# NM_201384.3(PLEC):c.4987_4989del (p.Glu1663del)

https://sugi.bio/variant/plec-p-glu1663del

## Summary

**PLEC p.Glu1663del (c.4987_4989del)** is classified **Uncertain significance** in PLEC (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-18). No gnomAD frequency available for this variant; Associated with epidermolysis bullosa simplex with nail dystrophy.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1824427429 · 1 submitter · 5 linked conditions · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the PLEC gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to epidermolysis bullosa simplex with nail dystrophy.

*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/0025010/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [PLEC](https://sugi.bio/atlas/gene/PLEC/) |
| Protein change (HGVS p.) | p.Glu1663del |
| Coding change (HGVS c.) | c.4987_4989del |
| MANE Select transcript | [NM_201384](https://www.ncbi.nlm.nih.gov/nuccore/NM_201384) |
| dbSNP | [rs1824427429](https://www.ncbi.nlm.nih.gov/snp/rs1824427429/) |
| Variant type | Deletion |
| Location | chr8:143924940-143924942 (GRCh38) |
| ClinVar | [VCV2929208](https://www.ncbi.nlm.nih.gov/clinvar/variation/2929208/) |

**All HGVS expressions:** `NC_000008.10:g.144999108_144999110del`, `NC_000008.11:g.143924940_143924942del`, `NG_012492.1:g.56804_56806del`, `NM_000445.5:c.5068_5070del`, `NM_001410941.1:c.4125+1842_4125+1844del`, `NM_201378.4:c.4945_4947del`, `NM_201379.3:c.4921_4923del`, `NM_201380.4:c.5398_5400del`, `NM_201381.3:c.4891_4893del`, `NM_201382.4:c.4987_4989del`, `NM_201383.3:c.4999_5001del`, `NM_201384.3:c.4987_4989del`

## 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 4.13, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **in-frame indel**.
- 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}

**PLEC** population constraint: LOEUF 0.726, pLI 5.951e-44, missense-Z -2.7548. *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):

- **PLEC-related muscular dystrophy-epidermolysis bullosa simplex spectrum disorder** — Definitive (AR)

## Protein context {#protein}

Residue **1663** lies in the 'required for interaction with intermediate filament proteins' region; the 'central fibrous rod domain' region.

**14 experimental structure(s)** (PDB): [1MB8](https://www.rcsb.org/structure/1MB8), [2N03](https://www.rcsb.org/structure/2N03), [2ODU](https://www.rcsb.org/structure/2ODU), [2ODV](https://www.rcsb.org/structure/2ODV), [3F7P](https://www.rcsb.org/structure/3F7P), [3PDY](https://www.rcsb.org/structure/3PDY) — incl. mutant structure 2ODV.

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

*Describes the biological roles of PLEC (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:** PLEC's established molecular role includes RNA binding. p.Glu1663del falls in the required for interaction with intermediate filament proteins region.


### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Assembly of collagen fibrils and other multimeric structures](https://reactome.org/content/detail/R-HSA-2022090) | curated |
| [Caspase-mediated cleavage of cytoskeletal proteins](https://reactome.org/content/detail/R-HSA-264870) | curated |
| [Type I hemidesmosome assembly](https://reactome.org/content/detail/R-HSA-446107) | curated |

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

**Molecular function:** RNA binding, structural constituent of muscle, ankyrin binding, cadherin binding.

**Biological process:** hemidesmosome assembly.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-10-18.

**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 | 2023-10-18 |

## Associated conditions {#conditions}

[epidermolysis bullosa simplex with nail dystrophy](https://sugi.bio/atlas/disease/epidermolysis-bullosa-simplex-with-nail-dystrophy/), [epidermolysis bullosa simplex 5A, Ogna type](https://sugi.bio/atlas/disease/epidermolysis-bullosa-simplex-5a-ogna-type/), [epidermolysis bullosa simplex 5B, with muscular dystrophy](https://sugi.bio/atlas/disease/epidermolysis-bullosa-simplex-5b-with-muscular-dystrophy/), [epidermolysis bullosa simplex 5C, with pyloric atresia](https://sugi.bio/atlas/disease/epidermolysis-bullosa-simplex-5c-with-pyloric-atresia/), [autosomal recessive limb-girdle muscular dystrophy type 2Q](https://sugi.bio/atlas/disease/autosomal-recessive-limb-girdle-muscular-dystrophy-type-2q/).

**Reported phenotype names (ClinVar):** Epidermolysis bullosa simplex with nail dystrophy, Autosomal recessive limb-girdle muscular dystrophy type 2Q, Epidermolysis bullosa simplex 5B, with muscular dystrophy, Epidermolysis bullosa simplex 5C, with pyloric atresia, Epidermolysis bullosa simplex, Ogna type, EPIDERMOLYSIS BULLOSA SIMPLEX AND LIMB-GIRDLE MUSCULAR DYSTROPHY, Epidermolysis bullosa simplex with muscular dystrophy, PLEC-Related Epidermolysis Bullosa with Pyloric Atresia, Epidermolysis bullosa simplex with pyloric atresia, PLEC1-Related Epidermolysis Bullosa with Pyloric Atresia.

## Similar variants {#similar}

Related PLEC variant pages (same residue, condition, or type): [PLEC p.Asn489fs](/variant/plec-p-asn489fs), [PLEC p.Glu3188fs](/variant/plec-p-glu3188fs), [PLEC p.Ala4499_Arg4502del](/variant/plec-p-ala4499-arg4502del), [PLEC p.Glu4123del](/variant/plec-p-glu4123del), [PLEC p.Ser2284_Leu2293del](/variant/plec-p-ser2284-leu2293del), [PLEC c.1815+18del](/variant/plec-c-1815-plus-18del), [PLEC c.2305-10del](/variant/plec-c-2305-minus-10del), [PLEC c.2305-11del](/variant/plec-c-2305-minus-11del).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 2026-10-14); 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 2929208). 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.*