm.nih.gov/clinvar/variation/3385235/) |

**All HGVS expressions:** `LRG_251:g.20047_20048del`, `LRG_251t1:c.616_617del`, `NC_000009.11:g.111681565_111681566del`, `NC_000009.12:g.108919285_108919286del`, `NG_008788.1:g.20047_20048del`, `NM_001318360.2:c.278_279del`, `NM_001330749.2:c.-307-1612_-307-1611del`, `NM_003640.5:c.620_621del`, `NM_003640.5:c.620_621delTT`

## 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 7.621, GERP 1.35, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.803, pLI 1.1953e-23. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 7 of 37**, 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}

**ELP1** population constraint: LOEUF 0.803, pLI 1.1953e-23, missense-Z 0.98074. *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):

- **Riley-Day syndrome** — Moderate (AR)

## Protein context {#protein}

Residue **207** lies in a β-strand.

AlphaFold model confidence (whole protein): pLDDT 84.31, 49% of residues very-high.

**5 experimental structure(s)** (PDB): [5CQR](https://www.rcsb.org/structure/5CQR), [8PTX](https://www.rcsb.org/structure/8PTX), [8PTY](https://www.rcsb.org/structure/8PTY), [8PTZ](https://www.rcsb.org/structure/8PTZ), [8PU0](https://www.rcsb.org/structure/8PU0).

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

*Describes the biological roles of ELP1 (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}

ELP1 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [HATs acetylate histones](https://reactome.org/content/detail/R-HSA-3214847) | electronic |

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-10-17.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Pathogenic | criteria provided, single submitter | clinical testing | 2024-10-17 |

## Associated conditions {#conditions}

[Riley-Day syndrome](https://sugi.bio/atlas/disease/riley-day-syndrome/).

**Reported phenotype names (ClinVar):** Familial dysautonomia, FD, HSAN III.

## Similar variants {#similar}

Related ELP1 variant pages (same residue, condition, or type): [ELP1 c.2860+1_2860+7del](/variant/elp1-c-2860-plus-1-2860-plus-7del), [ELP1 c.2958+1del](/variant/elp1-c-2958-plus-1del), [ELP1 c.954_958+7del](/variant/elp1-c-954-958-plus-7del), [ELP1 p.Asn225fs](/variant/elp1-p-asn225fs), [ELP1 p.Asn384_Ser385insTer](/variant/elp1-p-asn384-ser385inster), [ELP1 p.Asp495fs](/variant/elp1-p-asp495fs), [ELP1 p.Cys319fs](/variant/elp1-p-cys319fs), [ELP1 p.Gln577fs](/variant/elp1-p-gln577fs).

### 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 3385235). 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.*