Hereditary neuropathy or pain disorder

Gene: MT-TV

Green List (high evidence)

Comment on list classification: As reviewed by Alexander Rossor and Christopher Record, there is sufficient scientific evidence available for the association of MT-TV variants with hereditary neuropathy.

However, it should be noted that the GMS reviewers previously disagreed on the inclusion of genes of the mitochondrial genome including MT-TV with green rating on other WGS/ non-WGS panels suggesting that an alternative test is more suitable for syndromic mitochondrial disease: R300 Possible mitochondrial disorder - whole mitochondrial genome sequencing.

Hence, this gene has been tagged for expert review from GLH experts.

Created: 25 Jul 2026, 10:57 a.m. | Last Modified: 25 Jul 2026, 10:57 a.m.

Panel Version: 8.12

PMID:32715519 (2020) reported six affected individuals from a Venezuelan family with Charcot-Marie-Tooth disease (CMT). Electrodiagnostic testing showed a motor and sensory axonal polyneuropathy. They were identified with the m.1661A>G variant in MT-TV gene (present at nearly 100% heteroplasmy) via mitochondrial DNA sequencing.

PMID:38371303 (2024) reported five affected members from a Chinese family with CMT and they were identified harbouring the m.1661A>G variant in the MT-TV gene. Neuroelectrodiagnostic tests and nerve biopsy supported axonal polyneuropathy.

PMID:39468830 (2025) reported the identification of the same homoplasmic MT-TV variant (m.1661A > G) in all affected individuals across four generations of a family with complex hereditary spastic paraplegia. Neural biopsies revealed ultrastructural abnormalities in myelin and mitochondria and nerve conduction studies were abnormal in both sensory and motor nerves (although more affected in sensory nerves than motor nerves) suggesting neuropathy.

PMID:39243325 (2025) reported a 2-year-old Chinese boy with global developmental delay, Charcot-Marie-Tooth (CMT) disease, progressive myoclonic epilepsy, paroxysmal arrhythmia and brain atrophy. The whole-exome sequencing did not lead to identification of any variants, but the mtDNA genome sequencing of the proband and his mother revealed a different de novo novel heteroplasmic variant, m.1636A > G in MT-TV gene.

This gene has been associated with 'definitive' rating for mitochondrial disease (MONDO:0044970) and with 'moderate' rating for Leigh syndrome (MONDO:0009723) by the Mitochondrial Diseases GCEP in ClinGen.

Created: 25 Jul 2026, 10:49 a.m. | Last Modified: 25 Jul 2026, 10:49 a.m.

Panel Version: 8.9

Mode of inheritance
MITOCHONDRIAL

Phenotypes
mitochondrial disease, MONDO:0044970; Charcot-Marie-Tooth disease, MONDO:0015626

Publications

• 32715519
• 38371303
• 39468830
• 39243325

Green List (high evidence)

Three published large families (PMID: 32715519; 38371303, 39468830,) with M1661A>G (Venezuela, China) plus internal cases of one family and a separate sporadic case with the same variant and identical phenotype (CMT plus UMN signs/spasticity) - at least 5 families total thus far.

PMID 39243325 is different nearby variant m.1636A > G with complex syndrome including CMT

Created: 29 Jun 2026, 1:37 p.m. | Last Modified: 29 Jun 2026, 1:37 p.m.

Panel Version: 8.9

Mode of inheritance
MITOCHONDRIAL

Phenotypes
Peripheral neuropathy; spasticity

Publications

• PMID: 32715519
• 38371303
• 39468830, 39243325

Green List (high evidence)

Described in 3 unrelated families with neuropathy and spasticity
Sources: Other

Created: 13 Apr 2026, 8:39 p.m.

Mode of inheritance
MITOCHONDRIAL

Phenotypes
peripheral neuropathy; spasticity

Publications

• 32715519: 39468830: 38371303

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments