# NM_000140.5(FECH):c.1041_1048del (p.Glu347fs)

https://sugi.bio/variant/fech-p-glu347fs

## Summary

**FECH p.Glu347fs (c.1041_1048del)** is classified **Pathogenic** in FECH (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-30).

**At a glance:** Pathogenic · review: Single submitter · 1 submitter

## For patients & families {#patients}

This is a change in the FECH gene that is reported as disease-causing, but on limited review, submitted by 1 submitter.

*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.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [FECH](https://sugi.bio/atlas/gene/FECH/) |
| Protein change (HGVS p.) | p.Glu347fs |
| Coding change (HGVS c.) | c.1041_1048del |
| MANE Select transcript | [NM_000140](https://www.ncbi.nlm.nih.gov/nuccore/NM_000140) |
| Variant type | Deletion |
| Location | chr18:57554289-57554296 (GRCh38) |
| ClinVar | [VCV3609777](https://www.ncbi.nlm.nih.gov/clinvar/variation/3609777/) |

**All HGVS expressions:** `LRG_1080:g.37442_37449del`, `LRG_1080t1:c.1041_1048del`, `LRG_1080t2:c.1059_1066del`, `NC_000018.10:g.57554290_57554297del`, `NC_000018.9:g.55221522_55221529del`, `NG_008175.1:g.37442_37449del`, `NM_000140.5:c.1041_1048del`, `NM_001012515.4:c.1059_1066del`, `NM_001371094.1:c.942_949del`, `NM_001371095.1:c.825_832del`, `NM_001374778.1:c.1041_1048del`

## 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 11.191, GERP 1.89, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.859, pLI 1.0073e-07. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 9 of 11**, 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.

*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}

**FECH** population constraint: LOEUF 0.859, pLI 1.0073e-07, missense-Z 1.6367. *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):

- **protoporphyria, erythropoietic, 1** — Definitive (AR)

## Protein context {#protein}

Residue **347** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 87.37, 81% of residues very-high.

**25 experimental structure(s)** (PDB): [1HRK](https://www.rcsb.org/structure/1HRK), [2HRC](https://www.rcsb.org/structure/2HRC), [2HRE](https://www.rcsb.org/structure/2HRE), [2PNJ](https://www.rcsb.org/structure/2PNJ), [2PO5](https://www.rcsb.org/structure/2PO5), [2PO7](https://www.rcsb.org/structure/2PO7) — incl. mutant structure 2HRC.

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

*Describes the biological roles of FECH (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:** FECH's established molecular role includes protoporphyrin ferrochelatase activity.


### Pathways affected {#pathways}

FECH participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Heme biosynthesis](https://reactome.org/content/detail/R-HSA-189451) | curated |
| [Mitochondrial protein degradation](https://reactome.org/content/detail/R-HSA-9837999) | curated |

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

**Molecular function:** protoporphyrin ferrochelatase activity, identical protein binding, protein homodimerization activity.

**Biological process:** heme biosynthetic process, heme B biosynthetic process, obsolete protoporphyrinogen IX metabolic process.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-06-30.

**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 | 2024-06-30 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related FECH variant pages (same residue, condition, or type): [FECH p.Ala14fs](/variant/fech-p-ala14fs), [FECH p.Asp316fs](/variant/fech-p-asp316fs), [FECH p.Lys379fs](/variant/fech-p-lys379fs), [FECH p.Tyr194fs](/variant/fech-p-tyr194fs), [FECH c.1077+1del](/variant/fech-c-1077-plus-1del), [FECH p.Gln122fs](/variant/fech-p-gln122fs), [FECH p.Gly16fs](/variant/fech-p-gly16fs), [FECH p.Ile134fs](/variant/fech-p-ile134fs).

### 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 3609777). 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.*