# NM_012318.3(LETM1):c.888_889del (p.Arg299fs)

https://sugi.bio/variant/letm1-p-arg299fs

## Summary

**LETM1 p.Arg299fs (c.888_889del)** is classified **Conflicting classifications of pathogenicity** in LETM1 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-02-02). Ultra-rare (popmax 0.022%, mid); Associated with neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunction.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs775607436 · 4 submitters · 2 linked conditions · ultra-rare (popmax 0.022%, mid)

## For patients & families {#patients}

This is a change in the LETM1 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 4 submitters, and is linked to neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunction.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0027311/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [LETM1](https://sugi.bio/atlas/gene/LETM1/) |
| Protein change (HGVS p.) | p.Arg299fs |
| Coding change (HGVS c.) | c.888_889del |
| MANE Select transcript | [NM_012318](https://www.ncbi.nlm.nih.gov/nuccore/NM_012318) |
| dbSNP | [rs775607436](https://www.ncbi.nlm.nih.gov/snp/rs775607436/) |
| Variant type | Deletion |
| Location | chr4:1832935-1832936 (GRCh38) |
| ClinVar | [VCV1370872](https://www.ncbi.nlm.nih.gov/clinvar/variation/1370872/) |

**All HGVS expressions:** `NC_000004.11:g.1834662_1834663del`, `NC_000004.12:g.1832935_1832936del`, `NG_013063.1:g.28312_28313del`, `NM_012318.3:c.888_889del`, `NM_012318.3:c.888_889delAG`

## 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 7.526, GERP 1.87, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.881, pLI 1.3697e-11. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 6 of 14**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 33.0**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- 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 (gnomAD v4.1): grpmax **0.022%** (mid) · FAF95 0.0134% · FAF99 0.0127% · 1/4,546 in the highest group · 264/1,612,106 alleles overall — ultra-rare (popmax 0.022%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Ashkenazi Jewish (not grpmax-eligible) | 0.111% | 897 |
| Middle Eastern (grpmax) | 0.022% | 4,546 |
| Remaining individuals (not grpmax-eligible) | 0.0193% | 5,192 |
| European (non-Finnish) | 0.0153% | 6,555 |
| African / African-American | 0.0147% | 6,805 |
| Admixed American | 0.0117% | 8,570 |
| Finnish (not grpmax-eligible) | 0.0109% | 9,149 |
| South Asian | 0.00989% | 10,111 |
| East Asian | 0.00891% | 11,225 |

Ashkenazi Jewish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**LETM1** population constraint: LOEUF 0.881, pLI 1.3697e-11, missense-Z 1.7059; ClinGen dosage — haploinsufficiency 0/3, triplosensitivity 0/3. *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 **299** lies in the letm1 rbd domain.

AlphaFold model confidence (whole protein): pLDDT 67.36, 5% of residues very-high.

**2 experimental structure(s)** (PDB): [9BA1](https://www.rcsb.org/structure/9BA1), [9DMR](https://www.rcsb.org/structure/9DMR) — incl. mutant structure 9DMR.

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

*Describes the biological roles of LETM1 (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:** LETM1's established molecular role includes calcium:proton antiporter activity. p.Arg299fs falls in the letm1 rbd domain.


### Pathways affected {#pathways}

LETM1 participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [RHOG GTPase cycle](https://reactome.org/content/detail/R-HSA-9013408) | curated |
| [Complex III assembly](https://reactome.org/content/detail/R-HSA-9865881) | electronic |
| [Mitochondrial calcium ion transport](https://reactome.org/content/detail/R-HSA-8949215) | electronic |

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

**Molecular function:** calcium:proton antiporter activity.

**Biological process:** calcium ion transport, mitochondrial calcium ion transmembrane transport, inner mitochondrial membrane organization, cristae formation, mitochondrial calcium ion homeostasis, negative regulation of mitochondrial calcium ion concentration.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-02-02.

**Submitter consensus:** conflicting (3 Uncertain significance, 1 Likely pathogenic).

**Submission history:** 4 submissions (2025–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-01-16 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-01-24 |
| Genetics Laboratory, Great Ormond Street Hospital NHS Foundation Trust, North Thames Genomic Laboratory Hub | Uncertain significance | criteria provided, single submitter | clinical testing | 2026-02-02 |
| First Genomix Gene Laboratory, Genetic Diagnostics Department | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-06-02 |

## Associated conditions {#conditions}

[neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunction](https://sugi.bio/atlas/disease/neurodegeneration-childhood-onset-with-multisystem-involvement-due-to-mitochondrial-dysfunction/), [optic nerve disorder](https://sugi.bio/atlas/disease/optic-nerve-disorder/).

**Reported phenotype names (ClinVar):** Neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunction, not provided, Optic neuropathy, not specified, AllHighlyPenetrant, none provided, Optic nerve disorder.

## Similar variants {#similar}

Related LETM1 variant pages (same residue, condition, or type): [LETM1 p.Gln486fs](/variant/letm1-p-gln486fs), [LETM1 p.Asp699fs](/variant/letm1-p-asp699fs), [LETM1 p.Gln477Arg](/variant/letm1-p-gln477arg), [LETM1 p.Tyr598fs](/variant/letm1-p-tyr598fs), [LETM1 p.Pro513Leu](/variant/letm1-p-pro513leu), [LETM1 p.Ter740Tyr](/variant/letm1-p-ter740tyr), [LETM1 c.2071-9C>G](/variant/letm1-c-2071-minus-9c-g), [LETM1 p.Arg294Gln](/variant/letm1-p-arg294gln).

### 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 1370872). 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.*