# NM_000553.6(WRN):c.2427dup (p.Phe810fs)

https://sugi.bio/variant/wrn-p-phe810fs

## Summary

**WRN p.Phe810fs (c.2427dup)** is classified **Pathogenic** in WRN (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-14). Ultra-rare (gnomAD MAF 1.427e-06); Associated with Werner syndrome.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2130306151 · 1 submitter · 1 linked condition · ultra-rare (gnomAD MAF 1.427e-06)

## For patients & families {#patients}

This is a change in the WRN gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to Werner 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) | Adolescent, Adult |
| Prevalence | 1-9 / 1 000 000 (Europe) |
| Clinical trials | 3 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | WRN is a diagnostic-grade gene on 9 Genomics England panels |

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

- Hypogonadism — Very frequent (99-80%)
- Convex nasal ridge — Very frequent (99-80%)
- Cataract — Very frequent (99-80%)
- Abnormal thorax morphology — Very frequent (99-80%)
- Osteoporosis — Very frequent (99-80%)
- Slender build — Very frequent (99-80%)
- Abnormality of the voice — Very frequent (99-80%)
- Sparse scalp hair — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0007885/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [WRN](https://sugi.bio/atlas/gene/WRN/) |
| Protein change (HGVS p.) | p.Phe810fs |
| Coding change (HGVS c.) | c.2427dup |
| MANE Select transcript | [NM_000553](https://www.ncbi.nlm.nih.gov/nuccore/NM_000553) |
| dbSNP | [rs2130306151](https://www.ncbi.nlm.nih.gov/snp/rs2130306151/) |
| Variant type | Duplication |
| Location | chr8:31116505-31116506 (GRCh38) |
| ClinVar | [VCV2767130](https://www.ncbi.nlm.nih.gov/clinvar/variation/2767130/) |

**All HGVS expressions:** `LRG_524:g.88246dup`, `LRG_524t1:c.2427dup`, `NC_000008.10:g.30974023dup`, `NC_000008.11:g.31116507dup`, `NG_008870.1:g.88246dup`, `NM_000553.6:c.2427dup`

## 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 5.174, GERP 1.57, phastCons 0.979 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.9, pLI 8.3015e-34. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 20 of 35**, 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.
- Population frequency (gnomAD v4.1): global (via dbSNP) **0.000143%** — ultra-rare (gnomAD MAF 1.427e-06).

*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}

**WRN** population constraint: LOEUF 0.9, pLI 8.3015e-34, missense-Z 0.99458; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity 0/3. *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):

- **Werner syndrome** — Definitive (AR)

## Protein context {#protein}

Residue **810** lies in an α-helix; the helicase c-terminal domain.

AlphaFold model confidence (whole protein): pLDDT 68.75, 28% of residues very-high.

**51 experimental structure(s)** (PDB): [10AJ](https://www.rcsb.org/structure/10AJ), [10AK](https://www.rcsb.org/structure/10AK), [10AP](https://www.rcsb.org/structure/10AP), [2AXL](https://www.rcsb.org/structure/2AXL), [2DGZ](https://www.rcsb.org/structure/2DGZ), [2E1E](https://www.rcsb.org/structure/2E1E).

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

*Describes the biological roles of WRN (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:** WRN's established molecular role includes magnesium ion binding. p.Phe810fs falls in the helicase c-terminal domain. In Reactome, WRN is annotated in disease pathway(s) including **Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function**, **Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function**.

**Disease mechanism (Reactome):** WRN loss or alteration is curated in [Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function](https://reactome.org/content/detail/R-HSA-9704331), [Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function](https://reactome.org/content/detail/R-HSA-9704646), [Defective homologous recombination repair (HRR) due to BRCA1 loss of function](https://reactome.org/content/detail/R-HSA-9701192).

### Pathways affected {#pathways}

WRN participates in **17 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function](https://reactome.org/content/detail/R-HSA-9704331) | curated |
| ⚕ [Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function](https://reactome.org/content/detail/R-HSA-9704646) | curated |
| ⚕ [Defective homologous recombination repair (HRR) due to BRCA1 loss of function](https://reactome.org/content/detail/R-HSA-9701192) | curated |
| ⚕ [Impaired BRCA2 binding to PALB2](https://reactome.org/content/detail/R-HSA-9709603) | curated |
| ⚕ [Impaired BRCA2 binding to RAD51](https://reactome.org/content/detail/R-HSA-9709570) | curated |
| [G2/M DNA damage checkpoint](https://reactome.org/content/detail/R-HSA-69473) | curated |
| [HDR through Homologous Recombination (HRR)](https://reactome.org/content/detail/R-HSA-5685942) | curated |
| [HDR through Single Strand Annealing (SSA)](https://reactome.org/content/detail/R-HSA-5685938) | curated |
| [Homologous DNA Pairing and Strand Exchange](https://reactome.org/content/detail/R-HSA-5693579) | curated |
| [Presynaptic phase of homologous DNA pairing and strand exchange](https://reactome.org/content/detail/R-HSA-5693616) | curated |
| [Processing of DNA double-strand break ends](https://reactome.org/content/detail/R-HSA-5693607) | curated |
| [Processive synthesis on the C-strand of the telomere](https://reactome.org/content/detail/R-HSA-174414) | curated |
| [Regulation of TP53 Activity through Phosphorylation](https://reactome.org/content/detail/R-HSA-6804756) | curated |
| [Removal of the Flap Intermediate from the C-strand](https://reactome.org/content/detail/R-HSA-174437) | curated |
| [Resolution of D-loop Structures through Holliday Junction Intermediates](https://reactome.org/content/detail/R-HSA-5693568) | curated |
| [Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA)](https://reactome.org/content/detail/R-HSA-5693554) | curated |
| [SUMOylation of DNA damage response and repair proteins](https://reactome.org/content/detail/R-HSA-3108214) | curated |

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

**Molecular function:** magnesium ion binding, four-way junction DNA binding, Y-form DNA binding, bubble DNA binding, DNA binding, DNA helicase activity.

**Biological process:** telomere maintenance, DNA synthesis involved in DNA repair, DNA metabolic process, DNA replication, base-excision repair, mismatch repair.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-12-14.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2023-12-14 |

## Associated conditions {#conditions}

[Werner syndrome](https://sugi.bio/atlas/disease/werner-syndrome/).

**Reported phenotype names (ClinVar):** Werner syndrome.

## Similar variants {#similar}

Related WRN variant pages (same residue, condition, or type): [WRN p.Phe810Leu](/variant/wrn-p-phe810leu), [WRN c.1576+1dup](/variant/wrn-c-1576-plus-1dup), [WRN p.Ala1137fs](/variant/wrn-p-ala1137fs), [WRN p.Glu411fs](/variant/wrn-p-glu411fs), [WRN p.Ile665fs](/variant/wrn-p-ile665fs), [WRN p.Ile673fs](/variant/wrn-p-ile673fs), [WRN p.Thr1044fs](/variant/wrn-p-thr1044fs), [WRN p.Tyr110Ter](/variant/wrn-p-tyr110ter).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 2767130). 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.*