ClinVar

Description

The MT-ATP6 m.9035T>C (p.Leu170Pro) mitochondrial missense variant results in a substitution of leucine at amino acid position 170 with proline. This variant has been reported in at least seven studies, in either a homoplasmic or heteroplasmic state in ten individuals with primary mitochondrial disease (Sikorska et al. 2009; Pfeffer et al. 2012; Ng et al. 2019; Garret et al. 2019; Haraux et al. 2019 ; Stendel et al. 2020; Capiau et al. 2022). A broad spectrum of clinical findings of varying severity are reported in affected individuals and most often include developmental delay, learning difficulties, progressive ataxia and neuropathy. At least two individuals were diagnosed with Leigh syndrome. The age of onset in affected individuals was highly variable, ranging from six months to over fifty years. Where available, heteroplasmy levels were reported to be greater than 90% in the blood samples of affected individuals suggesting a high phenotypic threshold level (Ng et al. 2019). This variant is not found in a homoplasmic state in version 3.1.2 of the Genome Aggregation Database. Functional studies in transmitochondrial cybrid cell lines generated from patient lymphoblast cells showed a significant reduction in basal ATP content and in oligomycin sensitive ATPase activity, compared to control lines. Based on the available evidence, the m.9035T>C (p.Leu170Pro) variant is classified as a variant of uncertain significance for MT-ATP6-related primary mitochondrial disease.