# NM_000122.2(ERCC3):c.240dup (p.Asp81fs)

https://sugi.bio/variant/ercc3-p-asp81fs

## Summary

**ERCC3 p.Asp81fs (c.240dup)** is classified **Likely pathogenic** in ERCC3 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-11-08). Associated with xeroderma pigmentosum group B.

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

## For patients & families {#patients}

This is a change in the ERCC3 gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to xeroderma pigmentosum group B.

*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) | Infancy, Neonatal |
| Diagnostic panels | ERCC3 is a diagnostic-grade gene on 11 Genomics England panels |

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

- Hydrocephalus — Very frequent (99-80%)
- Microcephaly — Very frequent (99-80%)
- Hearing impairment — Very frequent (99-80%)
- Retinopathy — Very frequent (99-80%)
- Nystagmus — Very frequent (99-80%)
- Optic atrophy — Very frequent (99-80%)
- Dry skin — Very frequent (99-80%)
- Skin rash — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0005625/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ERCC3](https://sugi.bio/atlas/gene/ERCC3/) |
| Protein change (HGVS p.) | p.Asp81fs |
| Coding change (HGVS c.) | c.240dup |
| MANE Select transcript | [NM_000122](https://www.ncbi.nlm.nih.gov/nuccore/NM_000122) |
| Variant type | Duplication |
| Location | chr2:127292840-127292841 (GRCh38) |
| ClinVar | [VCV3779625](https://www.ncbi.nlm.nih.gov/clinvar/variation/3779625/) |

**All HGVS expressions:** `LRG_462:g.6336dup`, `LRG_462t1:c.238dup`, `NC_000002.11:g.128050419dup`, `NC_000002.12:g.127292843dup`, `NG_007454.1:g.6336dup`, `NM_000122.2:c.240dup`, `NM_000122.2:c.240dupC`, `NM_001303416.2:c.48dup`, `NM_001303418.2:c.48dup`

## 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 7.635, GERP 2.36, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.797, pLI 3.838e-11. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 3 of 15**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication 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}

**ERCC3** population constraint: LOEUF 0.797, pLI 3.838e-11, missense-Z 2.079. *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):

- **xeroderma pigmentosum group B** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 76.34, 30% of residues very-high.

**56 experimental structure(s)** (PDB): [28JM](https://www.rcsb.org/structure/28JM), [28JS](https://www.rcsb.org/structure/28JS), [28JV](https://www.rcsb.org/structure/28JV), [28KE](https://www.rcsb.org/structure/28KE), [29VF](https://www.rcsb.org/structure/29VF), [29WD](https://www.rcsb.org/structure/29WD).

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

*Describes the biological roles of ERCC3 (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:** ERCC3's established molecular role includes ATP hydrolysis activity. In Reactome, ERCC3 is annotated in disease pathway(s) including **Formation of HIV elongation complex in the absence of HIV Tat**, **Formation of HIV-1 elongation complex containing HIV-1 Tat**.

**Disease mechanism (Reactome):** ERCC3 loss or alteration is curated in [Formation of HIV elongation complex in the absence of HIV Tat](https://reactome.org/content/detail/R-HSA-167152), [Formation of HIV-1 elongation complex containing HIV-1 Tat](https://reactome.org/content/detail/R-HSA-167200), [Formation of the HIV-1 Early Elongation Complex](https://reactome.org/content/detail/R-HSA-167158).

