Optic neuropathy

Gene: MT-TL1

After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed and remains Amber. The GMS reviewers commented as follows: More appropriate for specialist mitochondrial lab to test for this - 1) Alternative panel test available for this gene (R42.2 - Leber hereditary optic neuropathy). 2). May not be technically feasible for all laboratories to include this gene on the panel.

Created: 11 Dec 2025, 4:54 p.m. | Last Modified: 11 Dec 2025, 4:54 p.m.

Panel Version: 5.28

Green List (high evidence)

Comment on list classification: As reviewed by Katherine Schon, there is sufficient evidence available for the association of m.3243 A > G heteroplasmic variant from MT-TL1 with optic neuropathy/ optic atrophy. Hence, this gene can be promoted to green rating in the next GMS update.

Created: 24 Jun 2025, 1:32 p.m. | Last Modified: 24 Jun 2025, 1:32 p.m.

Panel Version: 5.6

As per https://www.mitophen.org, there are seven different patients reported in peer-reviewed scientific literature with m.3243A>G variant and with optic atrophy as one of the presenting phenotypes. Two additional patients were reported with optic disc pallor as one of the phenotypes.

PMID:7599199 - 14 patients with heteroplasmic m.3243A>G variant, of which only six patients had seizures and recurrent strokes, the core clinical features of the MELAS phenotype. One of them presented with optic atrophy.

PMID:7600089 - 22 probands with heteroplasmic m.3243A>G variant, of which 10 had clinical features consistent with MELAS syndrome. One had optic atrophy.

PMID:8363452 - A 15-year-old boy was reported with heteroplasmic m.3243A>G variant and with bilateral optic atrophy since 8 years of age.

PMID:8676159 - An 18-year-old male patient was reported with myoclonic epilepsy with ragged red fibres (MERRF) syndrome and with heteroplasmic m.3243A>G variant. The patient had bialateral optic atrophy.

PMID:9228247 - Two patients with MELAS syndrome and m.3243A>G variant were reported with optic neuropathy.

PMID:9619647 - A 21 year-old male patient with overlapping MELAS (mitochondrial encephalomyopathy, lactic acidosis, and 'stroke-like' episodes) and Kearns-Sayre syndrome. The heteroplasmic m.3243A>G variant has been identified in muscle tissue (79%), fibroblasts (49%) and blood cells (37%). There was no variant identified in E1alpha gene. Optic atrophy reported.

PMID:22249460 - The m.3243A>G variant was identified in half of 14 patients reported in this study, of which optic atrophy was present in two.

PMID:37095452 - Ischemic optic neuropathy reported as the first presentation in a patient with m.3243 A > G variant responsible for MELAS syndrome.

Created: 24 Jun 2025, 1:29 p.m. | Last Modified: 24 Jun 2025, 1:29 p.m.

Panel Version: 5.3

Mode of inheritance
MITOCHONDRIAL

Phenotypes
MELAS syndrome caused by mutation in MTTL1, MONDO:0800032; optic atrophy, MONDO:0003608

Publications

• 7599199
• 7600089
• 8363452
• 8676159
• 9228247
• 9619647
• 22249460
• 37095452

Green List (high evidence)

Optic atrophy can be seen in m.3243A>G, including rare presentation with subacute visual loss.

Created: 23 Jun 2025, 11:36 a.m. | Last Modified: 23 Jun 2025, 11:36 a.m.

Panel Version: 5.3

Mode of inheritance
MITOCHONDRIAL

Publications

• 9228247
• 39423307
• 37095452

Mode of pathogenicity
Other