# NM_000082.4(ERCC8):c.162del (p.Glu55fs)

https://sugi.bio/variant/ercc8-p-glu55fs

## Summary

**ERCC8 p.Glu55fs (c.162del)** is classified **Pathogenic/Likely pathogenic** in ERCC8 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-01). Very rare (popmax 0.000346%, nfe); Associated with Cockayne syndrome type 1.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs756880941 · 3 submitters · 2 linked conditions · very rare (popmax 0.000346%, nfe)

## For patients & families {#patients}

This is a change in the ERCC8 gene that is considered likely disease-causing, submitted by 3 submitters, and is linked to Cockayne syndrome type 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 recessive |
| Age of onset (of this condition) | All ages |
| Prevalence | 1-9 / 1 000 000 (Europe) |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | ERCC8 is a diagnostic-grade gene on 16 Genomics England panels |

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

- Progressive microcephaly — Very frequent (99-80%)
- Progressive sensorineural hearing impairment — Very frequent (99-80%)
- Pigmentary retinopathy — Very frequent (99-80%)
- Atypical behavior — Very frequent (99-80%)
- Mental deterioration — Very frequent (99-80%)
- Cerebellar atrophy — Very frequent (99-80%)
- Growth delay — Very frequent (99-80%)
- Severe short stature — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0001415/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ERCC8](https://sugi.bio/atlas/gene/ERCC8/) |
| Protein change (HGVS p.) | p.Glu55fs |
| Coding change (HGVS c.) | c.162del |
| MANE Select transcript | [NM_000082](https://www.ncbi.nlm.nih.gov/nuccore/NM_000082) |
| dbSNP | [rs756880941](https://www.ncbi.nlm.nih.gov/snp/rs756880941/) |
| Variant type | Deletion |
| Location | chr5:60928875-60928875 (GRCh38) |
| ClinVar | [VCV1388419](https://www.ncbi.nlm.nih.gov/clinvar/variation/1388419/) |

**All HGVS expressions:** `LRG_466:g.21204del`, `NC_000005.10:g.60928876del`, `NC_000005.9:g.60224703del`, `NG_009289.1:g.21204del`, `NM_000082.4:c.162del`, `NM_001007233.3:c.-231del`, `NM_001007234.3:c.162del`, `NM_001290285.2:c.-216del`

## 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 5.964, GERP 1.68, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.608, pLI 1.7192e-11. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 2 of 12**, 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 (gnomAD v4.1): grpmax **0.000346%** (nfe) · FAF95 8.1e-05% · FAF99 5.5e-05% · 4/1,155,488 in the highest group · 5/1,585,592 alleles overall — very rare (popmax 0.000346%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.00163% | 61,436 |
| European (non-Finnish) (grpmax) | 0.000346% | 288,872 |

Remaining individuals 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}

**ERCC8** population constraint: LOEUF 1.608, pLI 1.7192e-11, missense-Z -0.66199. *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):

- **Cockayne syndrome type 1** — Definitive (AR)

## Protein context {#protein}

Residue **55** lies in a turn.

AlphaFold model confidence (whole protein): pLDDT 91.72, 87% of residues very-high.

**16 experimental structure(s)** (PDB): [4A11](https://www.rcsb.org/structure/4A11), [6FCV](https://www.rcsb.org/structure/6FCV), [7OO3](https://www.rcsb.org/structure/7OO3), [7OOB](https://www.rcsb.org/structure/7OOB), [7OOP](https://www.rcsb.org/structure/7OOP), [7OPC](https://www.rcsb.org/structure/7OPC).

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

*Describes the biological roles of ERCC8 (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:** ERCC8's established molecular role includes ubiquitin-like ligase-substrate adaptor activity.


### Pathways affected {#pathways}

ERCC8 participates in **5 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Dual incision in TC-NER](https://reactome.org/content/detail/R-HSA-6782135) | curated |
| [Formation of TC-NER Pre-Incision Complex](https://reactome.org/content/detail/R-HSA-6781823) | curated |
| [Gap-filling DNA repair synthesis and ligation in TC-NER](https://reactome.org/content/detail/R-HSA-6782210) | curated |
| [Neddylation](https://reactome.org/content/detail/R-HSA-8951664) | curated |
| [Transcription-Coupled Nucleotide Excision Repair (TC-NER)](https://reactome.org/content/detail/R-HSA-6781827) | curated |

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

**Molecular function:** ubiquitin-like ligase-substrate adaptor activity.

**Biological process:** single strand break repair, protein polyubiquitination, transcription-coupled nucleotide-excision repair, DNA damage response, response to oxidative stress, response to UV.

## Clinical significance {#significance}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-11-01.

**Submitter consensus:** conflicting (2 Pathogenic, 1 Likely pathogenic).

**Submission history:** 3 submissions (2023–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Fulgent Genetics, Fulgent Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-01-08 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2023-08-29 |
| CeGaT Center for Human Genetics Tuebingen | Pathogenic | criteria provided, single submitter | clinical testing | 2025-11-01 |

## Associated conditions {#conditions}

[Cockayne syndrome type 1](https://sugi.bio/atlas/disease/cockayne-syndrome-type-1/), [UV-sensitive syndrome 2](https://sugi.bio/atlas/disease/uv-sensitive-syndrome-2/).

**Reported phenotype names (ClinVar):** Cockayne syndrome type 1, not provided, UV-sensitive syndrome 2, none provided, Cockayne syndrome  type I, Cockayne syndrome classical, Cockayne syndrome classic form.

## Similar variants {#similar}

Related ERCC8 variant pages (same residue, condition, or type): [ERCC8 p.Arg217fs](/variant/ercc8-p-arg217fs), [ERCC8 p.Asn75fs](/variant/ercc8-p-asn75fs), [ERCC8 p.Thr143fs](/variant/ercc8-p-thr143fs), [ERCC8 p.Trp127fs](/variant/ercc8-p-trp127fs), [ERCC8 p.Ala191del](/variant/ercc8-p-ala191del), [ERCC8 p.Asn47fs](/variant/ercc8-p-asn47fs), [ERCC8 p.Asp199_Tyr200insTer](/variant/ercc8-p-asp199-tyr200inster), [ERCC8 p.Asp227fs](/variant/ercc8-p-asp227fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2026-10-14); 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 1388419). 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.*