### Pathways affected {#pathways}

ERCC3 participates in **29 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Formation of HIV elongation complex in the absence of HIV Tat](https://reactome.org/content/detail/R-HSA-167152) | electronic |
| ⚕ [Formation of HIV-1 elongation complex containing HIV-1 Tat](https://reactome.org/content/detail/R-HSA-167200) | electronic |
| ⚕ [Formation of the HIV-1 Early Elongation Complex](https://reactome.org/content/detail/R-HSA-167158) | electronic |
| ⚕ [HIV Transcription Initiation](https://reactome.org/content/detail/R-HSA-167161) | electronic |
| ⚕ [RNA Pol II CTD phosphorylation and interaction with CE during HIV infection](https://reactome.org/content/detail/R-HSA-167160) | electronic |
| ⚕ [RNA Polymerase II HIV Promoter Escape](https://reactome.org/content/detail/R-HSA-167162) | electronic |
| ⚕ [Tat-mediated elongation of the HIV-1 transcript](https://reactome.org/content/detail/R-HSA-167246) | electronic |
| ⚕ [Transcription of the HIV genome](https://reactome.org/content/detail/R-HSA-167172) | electronic |
| [Dual Incision in GG-NER](https://reactome.org/content/detail/R-HSA-5696400) | curated |
| [Dual incision in TC-NER](https://reactome.org/content/detail/R-HSA-6782135) | curated |
| [Formation of Incision Complex in GG-NER](https://reactome.org/content/detail/R-HSA-5696395) | curated |
| [Formation of RNA Pol II elongation complex ](https://reactome.org/content/detail/R-HSA-112382) | curated |
| [Formation of TC-NER Pre-Incision Complex](https://reactome.org/content/detail/R-HSA-6781823) | curated |
| [Formation of the Early Elongation Complex](https://reactome.org/content/detail/R-HSA-113418) | curated |
| [Gap-filling DNA repair synthesis and ligation in TC-NER](https://reactome.org/content/detail/R-HSA-6782210) | curated |
| [RNA Pol II CTD phosphorylation and interaction with CE](https://reactome.org/content/detail/R-HSA-77075) | curated |
| [RNA Polymerase I Promoter Escape](https://reactome.org/content/detail/R-HSA-73772) | curated |
| [RNA Polymerase I Transcription Initiation](https://reactome.org/content/detail/R-HSA-73762) | curated |
| [RNA Polymerase II Pre-transcription Events](https://reactome.org/content/detail/R-HSA-674695) | curated |
| [RNA Polymerase II Promoter Escape](https://reactome.org/content/detail/R-HSA-73776) | curated |
| [RNA Polymerase II Transcription Elongation](https://reactome.org/content/detail/R-HSA-75955) | curated |
| [RNA Polymerase II Transcription Initiation](https://reactome.org/content/detail/R-HSA-75953) | curated |
| [RNA Polymerase II Transcription Initiation And Promoter Clearance](https://reactome.org/content/detail/R-HSA-76042) | curated |
| [RNA Polymerase II Transcription Pre-Initiation And Promoter Opening](https://reactome.org/content/detail/R-HSA-73779) | curated |
| [TP53 Regulates Transcription of DNA Repair Genes](https://reactome.org/content/detail/R-HSA-6796648) | curated |
| [Transcription-Coupled Nucleotide Excision Repair (TC-NER)](https://reactome.org/content/detail/R-HSA-6781827) | curated |
| [mRNA Capping](https://reactome.org/content/detail/R-HSA-72086) | curated |
| [NoRC negatively regulates rRNA expression](https://reactome.org/content/detail/R-HSA-427413) | electronic |
| [RNA Polymerase I Transcription Termination](https://reactome.org/content/detail/R-HSA-73863) | electronic |

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

**Molecular function:** ATP hydrolysis activity, 3'-5' DNA helicase activity.

**Biological process:** DNA topological change, DNA repair, transcription-coupled nucleotide-excision repair, nucleotide-excision repair, transcription by RNA polymerase II, transcription initiation at RNA polymerase II promoter.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2019-11-08.

**Submitter consensus:** unanimous (1/1 Likely pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Department of Pathology and Laboratory Medicine, Sinai Health System | Likely pathogenic | criteria provided, single submitter | research | 2019-11-08 |

## Associated conditions {#conditions}

[xeroderma pigmentosum group B](https://sugi.bio/atlas/disease/xeroderma-pigmentosum-group-b/).

**Reported phenotype names (ClinVar):** Xeroderma pigmentosum group B, XPB/CS, XERODERMA PIGMENTOSUM B/COCKAYNE SYNDROME, XP, GROUP B, ERCC3-Related Xeroderma Pigmentosum.

## Similar variants {#similar}

Related ERCC3 variant pages (same residue, condition, or type): [ERCC3 p.Asp474fs](/variant/ercc3-p-asp474fs), [ERCC3 p.Trp374Ter](/variant/ercc3-p-trp374ter), [ERCC3 p.Asp81Asn](/variant/ercc3-p-asp81asn), [ERCC3 p.Glu588fs](/variant/ercc3-p-glu588fs), [ERCC3 c.1828-1G>C](/variant/ercc3-c-1828-minus-1g-c), [ERCC3 c.471+1G>A](/variant/ercc3-c-471-plus-1g-a), [ERCC3 c.657+1G>A](/variant/ercc3-c-657-plus-1g-a), [ERCC3 p.Arg109Ter](/variant/ercc3-p-arg109ter).

### 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 3779625). 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.*