# NM_001083614.2:c.(?_-8)_65del

https://sugi.bio/variant/ears2-c-minus-8

## Summary

**EARS2 c.(?_-8** is classified **Pathogenic** in EARS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-17). Associated with leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome.

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

## For patients & families {#patients}

This is a change in the EARS2 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to leukoencephalopathy-thalamus and brainstem anomalies-high lactate 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) | No data available |
| Age of onset (of this condition) | Infancy, Neonatal |
| Diagnostic panels | EARS2 is a diagnostic-grade gene on 13 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0013381/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [EARS2](https://sugi.bio/atlas/gene/EARS2/) |
| Coding change (HGVS c.) | c.(?_-8 |
| MANE Select transcript | [NM_001083614](https://www.ncbi.nlm.nih.gov/nuccore/NM_001083614) |
| Variant type | Deletion |
| ClinVar | [VCV3385233](https://www.ncbi.nlm.nih.gov/clinvar/variation/3385233/) |

**All HGVS expressions:** `NM_001083614.2:c.(?_-8)_65del`

## Gene constraint & dosage {#gene-context}

**EARS2** population constraint: LOEUF 1.138, pLI 7.0535e-14, missense-Z 0.080959; ClinGen dosage — haploinsufficiency 30, 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):

- **Leigh syndrome** — Definitive (AR)
- **mitochondrial disease** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 89.84, 79% of residues very-high.

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

*Describes the biological roles of EARS2 (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:** EARS2's established molecular role includes glutamate-tRNA ligase activity.


### Pathways affected {#pathways}

EARS2 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Mitochondrial tRNA aminoacylation](https://reactome.org/content/detail/R-HSA-379726) | electronic |

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

**Molecular function:** glutamate-tRNA ligase activity, glutamate-tRNA(Gln) ligase activity.

**Biological process:** glutamyl-tRNA aminoacylation, tRNA aminoacylation for mitochondrial protein translation.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-10-17.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Pathogenic | criteria provided, single submitter | clinical testing | 2024-10-17 |

## Associated conditions {#conditions}

[leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome](https://sugi.bio/atlas/disease/leukoencephalopathy-thalamus-and-brainstem-anomalies-high-lactate-syndrome/).

**Reported phenotype names (ClinVar):** Leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome, LEUKOENCEPHALOPATHY WITH THALAMUS AND BRAINSTEM INVOLVEMENT AND HIGH LACTATE, Combined oxidative phosphorylation deficiency 12.

## Similar variants {#similar}

Related EARS2 variant pages (same residue, condition, or type): [EARS2 p.Cys140fs](/variant/ears2-p-cys140fs), [EARS2 p.Phe71fs](/variant/ears2-p-phe71fs), [EARS2 p.Gly240fs](/variant/ears2-p-gly240fs), [EARS2 c.1488+61del](/variant/ears2-c-1488-plus-61del), [EARS2 p.Pro428fs](/variant/ears2-p-pro428fs), [EARS2 p.Arg107His](/variant/ears2-p-arg107his), [EARS2 p.Arg108Trp](/variant/ears2-p-arg108trp), [EARS2 p.Cys167Tyr](/variant/ears2-p-cys167tyr).

### 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 3385233). 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.*