Submissions for variant NC_012920.1(MT-ATP6):m.9035T>C

dbSNP: rs1603222000

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen	RCV002260672	SCV002540736	likely pathogenic	Mitochondrial disease	2022-06-30	reviewed by expert panel	curation	The m.9035T>C (p.L170P) variant in MT-ATP6 has been reported in 10 unrelated individuals with primary mitochondrial disease with shared features of cerebellar ataxia, progressive gait disturbance, sensory neuropathy, and fatigue; several showed developmental delays and learning disabilities (PS4_moderate; five from the literature; PMIDs: 19626676; 22577227; 31187502; an additional five cases with the same clinical presentations as above were submitted to this VCEP from expert panel members, and the expert panel agreed to include these cases). All cases were homoplasmic or near-homoplasmic (94-98%). There are no reported de novo occurrences of this variant to our knowledge. The first case reported with this variant (PMID: 19626676) was a member of a 4-generation, 17-member family with 16 affected maternal family members – the only one unaffected was the son of an affected male. Given this variant typically occurs at homoplasmy, there are no large families with varying heteroplasmy levels to consider for segregation. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.78 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). Cybrid studies show two different classes of function defects: (1) 85% reduction of F1F0 ATP synthase activity and a resulting 40-50% reduction in ATP output, and (2) an 8-fold higher level of damaging ROS (PS3_moderate; PMID: 19626676). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 Mitochondrial Disease Variant Curation Expert Panel on June 13, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PP3, PM2_supporting, PS3_moderate.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000854406	SCV000997441	pathogenic	Leigh syndrome	2019-10-17	criteria provided, single submitter	clinical testing	The NC_012920.1:m.9035T>C (YP_003024031.1:p.Leu170Pro) variant in MTATP6 gene is interpretated to be a Pathogenic variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: PS1, PS3
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001196557	SCV001367165	pathogenic	See cases	2018-10-05	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PP1-S,PP3. This variant was detected in homozygous state.
Mendelics	RCV002249546	SCV002517650	pathogenic	Leber optic atrophy	2022-05-04	criteria provided, single submitter	clinical testing
Pediatric Department, Xiangya Hospital, Central South University	RCV000854406	SCV002761212	uncertain significance	Leigh syndrome		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV002466594	SCV002762705	uncertain significance	MT-ATP6-related primary mitochondrial disease	2022-04-25	criteria provided, single submitter	clinical testing	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.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000851177	SCV000993411	likely pathogenic	Progressive cerebellar ataxia	2018-06-01	no assertion criteria provided	research