ClinVar Genomic variation as it relates to human health
NC_012920.1(MT-ATP6):m.9035T>C
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NC_012920.1(MT-ATP6):m.9035T>C
Variation ID: 690280 Accession: VCV000690280.33
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
MT: 9035 (GRCh38) [ NCBI UCSC ] MT: 9035 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Sep 22, 2019 Apr 20, 2024 Jun 30, 2022 - HGVS
-
Nucleotide Protein Molecular
consequenceNC_012920.1:m.9035T>C - Protein change
- Other names
- -
- Canonical SPDI
- NC_012920.1:9034:T:C
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
---|---|---|---|---|---|---|
HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
MT-ATP6 | - | - | GRCh38 | 265 | 310 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
---|---|---|---|---|
Likely pathogenic (1) |
no assertion criteria provided
|
Jun 1, 2018 | RCV000851177.1 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
|
Oct 17, 2019 | RCV000854406.4 | |
See cases
|
Pathogenic (1) |
criteria provided, single submitter
|
Oct 5, 2018 | RCV001196557.2 |
Pathogenic (1) |
criteria provided, single submitter
|
May 4, 2022 | RCV002249546.1 | |
MT-ATP6-related primary mitochondrial disease
|
Uncertain significance (1) |
criteria provided, single submitter
|
Apr 25, 2022 | RCV002466594.3 |
Likely pathogenic (2) |
reviewed by expert panel
|
Jun 30, 2022 | RCV002260672.2 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
---|---|---|---|---|---|
Likely pathogenic
(Jun 30, 2022)
|
reviewed by expert panel
Method: curation
|
Mitochondrial disease
(Mitochondrial inheritance)
Affected status: unknown
Allele origin:
germline
|
ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen
FDA Recognized Database
Accession: SCV002540736.1 First in ClinVar: Jul 09, 2022 Last updated: Jul 09, 2022 |
Comment:
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 … (more)
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. (less)
|
|
Pathogenic
(Oct 17, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Leigh syndrome
Affected status: unknown
Allele origin:
germline
|
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine
Accession: SCV000997441.1
First in ClinVar: Nov 02, 2019 Last updated: Nov 02, 2019 |
Comment:
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 … (more)
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 (less)
|
|
Pathogenic
(Oct 05, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
see cases
Affected status: yes
Allele origin:
unknown
|
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001367165.2
First in ClinVar: Jul 04, 2020 Last updated: Jul 04, 2020 |
Comment:
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.
Clinical Features:
Spasticity (present) , Spastic paraplegia (present) , Gait disturbance (present) , Difficulty walking (present) , Fatigue (present)
|
|
Pathogenic
(May 04, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Leber optic atrophy
Affected status: unknown
Allele origin:
germline
|
Mendelics
Accession: SCV002517650.1
First in ClinVar: May 28, 2022 Last updated: May 28, 2022 |
|
|
Uncertain significance
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Leigh syndrome
Affected status: yes
Allele origin:
maternal
|
Pediatric Department, Xiangya Hospital, Central South University
Accession: SCV002761212.1
First in ClinVar: Jun 17, 2023 Last updated: Jun 17, 2023 |
Clinical Features:
muscle weakness (present) , Hearing impairment (present) , Abnormal basal ganglia MRI signal intensity (present)
|
|
Uncertain significance
(Apr 25, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
MT-ATP6-related primary mitochondrial disease
Affected status: unknown
Allele origin:
unknown
|
Illumina Laboratory Services, Illumina
Accession: SCV002762705.1
First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022 |
Comment:
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 … (more)
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. (less)
|
|
Uncertain significance
(Apr 25, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Mitochondrial disease
Affected status: unknown
Allele origin:
unknown
|
Illumina Laboratory Services, Illumina
Accession: SCV004814140.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The MT-ATP6 m.9035T>C p.(Leu170Pro) mitochondrial missense variant has been reported in at least seven studies, in either a homoplasmic or heteroplasmic state in ten individuals … (more)
The MT-ATP6 m.9035T>C p.(Leu170Pro) mitochondrial missense 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. The variant is presumed to have occurred de novo in the proband, as it was not detected in the mother; however, only DNA from the mother's blood was tested. Based on the available evidence, the m.9035T>C p.(Leu170Pro) variant is classified as a variant of uncertain significance MT-ATP6-related primary mitochondrial disease. (less)
|
|
Likely pathogenic
(Jun 01, 2018)
|
no assertion criteria provided
Method: research
|
Progressive cerebellar ataxia
Affected status: yes
Allele origin:
maternal
|
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Accession: SCV000993411.1
First in ClinVar: Sep 22, 2019 Last updated: Sep 22, 2019 |
Number of individuals with the variant: 1
Sex: female
|
Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
---|---|---|---|---|
Clinical Heterogeneity in MT-ATP6 Pathogenic Variants: Same Genotype-Different Onset. | Capiau S | Cells | 2022 | PMID: 35159298 |
Delineating MT-ATP6-associated disease: From isolated neuropathy to early onset neurodegeneration. | Stendel C | Neurology. Genetics | 2020 | PMID: 32042921 |
Kinetic analysis of ATP hydrolysis by complex V in four murine tissues: Towards an assay suitable for clinical diagnosis. | Haraux F | PloS one | 2019 | PMID: 31461494 |
Deciphering exome sequencing data: Bringing mitochondrial DNA variants to light. | Garret P | Human mutation | 2019 | PMID: 31379041 |
Pathogenic variants in MT-ATP6: A United Kingdom-based mitochondrial disease cohort study. | Ng YS | Annals of neurology | 2019 | PMID: 31187502 |
Adult-onset spinocerebellar ataxia syndromes due to MTATP6 mutations. | Pfeffer G | Journal of neurology, neurosurgery, and psychiatry | 2012 | PMID: 22577227 |
Identification of ataxia-associated mtDNA mutations (m.4052T>C and m.9035T>C) and evaluation of their pathogenicity in transmitochondrial cybrids. | Sikorska M | Muscle & nerve | 2009 | PMID: 19626676 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/4406e032-85d0-428e-bba3-649609672a37 | - | - | - | - |
Text-mined citations for rs1603222000 ...
HelpRecord last updated May 19, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.