# NM_000055.4(BCHE):c.1073dup (p.Leu358fs)

https://sugi.bio/variant/bche-p-leu358fs

## Summary

**BCHE p.Leu358fs (c.1073dup)** is classified **Likely pathogenic** in BCHE (ClinVar, No assertion criteria, 1 submitter; last evaluated 2016-02-02). Very rare (popmax 8.48e-05%, nfe); Associated with butyrylcholinesterase deficiency.

**At a glance:** Likely pathogenic · review: No assertion criteria · rsID rs1057516450 · 1 submitter · 1 linked condition · very rare (popmax 8.48e-05%, nfe)

## For patients & families {#patients}

This is a change in the BCHE gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to butyrylcholinesterase deficiency.

*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 |
| Prevalence | 1-9 / 100 000 (Europe) |
| Clinical trials | 6 registered for this condition — see ClinicalTrials.gov |

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

- Abnormal enzyme/coenzyme activity — Very frequent (99-80%)
- Respiratory failure — Frequent (79-30%)
- Abnormality of the liver — Very rare (<4-1%)
- Congestive heart failure — Very rare (<4-1%)
- Myocardial infarction — Very rare (<4-1%)
- Neoplasm — Very rare (<4-1%)
- Paralysis — Very rare (<4-1%)
- Respiratory failure requiring assisted ventilation — Very rare (<4-1%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0007482/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [BCHE](https://sugi.bio/atlas/gene/BCHE/) |
| Protein change (HGVS p.) | p.Leu358fs |
| Coding change (HGVS c.) | c.1073dup |
| MANE Select transcript | [NM_000055](https://www.ncbi.nlm.nih.gov/nuccore/NM_000055) |
| dbSNP | [rs1057516450](https://www.ncbi.nlm.nih.gov/snp/rs1057516450/) |
| Variant type | Duplication |
| Location | chr3:165829960-165829961 (GRCh38) |
| ClinVar | [VCV370388](https://www.ncbi.nlm.nih.gov/clinvar/variation/370388/) |

**All HGVS expressions:** `NC_000003.11:g.165547754dup`, `NC_000003.12:g.165829966dup`, `NG_009031.1:g.12505dup`, `NM_000055.4:c.1073dup`, `NR_137636.2:n.1191dup`

## 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 0.056, GERP -3.3, phastCons 0.954 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.195, pLI 6.4275e-16. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 2 of 4**, 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): grpmax **8.48e-05%** (nfe) · 1/1,179,884 in the highest group · 1/1,461,532 alleles overall — very rare (popmax 8.48e-05%, nfe).

*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}

**BCHE** population constraint: LOEUF 1.195, pLI 6.4275e-16, missense-Z -1.274; ClinGen dosage — haploinsufficiency 30, triplosensitivity Not yet evaluated (0–3 scale). *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **358** lies in an α-helix; a UniProt-annotated variant site (in bched; bche variant form; fluoride-resistant).

AlphaFold model confidence (whole protein): pLDDT 93.30, 83% of residues very-high.

**111 experimental structure(s)** (PDB): [1P0I](https://www.rcsb.org/structure/1P0I), [1P0M](https://www.rcsb.org/structure/1P0M), [1P0P](https://www.rcsb.org/structure/1P0P), [1P0Q](https://www.rcsb.org/structure/1P0Q), [1XLU](https://www.rcsb.org/structure/1XLU), [1XLV](https://www.rcsb.org/structure/1XLV) — incl. mutant structure 2XMB.

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

*Describes the biological roles of BCHE (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:** BCHE's established molecular role includes cholinesterase activity.


### Pathways affected {#pathways}

BCHE participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Aspirin ADME](https://reactome.org/content/detail/R-HSA-9749641) | curated |
| [Neurotransmitter clearance](https://reactome.org/content/detail/R-HSA-112311) | curated |
| [Synthesis of PC](https://reactome.org/content/detail/R-HSA-1483191) | curated |
| [Synthesis, secretion, and deacylation of Ghrelin](https://reactome.org/content/detail/R-HSA-422085) | curated |

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

**Molecular function:** cholinesterase activity, identical protein binding.

## Clinical significance {#significance}

**Likely pathogenic** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2016-02-02.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Counsyl | Likely pathogenic | no assertion criteria provided | clinical testing | 2016-02-02 |

## Associated conditions {#conditions}

[butyrylcholinesterase deficiency](https://sugi.bio/atlas/disease/butyrylcholinesterase-deficiency/).

**Reported phenotype names (ClinVar):** Deficiency of butyrylcholinesterase, Deficiency of butyrylcholine esterase, Acholinesterasemia, Butyrylcholinesterase deficiency, BCHE, silent 1.

## Same-residue context {#hotspot}

Residue **358** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [BCHE p.Leu358Ile](/variant/bche-p-leu358ile). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related BCHE variant pages (same residue, condition, or type): [BCHE p.Leu358Ile](/variant/bche-p-leu358ile), [BCHE p.Thr343fs](/variant/bche-p-thr343fs), [BCHE p.Lys276delinsAsnTer](/variant/bche-p-lys276delinsasnter), [BCHE p.Pro313fs](/variant/bche-p-pro313fs), [BCHE c.1160_1161ins[N[342];1146_1160]](/variant/bche-c-1160-1161ins-n-342-1146-1160), [BCHE p.Trp458fs](/variant/bche-p-trp458fs), [BCHE p.Glu568_Ala573dup](/variant/bche-p-glu568-ala573dup), [BCHE p.Met539fs](/variant/bche-p-met539fs).

### 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 370388). 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.*