# NM_000390.4(CHM):c.419del (p.Pro140fs)

https://sugi.bio/variant/chm-p-pro140fs

## Summary

**CHM p.Pro140fs (c.419del)** is classified **Pathogenic** in CHM (ClinVar, Single submitter, 1 submitter; last evaluated 2020-01-09). No gnomAD frequency available for this variant; Associated with choroideremia.

**At a glance:** Pathogenic · review: Single submitter · rsID rs1930438584 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

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

*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) | X-linked recessive |
| Age of onset (of this condition) | Adolescent, Adult, Childhood |
| Prevalence | 1-9 / 100 000 (Europe) |
| Clinical trials | 32 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | CHM is a diagnostic-grade gene on 3 Genomics England panels |

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

- Visual impairment — Very frequent (99-80%)
- Abnormal electroretinogram — Very frequent (99-80%)
- Myopia — Very frequent (99-80%)
- Nyctalopia — Very frequent (99-80%)
- Abnormality of retinal pigmentation — Very frequent (99-80%)
- Progressive visual loss — Frequent (79-30%)
- Constriction of peripheral visual field — Frequent (79-30%)
- Choroideremia — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0006061/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CHM](https://sugi.bio/atlas/gene/CHM/) |
| Protein change (HGVS p.) | p.Pro140fs |
| Coding change (HGVS c.) | c.419del |
| MANE Select transcript | [NM_000390](https://www.ncbi.nlm.nih.gov/nuccore/NM_000390) |
| dbSNP | [rs1930438584](https://www.ncbi.nlm.nih.gov/snp/rs1930438584/) |
| Variant type | Deletion |
| Location | chrX:85963948-85963948 (GRCh38) |
| ClinVar | [VCV813165](https://www.ncbi.nlm.nih.gov/clinvar/variation/813165/) |

**All HGVS expressions:** `LRG_699:g.88615del`, `LRG_699t1:c.419del`, `NC_000023.10:g.85218954del`, `NC_000023.11:g.85963949del`, `NG_009874.2:g.88615del`, `NM_000390.4:c.419del`, `NM_001320959.1:c.-26del`, `NM_001362517.1:c.-26del`, `NM_001362518.2:c.-26del`, `NM_001362519.1:c.-26del`

## 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 1.225, GERP -4.08, phastCons 0.215 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene, supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 5 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 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}

**CHM** population constraint: ClinGen dosage — haploinsufficiency 3, triplosensitivity 0 (0–3 scale). *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):

- **choroideremia** — Definitive (XL)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 81.05, 66% of residues very-high.

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

*Describes the biological roles of CHM (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:** CHM's established molecular role includes small GTPase binding.


### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [RAB GEFs exchange GTP for GDP on RABs](https://reactome.org/content/detail/R-HSA-8876198) | curated |
| [RAB geranylgeranylation](https://reactome.org/content/detail/R-HSA-8873719) | curated |
| [TP53 regulates transcription of several additional cell death genes whose specific roles in p53-dependent apoptosis remain uncertain](https://reactome.org/content/detail/R-HSA-6803205) | curated |

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

**Molecular function:** small GTPase binding.

**Biological process:** protein targeting to membrane, protein geranylgeranylation.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2020-01-09.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Molecular Genetics Laboratory, Institute for Ophthalmic Research | Pathogenic | criteria provided, single submitter | research | 2020-01-09 |

## Associated conditions {#conditions}

[choroideremia](https://sugi.bio/atlas/disease/choroideremia/).

**Reported phenotype names (ClinVar):** Choroideremia, Chorioretinal scalloped atrophy.

## Similar variants {#similar}

Related CHM variant pages (same residue, condition, or type): [CHM p.Asp10fs](/variant/chm-p-asp10fs), [CHM p.Pro189fs](/variant/chm-p-pro189fs), [CHM p.Ser105Argfs](/variant/chm-p-ser105argfs), [CHM p.Ser218fs](/variant/chm-p-ser218fs), [CHM p.Ser468fs](/variant/chm-p-ser468fs), [CHM p.Ser561fs](/variant/chm-p-ser561fs), [CHM p.Tyr321fs](/variant/chm-p-tyr321fs), [CHM p.Tyr551fs](/variant/chm-p-tyr551fs).

### 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 813165). 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.*