Optic neuropathy

Gene: MT-ATP6

Red List (low evidence)

Comment on list classification: There are several cases reported in literature with optic neuropathy and variants in MT-ATP6. However, many of these variants are common and homoplasmic in multiple unaffected individuals (both family members and gnomAD cohort). They have also been classified as B/LB in ClinVar. Fiorini et al. (2025, PMID: 41234160) recently posed that the association between MT-ATP6 variants and LHON is questionable, and the optic neuropathy phenotype could be explained by variants in nuclear CI genes (especially if only mtDNA was sequenced). Based on the refuting evidence from literature, and following advice of NHS Mitochondrial Disorders team, we propose that MT-ATP6 should be downgraded to Red rating on Optic neuropathy.

Created: 27 May 2026, 1:26 p.m. | Last Modified: 27 May 2026, 1:27 p.m.

Panel Version: 6.41

PMID: 41234160 Fiorini et al., 2025
Proband in family A harboured biallelic NDUFS7 variants, and a m.9025G>A variant in MT-ATP6. However, the MT-ATP6 variant is relatively common: 45/56418 homoplasmic cases in gnomAD v4.1. Authors pose that the NDUFS7 biallelic variant is the true cause, and they put into question the association between MT-ATP6 variants and LHON.

PMID: 26448634 Widgren et al., 2015
Nine rare mutations in MT-ATP6 were identified in seven patients, of whom four manifested with retinopathy and three had clusters of MT-ATP6 mutations.
Variant m.8842A>G (MT-ATP6) found in an optic neuropathy patient (haplogroup H2). 2 other MT-ATP6 variants found in nystagmus cohort, and 4 other variants were unique to the retinal degeneration group. The m.8842A>G was not predicted to affect protein function. 128/56430 individuals are homoplasmic in gnomAD v3.1.2 (most in haplogroup H) - B/LB in ClinVar.

PMID: 26252090 Gao et al., 2015
Report of two Chinese families with Leber's hereditary optic neuropathy, with penetrance of 12.5% and 30.0% in the two families. Only mitochondrial genome was sequenced - this detected homoplasmic T8821G mutation in MT-ATP6, and distinct sets of polymorphisms belonging to haplogroups M10a.

PMID: 24986921 López-Gallardo et al., 2014
The m.9029A>G, p.His168Arg MT-ATP6 variant was detected in a proband with 'atypical' LHON - homoplasmic in 3/56429 individuals in gnomAD v3.1.2, VUS in ClinVar.

PMID: 7726182 Lamminen et al., 1995
Finnish proband with LHON, MT-ATP6:c.575T>C, p.Ile192Thr. Proband and 3 unaffected maternal family members were all homoplasmic for the variant. Variant is homoplasmic in 59/56427 individuals in gnomAD v3.1.2, B/LB in ClinVar.

Created: 27 May 2026, 1:02 p.m. | Last Modified: 27 May 2026, 1:18 p.m.

Panel Version: 6.39

Mode of inheritance
MITOCHONDRIAL

Phenotypes
NARP syndrome, MONDO:0010794

Publications

• 7726182
• 24986921
• 26252090
• 26448634
• 41234160

Green List (high evidence)

Mitochondrial - cannot be tested in panel with nuclear genes

Created: 19 Mar 2019, 3:33 p.m.

Mode of inheritance
MITOCHONDRIAL

Phenotypes
Leber optic atrophy, 535000; neurogenic weakness, ataxia, and retinitis pigmentosa; retinopathy

Publications

• 7726182
• 10676807
• 26448634
• 26252090
• 24118886 (functional evidence)
• 23266623

Comment on list classification: More than 3 cases reported.

Created: 7 Sep 2016, 8:27 a.m.